A new study from researchers at the Korea Food Research Institute, published in Food Science and Biotechnology, offers one of the most detailed answers yet for aging bodies. Led by Yu Ra Lee and corresponding author Yoonsook Kim, the team used targeted tandem mass spectrometry to track CML and CEL across five compartments in aged mice: blood plasma, kidney, liver, brain, and ileum, the final segment of the small intestine where most nutrient absorption occurs. The results reveal a strikingly uneven landscape, with dietary CML driving dramatic accumulations in some tissues while leaving others seemingly untouched, and with blood levels telling only a partial story about what is happening deep inside organs.

The experimental design was straightforward but technically demanding. Aged mice received a diet supplemented with CML, allowing the researchers to follow the fate of a single, well-defined dietary glycation product rather than the complex cocktail found in heat-processed foods. A second group received FPS-ZM1, a synthetic compound that blocks the receptor for advanced glycation end products, known as RAGE, a cell-surface protein that binds AGEs and triggers inflammatory signaling. By comparing these groups against controls, the researchers could disentangle how much of the tissue burden came from the diet itself and how blocking the AGE receptor might alter the picture.

The mass spectrometry approach deserves attention because quantifying AGEs is notoriously difficult. CML and CEL are small, chemically similar modifications of lysine, and tissues contain a bewildering array of proteins that may carry them. Targeted tandem mass spectrometry, often abbreviated LC-MS/MS when coupled to liquid chromatography, works by first separating the compounds chromatographically and then fragmenting them in the instrument, monitoring specific parent-to-fragment ion transitions that act like molecular fingerprints. This selective monitoring, typically run in multiple reaction monitoring mode, allows the method to distinguish CML from the sea of other molecules in a tissue digest and to quantify it against stable isotope-labeled internal standards, delivering accuracy that older colorimetric or antibody-based assays could not match.

What the numbers showed was remarkable. Compared with control animals, mice fed dietary CML accumulated 3.78 times more CML in their kidneys and a striking 10.26 times more in the ileum. CEL, which was not directly supplemented but can form downstream from related carbonyl chemistry, also rose significantly, increasing 2.33-fold in kidney and 1.69-fold in ileum. The ileum result is perhaps the most intuitive: as the site of absorption, the intestinal wall sees the highest concentration of anything arriving from the gut lumen, and the new data confirm that dietary CML does not simply pass through but accumulates in the tissue itself. The kidney, meanwhile, is a known hotspot for AGE deposition in aging and diabetes, and these findings reinforce its status as a primary sink for glycation products.

Just as telling were the tissues where the signal was weaker. The liver and brain did not show the same dramatic fold-changes, suggesting that tissue-selective barriers and metabolism shape the distribution of dietary AGEs. The blood-brain barrier, which tightly regulates what enters the central nervous system, may filter out a substantial share of circulating glycation products, though the receptor RAGE is known to mediate transport of certain ligands across that barrier under some conditions. The liver, as the body’s principal detoxification organ, may clear or process absorbed AGEs efficiently. Whatever the mechanisms, the study makes clear that a dietary bolus of CML does not blanket the body uniformly; it concentrates where physiology allows.

The correlation analysis added a layer of nuance with real clinical implications. Plasma CML levels correlated positively with CML levels in the brain, with a Spearman coefficient of 0.574 and a p-value of 0.002, and with the ileum, at a coefficient of 0.414 and p equal to 0.036. In other words, a blood draw gave a statistically meaningful window into glycation burden in at least two organs. But plasma CEL told a different story entirely, showing no significant correlations with any tissue measured. For researchers and clinicians who rely on circulating AGE markers as proxies for whole-body or organ-specific burden, this is a caution: the reliability of a blood marker depends on which AGE you are measuring and which tissue you care about.

The FPS-ZM1 arm of the experiment pointed toward a possible intervention strategy. Mice that received the RAGE antagonist showed lower AGE levels in selected tissues compared with animals that did not. RAGE is not merely a passive binding protein; when engaged by AGEs, it activates inflammatory and oxidative stress pathways that have been implicated in diabetic complications, kidney disease, cardiovascular damage, and neurodegeneration. Blocking the receptor has previously been shown in other mouse models to reduce amyloid-beta-related brain pathology, and the new findings suggest that RAGE signaling may also influence how glycation products distribute and persist in aging tissue. The authors describe the association carefully, and the study was not designed as a therapeutic trial, but the pattern supports the idea that the AGE-RAGE axis is a meaningful lever in age-related tissue accumulation.

