System N transporters belong to the SLC38 family of sodium-dependent neutral amino acid carriers. What makes them distinctive is their coupling mechanism: they move substrates such as glutamine, asparagine and histidine in either direction across the membrane, coupled to sodium symport and proton antiport. In practical terms, the direction of transport depends on the sodium gradient, the pH environment and the relative availability of amino acids inside and outside the cell. This bidirectionality is not a biochemical curiosity. It means that the same transporter can feed a tumor in one context and drain it in another, which is precisely why these carriers have been so hard to pin down functionally. Historically, they have attracted far less attention than celebrity cancer transporters such as ASCT2 (SLC1A5), LAT1 (SLC7A5) or xCT (SLC7A11), but the accumulating evidence now suggests they deserve a place at the metabolic table.

SLC38A3, also known as SNAT3, is the most ambivalent of the three. In healthy physiology it is a workhorse: it supports the glutamate-glutamine cycle in the brain, contributes to nitrogen detoxification in the liver and is dramatically upregulated in the kidney during metabolic acidosis, where it imports glutamine from the circulation to fuel ammoniagenesis and restore acid-base balance. Its importance is underscored by genetics. Loss-of-function mutations in mice are lethal early in development, and in humans, pathogenic biallelic variants cause developmental and epileptic encephalopathy, with affected children showing global developmental delay, intellectual disability, hypotonia and seizures. Metabolomic analyses of these patients reveal perturbations in glutamate, histidine and nitrogen metabolism, confirming that disrupted glutamine homeostasis is a central disease mechanism.

In cancer, however, SLC38A3 plays a double game. In triple-negative breast cancer, it promotes tumor growth and metastasis in vivo by maintaining intracellular amino acid pools, supporting glutathione production and inhibiting GSK3β, which activates β-catenin signaling and drives epithelial-mesenchymal transition. In non-small cell lung cancer, the transporter mediates the efflux of glutamine and histidine, which paradoxically activates PDK1 and downstream AKT signaling, promoting metastasis. In colorectal cancer, silencing SLC38A3 reduces proliferation and migration, possibly through regulation of the chaperone Hsp70. Yet in esophageal squamous cell carcinoma, SLC38A3 is frequently lost and its suppression correlates with lymph-node metastasis and poor survival, suggesting it can act as an EMT suppressor by physically linking to SETDB1 and impairing SNAIL transcription. In lung adenocarcinoma, some multi-omics analyses even propose a tumor-suppressive role, although the authors caution that this rests mainly on associations rather than functional transport data. The lesson, the Parma team argues, is that SLC38A3 expression alone cannot predict its pro-tumor or tumor-suppressive impact; the functional outcome emerges from the specific metabolic and lineage-dependent programs active within each cancer type.

SLC38A5, or SNAT5, is a different story altogether. It is overexpressed across all major subtypes of breast cancer, with the highest levels in triple-negative patient-derived xenografts, and its expression correlates with poor survival, reduced cisplatin sensitivity and increased proliferation. In pancreatic ductal adenocarcinoma, it is associated with higher tumor grade, poor prognosis and gemcitabine resistance. In colorectal cancer, it is induced by KRAS activation, ETV4 and Wnt/β-catenin signaling, and promotes proliferation, migration, invasion and resistance to oxaliplatin, 5-fluorouracil and irinotecan. In osteosarcoma, it fuels glutamine uptake that sustains glutathione synthesis and activates the PI3K/AKT/mTOR pathway, preventing reactive oxygen species accumulation. Mechanistically, SLC38A5 is a metabolic Swiss Army knife: it imports glutamine, asparagine, serine and glycine, all of which support anaplerosis, lipid biosynthesis and the one-carbon cycle for nucleotide synthesis. Its sodium/proton exchange activity exports protons during amino acid uptake, contributing to intracellular alkalinization and extracellular acidification, which promotes cytoskeletal remodeling and macropinocytosis, enabling cancer cells to scavenge extracellular proteins as an additional nutrient source.

Perhaps the most striking recent finding is SLC38A5’s role in ferroptosis resistance. Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation, and cancer cells go to great lengths to avoid it. SLC38A5-mediated glutamine uptake sustains glutathione synthesis, which is required for the activity of GPX4, the key enzyme that prevents lipid peroxidation. In triple-negative breast cancer, the transporter also imports selenium-containing methionine, which activates NRF2 and induces SLC7A11 expression, further reinforcing the antioxidant armamentarium. In colorectal cancer, SLC38A5 facilitates the nuclear translocation of YAP, a co-activator of NRF2, inducing antioxidant genes such as SLC7A11 and GPX4. This means that tumors with high SLC38A5 expression are not only metabolically flexible but also chemically armored against one of the most promising emerging cell death pathways in oncology.

But SLC38A5 does not confine itself to cancer cells. It is also expressed in stromal, immune and endothelial cells within the tumor microenvironment, where it mediates amino acid exchange between malignant and non-malignant populations. In B-cell precursor acute lymphoblastic leukemia, leukemic blasts secrete glutamine, which is taken up by bone marrow mesenchymal stromal cells and converted into asparagine, which is then exported through SLC38A5 and provided back to the leukemia cells. This mechanism protects the blasts against asparagine depletion during treatment with L-asparaginase, one of the mainstays of B-ALL chemotherapy, and is prevented if SLC38A5 is silenced or pharmacologically inhibited. A similar metabolic trade-off occurs in multiple myeloma, where malignant plasma cells release glutamate via SLC7A11, stromal cells internalize it through SLC1A1 and convert it into glutamine, which is subsequently secreted through SLC38A5 to sustain neoplastic growth. In clear cell renal cell carcinoma, SLC38A5 is more expressed in cancer-associated fibroblasts than in normal fibroblasts and sustains their pro-tumoral activity, with silencing lowering the secretion of the chemokine CCL5. This dual cancer-stroma activity positions SLC38A5 as a central metabolic hub of the tumor ecosystem.

SLC38A7, or SNAT7, is the least understood of the three but is rapidly gaining relevance. Unlike its plasma membrane siblings, SLC38A7 is predominantly localized on lysosomal membranes in cancer cells, where it exports proteolysis-derived glutamine and asparagine into the cytosol. Through this activity, it acts as a metabolic gatekeeper linking lysosomal nutrient recycling, derived mainly from internalized extracellular proteins, to mTORC1 activation, supporting cell growth under nutrient limitation. The most direct pro-tumor functional data come from pancreatic cancer, where KRAS-driven MIA PaCa-2 cells maintain proliferation under glutamine restriction by internalizing albumin via macropinocytosis, degrading it in lysosomes and exporting the resulting amino acids through SLC38A7. This pathway activates mTORC1 through a Rag-independent mechanism. In gastric cancer, SLC38A7 is associated with poor prognosis and promotes proliferation, migration, invasion and mitochondrial function, with its expression and pro-tumor effects promoted by METTL3-dependent N6-methyladenosine modification and IGF2BP2-mediated stabilization of its transcript. It also interacts with myosin heavy chain 9, facilitating GSK3β ubiquitination and degradation and thereby activating Wnt/β-catenin signaling. Evidence in lung squamous cell carcinoma, lung adenocarcinoma, cervical cancer and ER-positive breast cancer is growing, although functional validation of transport activity remains limited in many of these contexts.

When it comes to therapeutic targeting, SLC38A5 currently offers the most concrete opportunities. GluγHA, L-glutamic acid γ-monohydroxamate, is the only known direct competitive inhibitor of SLC38A5-mediated glutamine and asparagine influx and efflux, although it is endowed with low affinity, with an IC50 of approximately 0.6 millimolar. Indirect inhibitors include amiloride and the antihelminthic drug niclosamide, which interfere with the sodium/proton exchanger NHE-1, and melatonin, which downregulates SLC38A5 expression. Notably, in triple-negative breast cancer and colorectal cancer, SLC38A5 upregulation is associated with SLC7A11 overexpression, which would counteract ferroptosis but may render cells vulnerable to disulfidptosis, another regulated cell death pathway recently described in other cancer models. Under glucose starvation, reduced availability of NADPH prevents the reduction of SLC7A11-imported cystine, leading to disulfide stress through aberrant disulfide bond formation in cytoskeleton proteins, ultimately causing F-actin collapse and cell death. This suggests that SLC38A5 inhibition may simultaneously damage tumor-intrinsic metabolism and disarticulate microenvironmental nutrient support, pointing to the transporter as a tractable metabolic vulnerability.

In contrast, SLC38A3 and SLC38A7 remain pharmacologically undrugged. For SLC38A3, its context-dependent oncogenic versus tumor-suppressive roles complicate therapeutic inhibition, and its essential physiological roles in the brain, kidney and liver indicate that systemic inhibition may carry significant on-target toxicity. Tumor-selective delivery, perhaps through an Enhanced Permeability and Retention approach based on nanodrugs, coupled with careful pharmacodynamic monitoring, would be required. A database-guided docking analysis identified periodate-oxidized adenosine as a putative computational hit for SLC38A3, but this remains an in silico lead without biochemical binding or transport-inhibition data. SLC38A7 similarly lacks direct inhibitors, and its pharmacological targeting remains conceptual. Potential indirect strategies include targeting the METTL3-IGF2BP2 regulatory axis, the SLC38A7-MYH9 interaction, downstream Wnt/β-catenin signaling or glutaminase activity, but these represent pathway-level interventions rather than selective inhibition of the transporter itself. Moreover, compensatory increases in glycolysis may limit the efficacy of lysosome- and glutamine-targeted combinations.

The Parma researchers also raise an important methodological caveat. Standard cell-culture media differ markedly from human plasma, containing supraphysiological concentrations of several metabolites while lacking others that are present in vivo. Such discrepancies can profoundly bias the evaluation of metabolic dependencies, including amino acid transport and utilization. Supraphysiological concentrations of glutamine in conventional media may artificially increase cell dependence compared with physiological conditions, while the absence of glutamate and asparagine in several media forces their secretion in standard culture. These variations can affect the development of nutritional stress and the resulting cellular responses, meaning that functional assays capable of measuring amino acid flux, transport directionality and metabolic state under real-life conditions will be essential to determine the effective function of each transporter.

Beyond metabolism, System N transporters also exert regulatory functions that expand their impact on tumor biology. SLC38A3 may modulate transcriptional programs through SETDB1-SNAIL-associated mechanisms. SLC38A7 influences β-catenin signaling via MYH9. SLC38A5 affects antioxidant and ferroptosis pathways through the YAP-NRF2 axis. These emerging non-canonical roles, which are not directly linked to transport activity, suggest that System N transporters act not only as nutrient carriers but also as integrated metabolic-signaling nodes. Among the three, SLC38A5 stands out for its microenvironmental reach and finely tuned regulatory mechanisms, differently from SLC38A3 and SLC38A7, whose functions remain largely confined to cancer cells.

Future progress will be required to define how System N transporters integrate metabolic fluxes, macropinocytosis, ferroptosis sensitivity and signaling networks across tumor types. To date, most studies on SLC38A3 and SLC38A7 rely on in silico analyses or in vitro evaluation of mRNA and protein levels, with limited or absent functional validation of transport activity. In the case of SLC38A5, the number of studies has increased substantially in recent years and now includes more functional evidence, partly facilitated by the availability of inhibitors. Given their context-dependent roles, biomarker-guided stratification will be necessary to identify tumors in which these transporters represent dominant metabolic drivers, cooperative nodes or dispensable components. Such integrated approaches will be pivotal to uncover metabolic vulnerabilities and to design precision therapeutic strategies that disrupt the nutrient flow and regulatory networks existing between malignant and stromal compartments. For now, the message is clear: three overlooked transporters are stepping out of the shadow of their more famous SLC cousins, and the pharmaceutical industry may soon have three new metabolic targets to chase.

Subject of Research: System N amino acid transporters SLC38A3, SLC38A5 and SLC38A7 as emerging anti-cancer therapeutic targets

Article Title: The amino acid transporters SLC38A3–SLC38A5–SLC38A7 as novel anti-cancer therapeutic targets

Article References: Madenis, N. E., Chiu, M., Bianchi, M. G., Ughini, C., Castellucchio, M. E., Bussolati, O., & Taurino, G. (2026). The amino acid transporters SLC38A3–SLC38A5–SLC38A7 as novel anti-cancer therapeutic targets. Frontiers in Molecular Biosciences, 13, Article 1959729. https://doi.org/10.3389/fmolb.2026.1959729

Image Credits: AI Generated

DOI: 10.3389/fmolb.2026.1959729

Keywords: SLC38A3, SLC38A5, SLC38A7, System N transporters, amino acid transporters, cancer metabolism, glutamine, asparagine, ferroptosis, macropinocytosis, tumor microenvironment, mTORC1

The research team, led by Cornelia C. Metges and colleagues working at German research institutes, used a carefully controlled piglet model to isolate the effects of birth weight and supplementation. At birth, the scientists selected 24 pairs of male littermates: in each pair, one piglet had a low birth weight of roughly 1.10 kilograms and the other a normal birth weight of about 1.50 kilograms. This paired design is powerful because littermates share genetics and much of their prenatal environment, so differences observed later can be attributed more confidently to birth weight itself or to the experimental diet. On the first day of life, litters were standardized to twelve piglets to equalize competition at the udder, and from that point each piglet received a daily oral supplement until the age of five days.

The supplement itself was designed with surgical precision. Half of the animals received glutamine at a dose of one gram per kilogram of body weight, while the others received an isonitrogenous dose of alanine, 1.22 grams per kilogram, which supplies the same amount of nitrogen but a different amino acid. This control matters enormously. Without it, any observed effect could simply reflect extra nitrogen rather than glutamine’s specific biochemistry. By day five, the piglets were euthanized and an extraordinary array of samples was collected: stomach contents, duodenal and liver tissue, colon tissue, and blood plasma. From these, the team measured free amino acids, protein-bound amino acids, amino acid metabolites, biochemical indices, the abundance of messenger RNA for glutamine transport and metabolism genes, and the fractional protein synthesis rate in the duodenum, colon and liver.

Fractional protein synthesis rate is the key metric here, because it captures how fast tissue proteins are actually being built, not just how much building material is present. The technique relies on a flooding dose of a labeled amino acid that rapidly equilibrates across tissues, allowing researchers to calculate the proportion of existing protein that was newly synthesized during a short window. For a study asking whether glutamine stimulates growth of the splanchnic tissues, the gut and liver that sit at the crossroads of nutrient absorption and metabolism, this measurement is the gold standard. Surprisingly, the results showed only modest effects on protein synthesis. Colon fractional protein synthesis was higher in normal birth weight piglets given alanine than in low birth weight piglets given the same supplement, but glutamine itself did not significantly boost synthesis rates in the duodenum, colon or liver.

What the study did find was a clear biochemical fingerprint of glutamine metabolism along the digestive tract. Glutamine and glutamate concentrations in stomach digesta were markedly higher in supplemented animals, confirming that the oral dose reached the stomach intact. But the data also showed that not all of the glutamine simply passed through to the small intestine unchanged. The pattern of free amino acids and metabolites in duodenal tissue indicated that glutamine is absorbed and metabolized right there in the duodenum, the first segment of the small intestine, rather than traveling further downstream before being taken up. This local metabolism has consequences: the researchers suggest it may alter the intracellular pH of duodenal cells, a subtle but potentially meaningful shift in the chemical environment of the gut lining.

Even more striking was the evidence pointing toward oxidative stress. When the team applied a sophisticated statistical method called Data Integration Analysis for Biomarker Discovery using Latent Variable Approaches for Omics Studies, or DIABLO, the analysis separated the supplementation groups cleanly using glutamine, carnosine, citrulline and alanine as the discriminating molecules. More provocatively, the same integrative approach separated glutamine-supplemented low birth weight piglets from their alanine counterparts using the messenger RNA abundance of glutathione reductase, glutathione synthetase and tight junction protein 1. Glutathione is the cell’s master antioxidant, and elevated expression of the enzymes that build and recycle it is a classic sign that cells are working harder to cope with oxidative pressure. Tight junction protein 1, meanwhile, is central to the seals between gut lining cells that keep the intestinal barrier intact.

Reading these signals together, the authors propose that glutamine supplementation appears to increase markers of oxidative stress in the duodenum of low birth weight piglets. This is not necessarily a harmful outcome in itself; transient activation of antioxidant defenses can reflect adaptive metabolic activity, and the gut lining of a newborn is constantly remodeling. But it complicates the assumption that more glutamine is simply better for fragile newborns. It also helps explain an earlier finding from the same research program: glutamine supplementation did raise body weight and plasma glutamine concentrations in low birth weight piglets, yet it left jejunal glutamine concentrations, glutamine transport and the expression of metabolism-related genes in the jejunum untouched. The new duodenal data suggest the action, and the metabolic cost, may be concentrated further up the intestine than previously appreciated.

Other findings underscore how much birth weight alone shapes neonatal metabolism, independent of diet. Duodenal RNA content was lower and the protein-to-RNA ratio higher in glutamine-supplemented low birth weight piglets compared with alanine controls, hinting at differences in cellular composition or translational activity in that tissue. And in a study that measured hundreds of plasma metabolites, the circulating metabolome was essentially unaffected by supplementation, meaning the systemic metabolic ripple of the daily glutamine dose was small even though local gut chemistry shifted measurably. For anyone designing neonatal nutrition interventions, that dissociation between local tissue effects and the plasma picture is a cautionary lesson: what happens in the gut wall does not necessarily show up in a blood draw.

Why does this matter beyond the barn? Piglets are widely regarded as one of the best translational models for human neonatal physiology, particularly for studies of the gut, nutrition and low birth weight in premature infants. Intrauterine growth restriction affects millions of human babies each year and is linked to long-term metabolic and neurodevelopmental consequences. If glutamine, one of the most studied conditionally essential amino acids in neonatal nutrition, can reshape antioxidant gene expression and barrier-related signals in the newborn duodenum, then the timing, dose and tissue-specific consequences of such supplementation deserve closer scrutiny in both veterinary and pediatric contexts. The finding that glutamine is metabolized locally in the duodenum, potentially shifting intracellular pH, also gives formulators a concrete mechanism to consider when deciding whether to deliver glutamine orally, enterally further downstream, or parenterally.