Why does this matter for human health? The modern Western diet, rich in heat-processed and industrially prepared foods, delivers a substantial daily load of preformed AGEs, and epidemiological and mechanistic studies have linked high dietary AGE intake to obesity, early renal pathology, and chronic inflammation. Prior work with isotopically labeled dietary CML in mice demonstrated that a fraction of orally administered CML is absorbed and distributed to organs, but questions remained about how aging changes that distribution and whether blood measurements could stand in for tissue measurements. The new study addresses both gaps in aged animals, showing that the aging kidney and gut are particularly receptive to dietary CML and that plasma markers must be interpreted with tissue context in mind.

There are, of course, limits to how far mouse data can be extrapolated. The study used a purified CML supplement rather than the heterogeneous AGE mixture found in actual foods, and the doses, metabolism, and lifespan of laboratory mice differ from those of humans. The researchers also note that endogenous AGE formation, driven by oxidative stress and reactive carbonyls such as methylglyoxal and glyoxal, proceeds alongside dietary intake and can complicate attribution. Still, by applying a rigorously validated targeted mass spectrometry method across five biological compartments in aged animals, the Korean team has produced a map of where dietary glycation products actually go, and that map argues for caution in reading blood tests, continued scrutiny of AGE-rich diets, and sustained interest in RAGE as a target for protecting aging organs from the slow chemical wear of glycation.

Subject of Research: Tissue-selective accumulation of dietary advanced glycation end products in aged mice

Article Title: Tissue-selective accumulation of carboxymethyllysine and carboxyethyllysine after dietary carboxymethyllysine exposure in aged mice revealed by targeted tandem mass spectrometry

Article References: Tissue-selective accumulation of carboxymethyllysine and carboxyethyllysine after dietary carboxymethyllysine exposure in aged mice revealed by targeted tandem mass spectrometry. (n.d.). https://doi.org/10.1007/s10068-026-02332-4

Image Credits: AI Generated

DOI: 10.1007/s10068-026-02332-4

Keywords: advanced glycation end products, carboxymethyllysine, carboxyethyllysine, tandem mass spectrometry, aging, kidney, ileum, RAGE, dietary AGEs, plasma biomarkers, glycation, mice study

The findings arrive at a moment when nanotoxicologists are increasingly worried about the kidney. Silver nanoparticles, or AgNPs, are prized for their exceptional antimicrobial potency, their usefulness in clinical imaging and diagnostics, and their stability in consumer products ranging from bedding to electronics. Yet a growing body of evidence implicates them in cytotoxicity across multiple organ systems, and the kidneys appear particularly vulnerable. Previous animal studies have shown that AgNPs can accumulate within kidney cells, disrupt the delicate architecture of podocytes, the specialized cells that form the blood-filtration barrier in the glomeruli, and downregulate critical functional genes including those encoding nephrin and podocin. In laboratory-grown kidney cells, the particles have been observed to pile up inside lysosomes, scramble redox balance, and inflict direct damage on DNA.

To test whether taurine could counteract this cascade of harm, the researchers divided fifty adult male Wistar rats into five groups of ten animals each. One group served as untreated controls. A second received silver nanoparticles alone at a dose of 200 micrograms per kilogram of body weight, administered intraperitoneally each day. A third received taurine alone at 100 milligrams per kilogram by mouth. The remaining two groups received both the nanoparticles and taurine, at either 50 or 100 milligrams per kilogram. Treatment continued for twenty-one days, after which the animals were anesthetized, euthanized, and their kidneys and blood analyzed with an unusually thorough battery of biochemical, hormonal, and histological assays. The nanoparticles themselves were rigorously characterized before the experiment began, with transmission electron microscopy, dynamic light scattering, zeta potential analysis, and ultraviolet-visible spectroscopy confirming that the particles were a homogeneous 20 nanometers in diameter and stable in suspension.

The results in the nanoparticle-only group were stark. Serum creatinine and urea, the two classic workhorse markers of kidney function, rose dramatically compared with controls, with statistical significance values below 0.0001. Because creatinine and urea are waste products that healthy glomeruli filter freely and tubules barely reabsorb, their accumulation in the blood is a reliable signal that the kidneys are struggling to do their job. Equally striking was what happened to the thyroid hormones. Levels of triiodothyronine (T3) and thyroxine (T4), along with the ratio between them, fell sharply in the nanoparticle-exposed rats, indicating disruption of the hypothalamic-pituitary-thyroid axis. This hormonal collapse matters for the kidneys in very concrete ways: T3 normally drives the expression of sodium-potassium ATPase pumps and other ion transporters that renal tubular cells depend on to reabsorb electrolytes, and it also fuels the renin-angiotensin-aldosterone system, which governs glomerular filtration pressure.