The study’s limitations are those inherent to any tightly controlled animal trial: the piglets were five days old at sampling, the intervention window was short, and the paired male-only design, while rigorous, limits generalization to females and to older animals. Yet the sheer breadth of the measurements, spanning stomach contents, three splanchnic tissues, transcript-level markers and an untargeted plasma metabolome, makes this one of the most complete assessments of neonatal glutamine supplementation to date. The take-home message is nuanced but clear. Glutamine does reach and engage the newborn gut, it is processed in the duodenum, and it leaves detectable molecular traces in the intestinal lining of low birth weight piglets, including signs of heightened oxidative stress handling. But it does not dramatically rev up protein synthesis in the gut and liver within five days, and it leaves the circulating metabolome largely untouched. For the smallest piglets in the litter, the road to catch-up growth, it seems, will not be paved by glutamine alone, and the next generation of neonatal supplements will need to account for the gut’s own metabolic response to what it is fed.

Subject of Research: Effects of neonatal glutamine supplementation on amino acid profiles, protein synthesis and the plasma metabolome in low birth weight piglets

Article Title: Relationship between neonatal glutamine supplementation and amino acid profiles, protein synthesis in splanchnic tissues and the plasma metabolome in 5-day-old piglets with low birth weight

Article References: Sciascia, M., Buchallik-Schregel, J., Li, Z., Görs, S., Tuchscherer, A., Hoeflich, A., Henning, A.-K., Zentek, J., & Metges, C. C. (2026). Relationship between neonatal glutamine supplementation and amino acid profiles, protein synthesis in splanchnic tissues and the plasma metabolome in 5-day-old piglets with low birth weight. PLOS One, 21(10), e0359788. https://doi.org/10.1371/journal.pone.0359788

Image Credits: AI Generated

DOI: 10.1371/journal.pone.0359788

Keywords: glutamine, low birth weight, piglets, neonatal nutrition, duodenum, protein synthesis, amino acids, oxidative stress, plasma metabolome, splanchnic tissues, gut barrier, PLOS One

The platform itself is a feat of miniaturization. Fabricated from polydimethylsiloxane, the chip features a central culture chamber measuring just 2.5 by 1.3 millimeters, flanked by two lateral media channels. Into the chamber, the researchers injected a hydrogel of type I collagen at 6 milligrams per milliliter, seeded with human A549 lung adenocarcinoma cells at a density of 0.2 million cells per milliliter. Rather than pre-assembling spheroids and transferring them into the device, the team allowed the aggregates to form spontaneously within the matrix, guided entirely by microenvironmental conditions. This approach mimics a key aspect of early tumorigenesis, where isolated cells must organize themselves into multicellular structures before they can exploit the cooperative behaviors that make tumors dangerous.

Before perturbing the system, the researchers first characterized how glucose and oxygen behave inside the chip. By filling one lateral channel with high-glucose medium at 4.5 grams per liter and the other with glucose-free medium, they established a controlled gradient across the hydrogel. Glucose was detectable in the previously empty channel within 24 hours, and full equilibration between the two sides took about 48 hours, confirming that the collagen gel permits predictable diffusion. Oxygen, monitored with a fiber-optic dissolved oxygen probe at the channel inlets, drifted from roughly 10 parts per million down to a stable plateau near 7.5 parts per million over the first two days, a pattern that proved essentially identical whether cells were present or not. In other words, the chip’s intrinsic diffusion dynamics, rather than cellular consumption, dominate the oxygen profile at the device level, a detail the authors note as an important caveat when interpreting oxygen availability at the spheroid itself.

With the platform validated, the team launched a multifactorial experiment testing all eight combinations of glucose presence, glutamine presence, and normoxia or hypoxia. The outcome was unambiguous: glutamine is non-negotiable. When glutamine was removed, near-complete loss of cellular structures followed regardless of what else was available, and no spheroid-like formations could be detected by day 9. This aligns with a substantial body of literature showing that glutamine serves as a critical carbon and nitrogen source for biosynthesis, anaplerosis, and redox balance, and that blocking glutamine metabolism triggers apoptosis. Intriguingly, under hypoxia induced by sealing the chips with parafilm, some residual cellular growth persisted even without glutamine, hinting at a partial compensatory effect of low oxygen that the authors suggest may involve the exploitation of alternative metabolic routes, such as collagen-derived proline, though this proved insufficient to rescue full viability.

Glucose told a subtler and, in places, counterintuitive story. Spheroids deprived of glucose from the outset grew poorly, and withdrawing glucose at day 5 from cultures previously grown in low-glucose medium caused a marked arrest in growth. Yet, surprisingly, spheroids cultured continuously in low glucose at 1 gram per liter under normal oxygen levels grew faster than their high-glucose counterparts, a statistically significant difference. The authors attribute this to the known toxicity of elevated glucose concentrations, which can drive oxidative stress through reactive oxygen species production, glucose auto-oxidation, and the formation of advanced glycation end-products, alongside a hyperosmotic environment that disrupts proliferation and cytoskeletal organization. Under chemically induced hypoxia, however, the hierarchy flipped: spheroids in high glucose grew best, consistent with hypoxia-driven metabolic rewiring that upregulates glucose transporters and favors glycolytic flux.

The hypoxia signaling itself proved more nuanced than a simple oxygen meter. Using immunofluorescence for hypoxia-inducible factor 1-alpha, or HIF-1α, the researchers found that the only condition showing virtually no expression was normoxia with abundant glucose and glutamine, the metabolically comfortable state. But nutrient deprivation alone, even with normal oxygen, strongly induced HIF-1α, with the highest signals concentrated in the spheroid core and, under glutamine starvation, the strongest overall expression of all. Pimonidazole staining, which marks genuinely hypoxic tissue, revealed that these HIF-1α signals did not always track actual oxygen tension. The authors conclude that HIF-1α should be read as a marker of hypoxia-related signaling and metabolic adaptation rather than a direct proxy for local oxygen levels, a distinction with real consequences for how hypoxia is measured in cancer studies.

Perhaps the most visually compelling findings came from the structural analysis. Using confocal microscopy and 3D reconstructions from lattice light-sheet imaging, the team quantified actin organization, nuclear distribution, sphericity, and nearest-neighbor distances between nuclei. Well-fed spheroids in high glucose under normoxia were compact and beautifully layered, with a dense outer actin capsule, a proliferative periphery, and stable cellular protrusions extending into the matrix. Glucose withdrawal at day 5 dissolved those protrusions and spawned actin-rich knots in the interior, while chronic glucose absence produced spheroids that retained an outer shell but lost all internal organization, in some cases developing cavities at their cores. Remarkably, the external shape, captured by the sphericity metric, remained largely unchanged across glucose conditions, meaning that a tumor can look perfectly spherical from the outside while being hollowed out within.

Oxygen deprivation, by contrast, acted primarily on architecture rather than size. When hypoxia was induced at day 5, either chemically with ciclopirox olamine, a hypoxia mimetic that stabilizes HIF-1α, or physically by parafilm sealing, spheroids in high glucose showed no growth differences but suffered clear structural damage: loss of the peripheral actin capsule, reduced nuclear density at the rim, enlarged gaps between neighboring nuclei, and frequent internal cavities. Under glucose-free conditions, the combination proved devastating, with oxygen-depleted spheroids showing strong growth arrest and the most severe disorganization, including hollow, organoid-like structures. The authors interpret these cavities as most likely reflecting central necrosis or cell death, since live-dead staining showed spatial correspondence with ethidium homodimer-positive regions, though they caution that 2D imaging cannot definitively distinguish necrosis, apoptosis, or dysregulated autophagy as the underlying mechanism.

One finding carries particular therapeutic weight: when the researchers reintroduced depleted nutrients after prolonged deprivation, spheroids failed to resume normal growth, continuing to expand at the same suppressed rate for at least three days afterward. This suggests a form of metabolic memory, in which sustained nutrient stress leaves persistent adaptations, irreversible damage, or selected subpopulations that resist recovery. If such memory operates in real tumors, transient metabolic interventions could produce long-lasting suppression of tumor behavior well beyond the treatment window. The study has limitations the authors openly acknowledge, including reliance on a single cell line, the technical difficulty of measuring oxygen directly in the central chamber, and the low throughput inherent to sophisticated organ-on-chip systems. Yet the reproducibility of the trends across independent experiments and the platform’s demonstrated versatility with other cancer types in prior work suggest a robust foundation. As microfluidic tumor models mature, this chip offers something static cultures cannot: a dynamic, spatially resolved window into how tumors negotiate their metabolic environment, and a roadmap for exploiting the vulnerabilities that negotiation exposes.

Subject of Research: Effects of glucose, glutamine, and oxygen availability on the growth and architecture of lung adenocarcinoma spheroids in a microfluidic 3D collagen model

Article Title: Glucose and Oxygen Availability Shape Growth and Architecture of Tumor Spheroids in a Microfluidic 3D Model

Article References: Guerrero-López, P., & Garcia-Aznar, J. M. (2026). Glucose and Oxygen Availability Shape Growth and Architecture of Tumor Spheroids in a Microfluidic 3D Model. Annals of Biomedical Engineering. https://doi.org/10.1007/s10439-026-04377-2

Image Credits: AI Generated

DOI: 10.1007/s10439-026-04377-2

Keywords: tumor spheroids, microfluidics, cancer metabolism, glucose depletion, hypoxia, HIF-1α, glutamine, 3D cell culture, tumor microenvironment, lung adenocarcinoma, collagen hydrogel, organ-on-chip

For most of the history of leptospiral research, scientists have grown these fastidious organisms in Ellinghausen-McCullough-Johnson-Harris medium, commonly abbreviated as EMJH. That formulation, while effective for keeping cultures alive in the laboratory, bears little resemblance to the chemical landscape a pathogen actually encounters inside a mammalian host. Nutrient concentrations in EMJH differ dramatically from those in blood plasma, which means that metabolic behaviors observed in conventional cultures may not reflect what happens during a genuine infection. The research team recognized that this mismatch could be masking important aspects of leptospiral biology, and they set out to build a more faithful experimental system.

Their solution was a culture medium they call supplemented Human Plasma-Like Medium, or sHPLM. As the name suggests, the formulation was designed to mimic the composition of human plasma far more closely than traditional media do, with physiologically relevant concentrations of amino acids, vitamins, salts, and other metabolites. The researchers established and validated the medium specifically for Leptospira culture, confirming that the organism could grow in it reliably. By moving the bacteria into an environment that better approximates the host, the team hoped to reveal metabolic dependencies that standard conditions would never expose. The gamble paid off almost immediately.

To interrogate what the bacteria were actually consuming, the group pioneered a set of metabolomics approaches tailored to leptospiral cultures. They developed a liquid chromatography coupled with mass spectrometry workflow capable of performing two complementary tasks: profiling the metabolites present in the medium itself, and tracing the fate of specific labeled nutrients as the bacteria metabolized them. Stable isotope tracing is a powerful technique in which a nutrient is supplied in a chemically identical but isotopically tagged form, allowing researchers to follow exactly where its atoms end up inside the cell. Applying this workflow to L. interrogans growing in sHPLM gave the team an unprecedented, real-time picture of the pathogen’s feeding habits.

The central finding was striking. Among the many nitrogen-containing compounds available in the plasma-like medium, glutamine stood out as a major nitrogen source for the bacteria. This was unexpected because ammonium has long been considered the sole nitrogen source for Leptospira species. Nitrogen is an indispensable element for every living cell, forming the backbone of amino acids, nucleotides, and countless other building blocks, so identifying an alternative and physiologically abundant nitrogen supply fundamentally changes how scientists should think about the pathogen’s nutritional strategy inside the host. Glutamine, one of the most plentiful amino acids in human blood, appears to be far more than passive background chemistry for these organisms.

To confirm that the observation was not an artifact of a single strain or condition, the researchers ran growth experiments across three pathogenic Leptospira strains as well as the nonpathogenic strain L. biflexa Patoc-1. When glutamine-derived nitrogen was the only nitrogen available, all of the tested strains proliferated robustly. That breadth matters. It indicates that the capacity to assimilate glutamine nitrogen is not a quirk of one laboratory isolate but a shared trait across the genus, present in both disease-causing and benign relatives. From an evolutionary standpoint, this suggests that glutamine utilization is a deeply rooted metabolic capability rather than a recent adaptation confined to virulent lineages.

The findings also carried immediate therapeutic implications. The team tested JHU-083, a small-molecule inhibitor designed to interfere with glutamine utilization, and found that it effectively impaired the proliferation of L. interrogans cultures. Because severe leptospirosis currently lacks consistently effective treatments, and because the bacterium’s unusual biology makes it resistant to many conventional antibiotic strategies, a metabolic inhibitor that targets nitrogen assimilation represents an intriguing conceptual blueprint. The result does not mean JHU-083 itself is ready for clinical use, but it demonstrates that blocking glutamine metabolism can starve the organism of a resource it clearly depends on under host-like conditions.

Perhaps the most surprising result came when the researchers added glutamine to the non-physiological EMJH medium. Even in that artificial environment, the amino acid rapidly induced a short-term boost in proliferation and increased biofilm formation in L. interrogans. Biofilms, the structured bacterial communities that adhere to surfaces and often display heightened tolerance to antimicrobial agents, are increasingly recognized as important in persistent infections. The fact that a single nutrient could trigger both faster growth and biofilm development hints that glutamine is not merely food but also a signal, a molecule the bacterium uses to sense its surroundings and reprogram its behavior accordingly.

RNA sequencing reinforced that interpretation. After exposing the bacteria to glutamine, the team observed transcriptional trends pointing toward increased biosynthetic activity, consistent with the organism ramping up its internal manufacturing to support the accelerated growth and biofilm phenotypes. In other words, the presence of glutamine appears to shift the pathogen’s gene expression in ways that prepare it for expansion. If similar signaling occurs during infection, glutamine availability in the host could influence not only how fast L. interrogans multiplies but also how it organizes itself and resists clearance, factors that directly affect disease severity and transmission.

Taken together, the study delivers a two-part message. First, glutamine provides a second nitrogen source for biosynthesis in multiple Leptospira strains, overturning the textbook view that ammonium is the only option. Second, the amino acid may act as a metabolite signal that alters L. interrogans physiology in ways that could shape infection. Both conclusions underscore the methodological lesson embedded in the work: studying pathogens under physiological conditions is not a luxury but a necessity, because nutrient environments that look adequate in the laboratory can conceal the very dependencies that matter most in the host. Nitrogen assimilation now stands as a candidate target for new therapies, and the sHPLM platform combined with isotope tracing offers a template for uncovering similar metabolic blind spots in other understudied pathogens.

Subject of Research: Glutamine utilization as a nitrogen source in the pathogenic bacterium Leptospira interrogans

Article Title: Glutamine from plasma-like medium fuels nitrogen metabolism and influences proliferation in Leptospira interrogans

Article References: Ward, M. H., Scherer, N., Shriver, L. P., & Patti, G. J. (2026). Glutamine from plasma-like medium fuels nitrogen metabolism and influences proliferation in Leptospira interrogans. PLOS Pathogens, 22(10), e1014534. https://doi.org/10.1371/journal.ppat.1014534

Image Credits: AI Generated

DOI: 10.1371/journal.ppat.1014534

Keywords: Leptospira interrogans, leptospirosis, glutamine, nitrogen metabolism, metabolomics, stable isotope tracing, Human Plasma-Like Medium, biofilm, JHU-083, PLOS Pathogens, bacterial physiology, antimicrobial targets

The review, authored by Yujing Li and Zhuoli Zhang of Peking University First Hospital together with Hong Yu of the University of Texas Health Science Center at San Antonio, synthesizes a growing body of experimental and clinical evidence linking nutrient metabolism to immune dysfunction. Its central claim is deceptively simple: the way immune cells process glutamine and convert it into glutamate is not a passive background process but an active regulatory network that shapes immune cell fate, differentiation, and effector function. When that network is disrupted, the result may be the loss of self-tolerance and persistent immune activation that define autoimmune rheumatic diseases.

To appreciate why this matters, it helps to understand what the glutamine-glutamate axis actually does. Glutamine is the most plentiful free amino acid in plasma, and immune cells consume it voraciously. Once transported into a cell, glutamine can be converted to glutamate through a reaction catalyzed by the enzyme glutaminase, releasing ammonia in the process. Glutamate then feeds into multiple downstream routes: it can be further converted to alpha-ketoglutarate, which enters the tricarboxylic acid cycle to generate energy and biosynthetic intermediates; it can supply nitrogen for the production of other amino acids, nucleotides, and the antioxidant glutathione; and it can participate in non-essential amino acid synthesis that rapidly dividing cells require. In effect, the axis is a metabolic junction connecting fuel supply, building-block production, and redox balance.

What has become increasingly clear over the past decade is that this junction does far more than keep cells alive. Metabolic reprogramming, the wholesale shift in how a cell generates and spends energy, is now recognized as a prerequisite for immune cell activation and lineage commitment. A resting lymphocyte and an activated lymphocyte look almost nothing alike on the inside, and much of that difference is driven by changes in glutamine flux. The same is true of monocytes and macrophages, the innate immune cells that patrol tissues and coordinate inflammatory responses. By controlling the availability of alpha-ketoglutarate and other metabolites, the glutamine-glutamate axis influences epigenetic modifications, signaling cascades, and transcriptional programs that determine which genes a cell expresses and, ultimately, what that cell becomes.