Beneath the functional decline, the researchers documented a cellular war zone. Kidney tissue from the nanoparticle-exposed rats showed soaring levels of hydrogen peroxide, reactive oxygen and nitrogen species, and lipid peroxidation products, the chemical fingerprints of membranes under oxidative assault. Meanwhile, the kidney’s own antioxidant arsenal was depleted: the activities of the enzymes superoxide dismutase, catalase, glutathione-S-transferase, and glutathione peroxidase all dropped significantly, as did levels of glutathione, the cell’s principal non-enzymatic antioxidant tripeptide. The chemistry here is unforgiving. Hydrogen peroxide, though relatively stable on its own, can participate in Fenton and Haber-Weiss reactions to generate hydroxyl radicals, among the most destructive reactive species in biology. Renal cells are especially susceptible because iron reabsorbed in the tubules provides abundant catalyst for these reactions, converting a modest peroxide burden into a localized radical storm.

Inflammation followed the oxidative damage, as it so often does. The activity of myeloperoxidase, an enzyme released by neutrophils and monocytes that serves as a hallmark of their recruitment to injured tissue, climbed sharply in the nanoparticle-exposed kidneys, and nitric oxide levels rose in parallel, reflecting induction of inflammatory signaling. When the researchers examined stained tissue sections under the microscope, the structural toll was unmistakable: the renal cortex showed epithelial degeneration, glomerular lesions and hyperplasia, and widened capsular spaces, architectural damage consistent with the failing filtration function reflected in the blood chemistry.

Taurine co-treatment reversed nearly all of it. In rats given the amino sulfonic acid alongside the nanoparticles, creatinine and urea fell back toward normal, T3 and T4 recovered in a dose-dependent fashion, and the T3-to-T4 ratio improved. The antioxidant enzymes rebounded, glutathione was restored, and the markers of oxidative damage, peroxide, reactive species, and lipid peroxidation, all declined significantly. Myeloperoxidase activity and nitric oxide levels dropped, indicating that the inflammatory mobilization had been quieted. Most visibly, the histological sections from co-treated animals showed substantially preserved renal architecture compared with the devastated tissue of the nanoparticle-only group. The higher dose of taurine generally outperformed the lower one, suggesting a concentration-dependent protective effect.

The study’s authors, led by Adesina A. Babalola and senior investigator Isaac A. Adedara of the Drug Metabolism and Toxicology Research Laboratories, note that this is the first demonstration that taurine can restore thyroid-dependent renal tubular function following silver nanoparticle exposure. The choice of taurine was no accident. The compound, which mammals synthesize endogenously and obtain chiefly from animal-derived foods, participates in bile salt formation, calcium signaling, and osmoregulation, and it exerts antioxidant, anti-inflammatory, and anti-apoptotic effects across tissues. Taurine deficiency has been linked to retinal degeneration, cardiomyopathy, and pancreatic beta-cell dysfunction, and taurine depletion is documented in renal disease itself. The body’s capacity to make taurine declines with age, and infants cannot synthesize it adequately, making dietary and supplemental sources increasingly relevant. The Ibadan group had previously shown that taurine protects against silver nanoparticle neurotoxicity and reproductive toxicity in rats, and the new work extends that protective umbrella to the kidneys.

The authors are candid about one limitation: their design lacked a control group exposed to silver ions alone. Silver nanoparticles release silver ions in the body, and these ions distribute and behave differently from the intact particles, potentially producing distinct toxic effects. Prior work by other researchers, however, suggests that the nanoparticles themselves may be the more insidious threat, because cells take them up slowly through endocytosis, sequester them in lysosomes, and then release silver ions gradually, producing a prolonged and localized toxic exposure. That mechanism, if confirmed across more models, makes the kidney’s vulnerability to chronic nanoparticle exposure all the more consequential, and makes a protective agent that works against the particles themselves particularly valuable.

For now, the findings remain anchored in rodents, and translating a rat dose of taurine into human guidance requires the usual caution. But the study adds to a compelling picture: as engineered nanomaterials saturate the built environment and the marketplace, the search for accessible, low-toxicity countermeasures becomes a public health question rather than a purely academic one. Taurine, cheap, water-soluble, and already a common ingredient in energy drinks and infant formula, is about as accessible as candidate protective agents come. Whether it can shield human kidneys from the silver nanoparticles already woven into daily life will demand clinical evidence that does not yet exist. What the Nigerian team has established is the mechanistic blueprint, oxidative stress, thyroid disruption, inflammation, and tissue destruction, and a demonstration that a single dietary compound can intervene at every step of that destructive sequence.