The review emphasizes that this regulation operates across multiple immune cell populations. In lymphocytes, glutamine metabolism supports the proliferation and differentiation needed for adaptive immune responses, and alterations in flux can bias cells toward inflammatory or regulatory fates. In monocytes and macrophages, the axis helps govern polarization, the process by which these cells adopt pro-inflammatory or tissue-repairing identities. Because autoimmune rheumatic diseases involve both arms of immunity, dysregulated glutamine metabolism provides a mechanistic bridge that can explain how nutrient utilization becomes entangled with immune pathology in conditions as heterogeneous as rheumatoid arthritis, lupus, and related disorders.

Autoimmune rheumatic diseases themselves are a formidable clinical challenge. They are characterized by the immune system’s loss of tolerance to the body’s own components, producing chronic inflammation that damages joints, skin, kidneys, blood vessels, and other organs. Current therapies, ranging from conventional immunosuppressants to modern biologics, have transformed outcomes for many patients, but they do not work for everyone, and long-term immunosuppression carries significant risks. This therapeutic gap has pushed researchers toward immunometabolism, the study of how metabolic pathways govern immune behavior, in the hope that rewiring cellular metabolism might calm inflammation more precisely than broadly blunting the immune system.

Accumulating experimental and clinical evidence, the authors write, associates dysregulated glutamine-glutamate metabolism with immune dysregulation and tissue injury in rheumatic diseases. In practical terms, this means that abnormalities in how immune cells take up glutamine, convert it to glutamate, and channel the resulting metabolites into energy production and biosynthesis appear to track with the inflammatory damage seen in patients. The review frames this axis as an immunometabolic regulatory network that links nutrient utilization and cellular metabolic remodeling to immune cell fate and function, positioning it as a candidate mechanism underlying the chronic immune activation that keeps these diseases smoldering.

The therapeutic implications are considerable. If the glutamine-glutamate axis drives immune pathology, then targeting it offers a strategy that is conceptually distinct from existing drugs. Rather than blocking a single cytokine or surface receptor, metabolic interventions could alter the fundamental operating conditions of overactive immune cells, starving them of the biosynthetic support they need to sustain inflammation while potentially sparing cells that are behaving normally. The authors suggest that a deeper understanding of these immunometabolic mechanisms may facilitate the development of precision metabolism-based therapeutic strategies for autoimmune rheumatic diseases, an approach that would tailor metabolic interventions to the specific metabolic fingerprints of a patient’s immune cells.

Precision is the operative word. Glutamine is not simply a villain to be eliminated; it is essential for gut integrity, kidney function, and the survival of many cell types, including regulatory immune cells that restrain autoimmunity. Blanket depletion of glutamine would almost certainly cause collateral harm. The challenge, and the opportunity, lies in identifying which enzymatic steps, transporters, and downstream pathways within the axis are selectively exploited by pathogenic immune cells, and in designing drugs or dietary strategies that exploit those vulnerabilities. The review’s comprehensive mapping of the axis across lymphocytes and monocytes/macrophages is intended to provide exactly that kind of mechanistic roadmap for future drug development.

The work also reflects a broader shift in how immunology is practiced. For much of the twentieth century, immune cells were studied primarily as signaling machines, with metabolism treated as housekeeping. The immunometabolism revolution has inverted that view, revealing that metabolic state and immune identity are two sides of the same coin. The glutamine-glutamate axis, sitting at the intersection of nutrition, bioenergetics, and gene regulation, exemplifies this new paradigm. As Li, Yu, and Zhang’s synthesis makes clear, understanding how a single amino acid and its conversion product orchestrate the behavior of the very cells that attack our own tissues may prove to be one of the more consequential ideas in modern rheumatology, and a promising frontier for patients whose diseases remain beyond the reach of current therapies.

Subject of Research: The role of the glutamine-glutamate metabolic axis in regulating immune cell function and autoimmune rheumatic disease pathogenesis

Article Title: The glutamine-glutamate metabolic axis in autoimmune rheumatic diseases: immunometabolic regulation and therapeutic potential

Article References: Li, Y., Yu, H., & Zhang, Z. (2026). The glutamine-glutamate metabolic axis in autoimmune rheumatic diseases: immunometabolic regulation and therapeutic potential. Journal of Translational Medicine. https://doi.org/10.1186/s12967-026-08904-6

Image Credits: AI Generated

DOI: 10.1186/s12967-026-08904-6

Keywords: glutamine, glutamate, immunometabolism, autoimmune rheumatic diseases, rheumatoid arthritis, systemic lupus erythematosus, metabolic reprogramming, lymphocytes, macrophages, inflammation, precision medicine, Journal of Translational Medicine

The scope of the stress problem in aquaculture is enormous. Farmed fish face environmental fluctuations such as temperature swings, poor water quality, and salinity changes, alongside physiological challenges including handling, transportation, and overcrowding. Disease outbreaks and suboptimal feeding practices compound the burden. When fish perceive a threat, their bodies activate the hypothalamus-pituitary-interrenal axis, releasing cortisol and catecholamines—the primary stress hormones in teleosts. While these responses are adaptive in the short term, chronic activation leads to immunosuppression, impaired growth, altered behaviour, and oxidative damage. The metabolic demands of stressed fish rise sharply, dramatically increasing their need for amino acids to sustain cellular functions, support immune responses, and maintain overall health.

Among the most extensively studied functional amino acids is glutamine, a non-essential amino acid that becomes conditionally essential during stress. Glutamine serves as the primary energy source for rapidly dividing cells, particularly those of the immune system and gastrointestinal tract. When fish endure poor water quality or overcrowding, their glutamine reserves can deplete, compromising gut integrity and immune function. Supplementation with L-glutamine supports the growth and repair of enterocytes, the cells lining the intestine, preventing the translocation of pathogens and toxins into the bloodstream. Research cited in the review shows that dietary glutamine enhanced growth performance in Nile tilapia under chronic hyperosmotic stress by boosting antioxidant capacity and improving osmoregulation, although one study found no growth benefit for Atlantic salmon parr under high temperatures, underscoring that responses are species- and context-dependent.

Tryptophan offers perhaps the most striking example of how a single amino acid can reshape behaviour and physiology. As the precursor to serotonin, L-tryptophan influences mood, aggression, and the stress response itself. Serotonin exerts an inhibitory effect on the HPI axis, reducing cortisol release during challenging events such as transport or high stocking density. In Atlantic salmon, dietary supplementation with L-tryptophan or melatonin effectively mitigated stress-induced cortisol elevation, enhanced antioxidant defences, and improved osmoregulatory function following acute handling stress. Tryptophan also feeds the kynurenine pathway, which produces immunosuppressive metabolites that prevent excessive inflammation, and serves as a precursor to melatonin, the neurohormone governing sleep and circadian rhythms essential for recovery.

Arginine operates through an entirely different but equally vital mechanism: the L-arginine-nitric oxide pathway. The enzyme nitric oxide synthase converts arginine into nitric oxide, a signalling molecule that promotes vasodilation, improving blood flow, oxygen delivery, and waste removal in stressed tissues. Nitric oxide also modulates the sensitivity of inter-renal cells to adrenocorticotropic hormone and activates macrophages for pathogen defence. Beyond circulation, arginine supports ammonia detoxification through the urea cycle—critical when stress accelerates protein breakdown—and stimulates the proliferation of lymphocytes and macrophages. Studies in common carp, turbot, and Indian major carps have consistently shown that arginine supplementation improves stress resilience, lowers plasma cortisol, and enhances immune parameters.

The antioxidant dimension of amino acid nutrition centres on the glutathione system, and here cysteine and methionine take centre stage. Glutathione, a tripeptide composed of glutamine, cysteine, and glycine, is one of the most important intracellular antioxidants in fish, neutralizing the reactive oxygen species that accumulate during stress. Methionine, an essential sulfur-containing amino acid, is first converted to S-adenosylmethionine, a universal methyl donor, before feeding cysteine and ultimately glutathione synthesis. N-acetyl cysteine, a supplemental form of cysteine, facilitates de novo glutathione production by gamma-glutamylcysteine synthetase, the rate-limiting enzyme in the pathway, and accelerates glutathione regeneration through glutathione reductase. Histidine adds further antioxidant firepower, with its imidazole group capable of directly scavenging free radicals; histidine-deficient grass carp showed increased red blood cell fragility and reduced hypoxia tolerance.

Other amino acids play more specialized protective roles. Taurine, a sulfur-containing compound not incorporated into proteins, functions as a key osmolyte for marine and brackish water species, regulating ion transport across gill and kidney epithelial cells to maintain cellular osmotic balance during salinity fluctuations. It also stabilizes cell membranes, scavenges reactive oxygen species, and supports cardiac and nervous system function. Proline acts as an osmoprotectant shielding cellular membranes and proteins from damage, while contributing to collagen synthesis for tissue repair. Leucine, a branched-chain amino acid, stimulates the mTOR signalling pathway to preserve muscle protein during catabolic stress, though the review cautions that excessive leucine can suppress feed intake through amino acid sensing mechanisms in the brain. Glycine, the simplest amino acid, acts as an inhibitory neurotransmitter that calms nervous system excitability, reducing anxiety and aggression.

The review also highlights tyrosine, the precursor to the catecholamine stress hormones dopamine, norepinephrine, and epinephrine. Although tyrosine can be synthesized from phenylalanine, endogenous production may become insufficient during rapid growth or physiological stress. Studies in stinging catfish fingerlings identified an optimal phenylalanine-to-tyrosine ratio of roughly 65:35 for growth, antioxidant status, and digestive enzyme activity, while research in mrigal fingerlings established a total aromatic amino acid requirement of 21.5 grams per kilogram of diet, with tyrosine able to replace about 36 percent of the phenylalanine requirement. Tyrosine additionally supports melanin production for camouflage and cognitive functions aiding adaptation to changing environments.

Beyond individual mechanisms, the review emphasizes how amino acids intersect with energy metabolism and growth under stress. When carbohydrate and lipid reserves are depleted, fish increasingly rely on amino acids as fuel, converting them to glucose through gluconeogenesis or oxidizing them in the tricarboxylic acid cycle to generate ATP. Glutamine feeds the TCA cycle via alpha-ketoglutarate, while branched-chain amino acids are catabolized in skeletal muscle to produce acetyl-CoA and succinyl-CoA. This metabolic flexibility allows fish to maintain energy homeostasis, but only if dietary amino acid supplies are adequate. The authors argue that strategically timed supplementation—initiated before or during anticipated stress events—can prevent the muscle wasting, immunosuppression, and growth impairment that characterize chronic stress.

The practical implications extend well beyond fish welfare. As aquaculture shifts toward plant-based proteins for sustainability reasons, diets increasingly lack certain essential amino acids and contain anti-nutritional factors that stress the gut mucosa. Supplementing limiting amino acids such as lysine, methionine, and threonine restores amino acid balance, improves feed conversion ratios, and allows feed manufacturers to reduce fishmeal use, easing pressure on marine ecosystems. Improved nitrogen utilization also lowers nitrogenous waste output, a critical concern in intensive systems. Although crystalline amino acids carry a cost premium, the review concludes that their benefits—better stress tolerance, reduced mortality, and enhanced productivity—make them not merely a nutritional necessity but a genuine sustainability tool. Advances in microbial fermentation are further improving the affordability and environmental footprint of amino acid production, positioning these remarkable molecules at the heart of the future of responsible fish farming.

Subject of Research: The role of dietary amino acids in mitigating stress in aquaculture species

Article Title: Amino acids as functional nutrients in stress mitigation of aquatic species: mechanisms and applications in aquaculture

Article References: Chuphal, N., Malik, M. A., Kishore, P. S., & Mohanta, K. N. (2025). Amino acids as functional nutrients in stress mitigation of aquatic species: mechanisms and applications in aquaculture. Blue Biotechnology, 2(1), Article 20. https://doi.org/10.1186/s44315-025-00040-y

Image Credits: AI Generated

DOI: 10.1186/s44315-025-00040-y

Keywords: amino acids, aquaculture, fish stress, glutamine, tryptophan, arginine, taurine, glutathione, cortisol, osmoregulation, fish welfare, sustainable aquafeeds

The biology behind the problem is unforgiving. In genetically susceptible individuals carrying the HLA-DQ2 or HLA-DQ8 variants, dietary gluten triggers an adaptive immune cascade in which the enzyme tissue transglutaminase-2 chemically modifies gliadin peptides, provoking T-cell-driven destruction of the small intestinal lining. The result is villous atrophy and crypt hyperplasia, which shrink the absorptive surface of the gut and compromise the epithelial barrier. Diagnosis still requires positive serology, typically tissue transglutaminase IgA antibodies, together with a small-intestinal biopsy demonstrating villous damage, yet many people who self-diagnose or drift onto gluten-free diets have never been formally tested. Survey data suggest a global prevalence of about 1.4 percent, but an iceberg effect means most cases remain undiagnosed, and athlete-specific figures are almost nonexistent.

The numbers that do exist are telling. In a survey of 141 NCAA collegiate athletes, roughly 2.8 percent reported a physician diagnosis of celiac disease, while about 11.3 percent scored above the threshold for celiac-consistent symptoms, yielding odds of high-symptom status nearly 18 times higher than a general-population benchmark. The authors of the review caution that these figures rely on self-report, were drawn from a small convenience sample skewed toward white Midwestern athletes, and were compared against general-population rather than age-matched non-athlete controls. Still, the signal is hard to ignore, particularly because intense endurance exercise independently raises intestinal permeability, elevates serum zonulin, and upregulates the pore-forming tight junction protein claudin-2, mechanisms that converge with celiac pathology and could amplify risk or mask symptoms in genetically susceptible athletes through what researchers call Exercise-Induced Gastrointestinal Syndrome.

Even after diagnosis, the challenges multiply. The gold-standard treatment, a strict gluten-free diet, is nutritionally treacherous for people whose energy demands can reach 50 to 80 kilocalories per kilogram of body weight per day in endurance sports. Gluten-free products are frequently made from refined rice, tapioca, and potato starches, carry a higher glycemic index than wheat equivalents, and lack the iron and calcium fortification of conventional foods. Cross-contamination is a persistent hazard: studies of restaurant meals labeled gluten-free have found that roughly a third contain detectable gluten, and sensitive patients can suffer mucosal injury at daily exposures as low as 10 milligrams. The socioeconomic burden compounds the problem, with gluten-free foods costing 76 to 518 percent more than conventional equivalents in the United Kingdom, roughly double in Saudi Arabia, and up to 259 percent more on average in the United Arab Emirates, a burden that falls hardest on young, underfunded athletes who report food-related anxiety, social isolation, and meals skipped before competition.

The nutritional consequences are measurable and severe. Iron deficiency anemia affects up to 82 percent of celiac patients, and only about half restore their iron stores within a year of starting the gluten-free diet. Exercise compounds the deficit because the hormone hepcidin, which blocks iron absorption, remains elevated for up to six hours after training, cutting fractional iron absorption by more than a third. The review recommends timing iron-rich meals and supplements to the early morning, avoiding the three-to-six-hour post-exercise window, and pairing plant-based iron sources with vitamin C. Vitamin D deficiency, present in 8 to 88 percent of celiac patients, carries a staggering 23.3-fold higher risk of fifth metatarsal stress fractures at low serum levels, prompting suggested intakes of 2,000 to 6,000 IU per day for affected athletes. Calcium, magnesium, zinc, and B vitamins follow similar patterns of depletion driven jointly by malabsorption and the poor nutrient density of gluten-free substitutes.

The review also ventures into emerging territory. Sucrosomial iron formulations are preferred for athletes who cannot tolerate ferrous sulfate, and magnesium citrate or glycinate outperform oxide, whose bioavailability is a mere 4 percent. Genetic polymorphisms in the vitamin D-binding protein and receptor genes may explain why some athletes need substantially larger doses to reach the same serum 25-hydroxyvitamin D target of 30 to 50 nanograms per milliliter. On the supplement front, multi-strain probiotics containing Bifidobacterium breve and Lactobacillus plantarum reduced gastrointestinal symptoms 29 percent more than placebo in meta-analysis, while the alanyl-glutamine dipeptide, which survives gastric digestion and upregulates the tight junction proteins claudin and occludin, shows theoretical promise for a gut battered both by disease and by exercise-induced ischemia, though no trial has yet tested it in celiac athletes.

Perhaps the most underappreciated dimension is psychological. A meta-analysis found that people with celiac disease face roughly six-fold higher odds of anxiety and more than double the odds of depression, and collegiate athletes with more celiac-consistent symptoms reported poorer quality of life across physical, psychological, social, and environmental domains, along with greater depression and perceived stress. Childhood celiac disease carries a 19 percent increased risk of psychiatric disorder that persists into adulthood. Disordered eating is another red flag, with a pooled prevalence of nearly 9 percent and a significantly elevated risk of anorexia nervosa, a dangerous overlap in athletic populations where restrictive eating is already common. Even cognition is affected: neuroimaging studies have documented slower reaction times and white matter microstructural changes, the so-called brain fog, with direct implications for tactical decision-making and reaction-time precision in sport.

To bring order to this fragmented picture, the authors lay out a monitoring architecture that spans serology, biochemistry, and performance. Tissue transglutaminase IgA with total IgA remains the first-line screen, and clinicians are urged to test athletes presenting with unexplained fatigue, recurrent infections, refractory iron deficiency, or disproportionate stress fractures, noting that classic gastrointestinal symptoms may be absent in up to half of atypical cases. HLA-DQ2/DQ8 genotyping, with a negative predictive value above 99 percent when both alleles are absent, helps when athletes have already gone gluten-free. Blood sampling should be standardized, ideally in the morning after at least 48 hours of rest, to control for exercise-induced analytical variation, a detail routinely neglected in clinical practice. Dual-energy X-ray absorptiometry tracks bone mineral density and distinguishes genuine fat-free mass recovery from the fat gain and sarcopenic pattern that has been observed after a year on a gluten-free diet, while countermovement jump, handgrip strength, VO2 max, heart rate variability, and patient-reported symptom and quality-of-life scales complete the functional picture.

The review is candid about its limits. It is a structured narrative review conducted under the SANRA quality framework, not a systematic review with risk-of-bias assessment or meta-analysis, and much of its practical guidance extrapolates from the general celiac population, athletic populations without the disease, and mechanistic studies rather than from trials in biopsy-confirmed celiac athletes, of which there are almost none. Its recommendations should therefore be read as hypothesis-generating and practice-oriented rather than graded clinical guidelines. Still, the authors argue that no existing review has previously woven nutritional assessment, supplementation, and performance monitoring into a single athlete-centered framework, and they call for randomized controlled trials with biopsy-confirmed enrollment, adherence-verified comparator arms, and stratification by sport type, sex, age, and mucosal healing status.

The broader message resonates beyond the locker room. Celiac disease sits at the intersection of immunology, gastroenterology, exercise physiology, and psychology, and athletes amplify every one of those variables. If future research confirms that the physiological stress of training lowers the threshold for disease expression in genetically susceptible individuals, sports medicine will need athlete-specific epidemiology, screening checklists, and possibly an international registry to track adherence, biomarkers, and performance over time. For now, the review offers coaches, dietitians, and team physicians a practical warning: when an athlete’s engine keeps misfiring for reasons that training loads and talent cannot explain, it may be worth checking whether the fuel line itself is under attack.

Subject of Research: Integrated nutritional and performance monitoring for athletes with celiac disease

Article Title: An Integrated Nutritional and Performance Monitoring Framework for Athletes with Celiac Disease: A Structured Narrative Review

Article References: Yamani, O. B., Alghamdi, M. M., Zagzoog, A. M., Noorwali, E. A., Alotaibi, R. A., Alghannam, A. F., Aljaloud, K. S., Aragon, A. A., & Elsahoryi, N. A. (2026). An integrated nutritional and performance monitoring framework for athletes with celiac disease: A structured narrative review. Current Research in Food Science, 13, Article 101568. https://doi.org/10.1016/j.crfs.2026.101568

Image Credits: AI Generated

DOI: 10.1016/j.crfs.2026.101568

Keywords: celiac disease, athletes, sports nutrition, gluten-free diet, iron deficiency, vitamin D, intestinal permeability, micronutrients, performance monitoring, probiotics, glutamine, athlete health

The scale of the problem the framework addresses is sobering. According to the ESPEN clinical nutrition guidelines cited in the review, tumor-induced metabolic disturbances and treatment-related toxicities contribute to malnutrition in a large proportion of patients, and an estimated 10 to 20 percent of people with cancer die from malnutrition rather than from the tumor itself. Recent meta-analyses report that severe malnutrition affects roughly 20 percent of cancer patients, with prevalence climbing to 46 percent among hospitalized patients assessed using the GLIM criteria. The consequences ripple across every dimension of care: a global multicenter study found that one third of patients undergoing gastrointestinal cancer surgery were severely malnourished, a condition linked to significantly higher 30-day postoperative mortality, while a separate meta-analysis showed that GLIM-defined malnutrition nearly triples the risk of death within one year compared with well-nourished patients.

The authors contend that the reason conventional nutritional support often falls short is structural rather than conceptual. Standard practice includes individualized dietary counseling, oral nutritional supplements, enteral nutrition, and parenteral nutrition, with the oral and enteral routes preferred whenever the gastrointestinal tract is functional. These interventions can improve intake, weight, and some patient-reported outcomes, but their effects vary widely depending on tumor type, baseline nutritional status, inflammatory burden, and treatment phase. Perioperative immunonutrition containing arginine, omega-3 fatty acids, and nucleotides has shown benefit in selected surgical populations, yet most existing strategies remain single-component or non-targeted. Cancer-associated wasting, by contrast, is a tangled web of metabolic reprogramming, systemic inflammation, immune dysfunction, gut-barrier injury, microbiota disturbance, and treatment toxicity, and no single nutrient can plausibly address all of these dimensions at once.

Enter the traditional Chinese medicine concept of prescription compatibility. In classical Chinese formularies, Jun herbs target the primary pathological mechanism, Chen herbs provide supportive and synergistic effects, Zuo herbs mitigate toxicity or moderate adverse effects, and Shi herbs guide the actions of the principal components and harmonize the whole formulation. The authors are careful to frame this as a translational metaphor rather than proof of pharmacological equivalence between herbs and nutrients. Still, they argue, the compatibility logic is unusually well suited to oncology nutrition because malnourished cancer patients often simultaneously face insufficient intake, inflammation, insulin resistance, skeletal muscle loss, mucosal injury, diarrhea, micronutrient deficiency, anxiety, and fatigue. A hierarchical structure helps clinicians distinguish non-negotiable foundations from optional adjuncts and prevents the substitution of essential energy and protein support with poorly evidenced supplements.

In the proposed model, Jun nutrients constitute the foundational substrate layer: proteins, carbohydrates, and fats. Protein is the centerpiece, with guidelines recommending at least 1.0 gram per kilogram of body weight per day in cancer patients, ideally raised to 1.2 to 1.5 grams per kilogram. Review evidence suggests that daily intake above 1.4 grams per kilogram during treatment helps preserve muscle mass, while intake below 1.2 grams is commonly associated with muscle loss. The PRIMe trial in colorectal cancer explored a high-protein intake of 2.0 grams per kilogram during chemotherapy, with preliminary findings suggesting that roughly half of the patients maintained or improved muscle mass. Carbohydrates serve as an efficient energy source that spares protein from oxidation, with complex carbohydrates and dietary fiber from whole grains, fruits, and vegetables improving insulin sensitivity and reducing inflammatory mediators, whereas refined sugars and high glycemic loads warrant caution given the Warburg effect and the possible association of hyperglycemia with tumor growth and invasion. Fats supply concentrated energy and essential fatty acids, with priority given to monounsaturated and polyunsaturated sources such as olive oil, nuts, and deep-sea fish oil. A randomized controlled trial showed that daily supplementation with six grams of medium-chain triglycerides improved muscle strength and daily functioning in frail older adults within three months, suggesting a potential role against cancer-related wasting, and Mediterranean-style, olive-oil-rich dietary patterns have been linked to substantially reduced breast cancer incidence.

Chen nutrients are the reinforcing layer, selected when a patient shows inflammation, muscle wasting, or impaired anabolic response. The prototype is the omega-3 polyunsaturated fatty acids EPA and DHA, which suppress pro-inflammatory eicosanoids and cytokines, inhibit nuclear factor-kappa B activation, and enhance insulin sensitivity. Clinical studies report that fish oil supplementation improves appetite, increases skeletal muscle mass, and stabilizes body weight in advanced cancer, and a meta-analysis found that oral supplements containing omega-3 fatty acids increased body weight in patients with cancer cachexia by an average of approximately 1.22 kilograms alongside significant improvements in quality-of-life scores. Branched-chain amino acids, particularly leucine, and its metabolite beta-hydroxy-beta-methylbutyrate, activate the mTOR pathway and suppress muscle protein breakdown, respectively. A meta-analysis in hepatocellular carcinoma showed that perioperative supplementation reduced postoperative infections and ascites and produced average weight gains of nearly two kilograms. L-carnitine completes this tier by transporting long-chain fatty acids into mitochondria, suppressing proteolysis through AKT and FOXO3a signaling, and, in early clinical work, improving fatigue, body composition, and quality of life in patients with advanced cancer.

Zuo nutrients act as coordinating adjuncts that protect the gut and buffer treatment toxicity. Probiotics such as Lactobacillus and Bifidobacterium species, together with prebiotics like inulin, support intestinal barrier function and short-chain fatty acid production. Systematic reviews indicate that probiotic use among patients receiving chemotherapy or radiotherapy reduces the risk of diarrhea of any grade by approximately 65 percent and severe diarrhea by about 57 percent, while another meta-analysis reported a roughly 30 percent reduction in chemotherapy-induced diarrhea and a halving of severe cases, alongside markedly lower rates of oral mucositis. Glutamine, a conditionally essential amino acid during physiological stress, fuels intestinal epithelial cells, promotes mucosal repair, and reduces permeability and bacterial translocation. Meta-analyses show that glutamine nearly halves the risk of grade III to IV oral mucositis from chemotherapy or radiotherapy, prompting MASCC to list oral glutamine as an optional prophylactic measure, and supplementation has also reduced chemotherapy-induced diarrhea in colorectal cancer patients by roughly 35 percent.

Shi nutrients, the guiding cofactors, include vitamins, trace elements, and coenzymes that make the entire system work. B vitamins drive energy metabolism and hematopoiesis, vitamins A, C, and E support epithelial integrity and antioxidant defense, and vitamin D carries endocrine and immunomodulatory functions, with higher serum levels associated with longer survival in patients receiving immune checkpoint inhibitors. Trace elements matter enormously: in a retrospective study of gynecological malignancies, serum zinc declined significantly after surgery and chemoradiotherapy, and zinc deficiency was 4.8 times more likely in patients whose tumors recurred, with levels below 61 micrograms per deciliter independently predicting recurrence. Iron, folate, and vitamin B12 are essential for erythropoiesis, though excessive iron must be avoided for its possible tumor-promoting effects. Coenzyme Q10, a mitochondrial electron carrier, has shown in breast cancer trials that 100 milligrams daily for six to twelve weeks significantly reduced circulating VEGF and IL-8 and suppressed matrix metalloproteinase activity, suggesting a possible role in easing fatigue and inflammation.

The framework’s greatest practical promise may lie in its adaptability to specific cancers and complications. In breast cancer, vitamin D and calcium anchor skeletal health during endocrine therapy while glutamine and probiotics buffer chemotherapy toxicity; in lung cancer, anti-inflammatory omega-3 fatty acids and branched-chain amino acids counter the cachexia that affects so many patients at diagnosis; in esophageal cancer, tube-fed enteral nutrition and perioperative immunonutrition with arginine and fish oil reduce postoperative infections; in hepatocellular carcinoma, branched-chain amino acid-enriched formulas meet protein needs while limiting ammonia-related metabolic burden. The authors stress that traditional Chinese medicine formulas, including Huangqi Sijunzi, Liujunzi, and Buzhong Yiqi decoctions, should complement rather than replace standard oncologic nutrition care, and they acknowledge that randomized controlled trials of structured nutrition-TCM integrative strategies remain limited. Looking ahead, they propose that patient stratification using metabolomics, inflammatory markers, and microbiome profiles, combined with nutritional informatics and systems modeling, could transform this ancient hierarchy into testable combination hypotheses and dosing rules, moving supportive oncology from experience-based practice toward genuinely data-driven, precision nutritional medicine.

Subject of Research: Application of the traditional Chinese medicine principle of Jun-Chen-Zuo-Shi to individualized nutritional therapy for cancer-associated malnutrition and cachexia.

Article Title: “Jun-Chen-Zuo-Shi” – the Chinese medical perspective on clinical oncology nutritional therapy

Article References: Lin, S., Li, B., & Yao, Q. (2026). “Jun-Chen-Zuo-Shi” – the Chinese medical perspective on clinical oncology nutritional therapy. Holistic Integrative Oncology, 5(1), Article 62. https://doi.org/10.1007/s44178-026-00282-9

Image Credits: AI Generated

DOI: 10.1007/s44178-026-00282-9

Keywords: cancer cachexia, malnutrition, Jun-Chen-Zuo-Shi, traditional Chinese medicine, oncology nutrition, omega-3 fatty acids, branched-chain amino acids, glutamine, probiotics, micronutrients, nutritional therapy, lean body mass

The research team set out to answer a deceptively simple question: when prostate cancer cells stop responding to enzalutamide, what has actually changed inside them? Resistance is often described in terms of genetic mutations in the androgen receptor or amplification of the receptor gene itself, but these alterations explain only a fraction of clinical cases. Increasingly, cancer biologists have recognized that drug-tolerant cells frequently survive by adjusting their metabolism, the network of chemical reactions that converts nutrients into energy, building blocks and signaling molecules. Because metabolic rewiring is a physical requirement for survival rather than an optional accessory, it may represent a more universal and more druggable hallmark of resistance than any single mutation.

To capture that rewiring comprehensively, the investigators applied a multi-omic pipeline to paired models of enzalutamide-sensitive and enzalutamide-resistant prostate cancer cells. Transcriptomic sequencing revealed which genes were switched on or off; proteomic mass spectrometry quantified the enzymes actually present in the cells; and metabolomic profiling measured the small molecules, sugars, amino acids and lipids that flow through the metabolic network. The power of this approach lies in its convergence. A change in a single data type can be misleading, but when altered messenger RNA, altered protein and altered metabolite levels all point to the same pathway, the evidence becomes difficult to dismiss.

The analysis converged on several interconnected metabolic shifts. Resistant cells displayed a marked reorganization of lipid metabolism, upregulating pathways for fatty acid synthesis and elongation while also altering cholesterol handling. This makes biological sense for prostate cancer in particular, because the androgen receptor does more than respond to testosterone; it also regulates genes involved in lipid acquisition and synthesis, and membrane lipid composition influences receptor signaling at the cell surface. By boosting de novo lipogenesis, resistant cells appear to buffer themselves against the loss of androgen-driven lipid programs that enzalutamide imposes, effectively rebuilding a supply line the drug was designed to cut.

Energy metabolism showed equally telling changes. Profiling of central carbon metabolism indicated that resistant cells leaned more heavily on glycolysis and on glutamine-fueled anaplerosis, the process by which the amino acid glutamine tops up the tricarboxylic acid cycle with carbon. Mitochondrial oxidative phosphorylation was also reconfigured, with altered expression of electron transport chain components suggesting a shift in how resistant cells balance ATP production against the generation of biosynthetic precursors. These are not idle adjustments. Rapidly dividing tumor cells must simultaneously produce energy, reduce cellular building blocks and maintain antioxidant defenses, and the observed pattern is characteristic of cells that have traded metabolic efficiency for metabolic flexibility.

Crucially, the study did not stop at description. The researchers tested whether the metabolic alterations they detected could be exploited therapeutically. Inhibiting key enzymes in the upregulated lipid synthesis pathway reduced the viability of enzalutamide-resistant cells more severely than that of their drug-sensitive counterparts, indicating a genuine dependence rather than incidental correlation. Similar experiments targeting glutamine metabolism and mitochondrial respiration produced the same pattern of selective vulnerability. When metabolic inhibitors were combined with continued enzalutamide treatment, the effect was additive, and in some settings synergistic, meaning that the resistant cells could be resensitized to the drug they had learned to ignore.

The concept underlying these results is known as collateral vulnerability. When cancer cells evolve resistance to one pressure, the evolutionary path they take often creates new dependencies that did not exist before. A cell that ramps up fatty acid synthesis to survive androgen receptor blockade, for example, becomes exquisitely sensitive to inhibitors of that synthesis pathway. Because these dependencies are consequences of the resistance program itself, they are less likely to be bypassed by further tumor evolution without a significant fitness cost. This is the same logic that has made synthetic lethal strategies, such as PARP inhibition in DNA repair-deficient tumors, one of the most productive ideas in modern oncology, now extended into the metabolic arena.

The findings carry practical implications for the clinic. Enzalutamide resistance currently marks a transition point at which patients move toward chemotherapy, androgen biosynthesis inhibitors or, for those with suitable tumor biology, radioligand therapy. If metabolic vulnerabilities of the kind identified here can be confirmed in patient-derived models and ultimately in clinical trials, metabolic inhibitors could be layered onto existing regimens at the first sign of rising prostate-specific antigen during enzalutamide treatment, potentially delaying or preventing overt resistance. The study also raises the possibility of using metabolic imaging or circulating metabolite profiles as biomarkers, allowing clinicians to detect the metabolic shift before the tumor has fully escaped hormonal control.

Several caveats temper the enthusiasm. Cell line models, even well-characterized ones, capture only part of the complexity of human tumors, which contain stromal cells, immune infiltrates, variable oxygen and nutrient availability and extensive intratumoral heterogeneity. Metabolic phenotypes are notoriously context-dependent, shaped by the culture conditions in which cells are grown and by the specific evolutionary path each resistant line has taken. The authors’ use of multiple paired models and convergent multi-omic evidence strengthens their conclusions, but translating these dependencies into patients will require validation in organoids, xenografts and ultimately biopsy material from men whose disease has progressed on enzalutamide. Dose-limiting toxicities of metabolic inhibitors, particularly those affecting normal tissues with high metabolic flux, will also need careful management.

Nevertheless, the study represents a meaningful step toward a more complete picture of how prostate cancer defeats one of its most important therapies. By treating metabolism not as background housekeeping but as a central player in drug resistance, and by interrogating that metabolism with layers of molecular data rather than single measurements, the work provides both a mechanistic map and a practical target list. For the growing population of men living with castration-resistant prostate cancer, the hope is that the very adaptations tumors use to survive enzalutamide will become the handles by which the next generation of treatments pulls them back into vulnerability.

Subject of Research: Metabolic rewiring in enzalutamide-resistant prostate cancer identified through integrated transcriptomic, proteomic and metabolomic profiling

Article Title: Multi-omic profiling reveals metabolic vulnerabilities in enzalutamide resistant prostate cancer

Article References: Lee, O., Fidelito, G., Zhao, Q., Liu, B., Choi, H., Taylor, R. A., & Watt, M. J. (2026). Multi-omic profiling reveals metabolic vulnerabilities in enzalutamide resistant prostate cancer. Cell Death Discovery. https://doi.org/10.1038/s41420-026-03332-3

Image Credits: AI Generated

DOI: 10.1038/s41420-026-03332-3

Keywords: prostate cancer, enzalutamide, drug resistance, multi-omics, metabolism, lipid metabolism, glutamine, androgen receptor, oxidative phosphorylation, collateral vulnerability, cancer therapeutics, Cell Death Discovery