Subject of Research: Protective effects of taurine against silver nanoparticle-induced kidney toxicity, oxidative stress, and thyroid dysfunction in rats

Article Title: Taurine mitigates oxidative stress, thyroid dysfunction and renal damage in silver nanoparticles-treated rats

Article References: Babalola, A. A., Ileola-Gold, A. V., Adelaja, U. A., Njoku, C. A., Adedara, I. A., & Farombi, E. O. (2025). Taurine mitigates oxidative stress, thyroid dysfunction and renal damage in silver nanoparticles-treated rats. Discover Toxicology, 2(1), Article 23. https://doi.org/10.1007/s44339-025-00045-7

Image Credits: AI Generated

DOI: 10.1007/s44339-025-00045-7

Keywords: silver nanoparticles, taurine, nephrotoxicity, oxidative stress, thyroid hormones, kidney, nanotoxicology, antioxidant enzymes, inflammation, Wistar rats, renal function, toxicology

Multiple myeloma is a cancer of plasma cells, the antibody-producing white blood cells that reside in the bone marrow. As malignant plasma cells proliferate, they flood the bloodstream with abnormal proteins called free light chains, which are filtered by the kidneys and can precipitate inside the delicate tubules, causing progressive injury. Renal impairment is one of the most feared complications of the disease, affecting a substantial minority of patients at diagnosis, and it has consistently been identified as a risk factor for poorer outcomes across virtually every treatment modality. The standard of care for eligible myeloma patients includes high-dose melphalan chemotherapy followed by rescue with the patient’s own blood-forming stem cells, a procedure known as autologous hematopoietic cell transplantation. But because melphalan is partially cleared by the kidneys, patients with impaired renal function face a pharmacological dilemma: a full dose may accumulate to toxic levels, while a reduced dose may compromise the anti-cancer effect.

The Brazilian research team set out to address a gap that has persisted in the transplant literature. Most published data on transplantation in myeloma patients with renal impairment come from high-volume centers in Europe and North America, equipped with extensive intensive care capacity and multidisciplinary support. Whether similar outcomes could be achieved in resource-constrained settings, where access to dialysis, critical care beds, and broad-spectrum antimicrobials may be more limited, remained an open question. The study therefore examined outcomes at a public hospital in Brazil, capturing the realities of transplant medicine as it is practiced in much of the world rather than only in its most privileged enclaves.

The researchers defined renal impairment strictly, requiring either a serum creatinine above 2 milligrams per deciliter or a creatinine clearance below 40 milliliters per minute, thresholds that indicate serious compromise of kidney function. The 53 patients enrolled in the analysis had a median age of 59 years, and the cohort was characterized by advanced disease at presentation: 82 percent had Durie-Salmon stage IIIA or IIIB disease, and 63 percent fell into stage III of the International Staging System, the most severe category. Notably, 15 of the patients, amounting to 28 percent of the cohort, were dependent on dialysis at the time of their transplant, meaning their kidneys could no longer sustain them without mechanical blood filtration. The vast majority, 81 percent, received a reduced melphalan dose of 140 milligrams per square meter of body surface area or less, reflecting the common clinical practice of dose adjustment in the setting of renal dysfunction.

The toxicity profile documented in the study underscores how demanding this treatment is for patients with failing kidneys. Fifteen patients, or 29 percent of the cohort, experienced grade 3 or 4 overall toxicity, the most severe categories of adverse effects on standard clinical grading scales. Severe oral mucositis, the painful inflammation and ulceration of the lining of the mouth that follows high-dose chemotherapy, affected 17 percent of patients, while 13 percent suffered grade 3 or 4 diarrhea and a comparable proportion experienced severe nausea. Fourteen patients, 26 percent of the total, required admission to the intensive care unit at some point during their transplant course, a figure that highlights the considerable critical care resources consumed by this population and the fragility of patients whose kidneys cannot buffer the metabolic stresses of conditioning chemotherapy.

Perhaps the most clinically actionable finding concerns which factors predicted severe toxicity. Patients who came to transplant in only a partial response to prior therapy, rather than a very good partial or complete response, were significantly more likely to develop grade 3 or 4 toxicity, with a p-value of 0.024 indicating a statistically robust association. Low serum albumin at the time of transplant, a marker of poor nutritional status and general physiological reserve, was also linked to severe toxicity, as was receiving a melphalan dose above 140 milligrams per square meter. Taken together, these associations suggest a coherent biological picture: patients with more active disease, less nutritional reserve, and higher chemotherapy exposure are precisely those whose bodies are least equipped to withstand the conditioning regimen, and clinicians may be able to identify them in advance.

The survival statistics tell a nuanced story. Non-relapse mortality, the proportion of patients who died from causes other than their cancer, such as infections or organ failure related to the transplant itself, stood at 13 percent at 100 days, with infections being the leading cause of these early deaths. At 24 months after transplantation, 48 percent of patients had not experienced disease progression, and 65 percent were still alive. The authors note that these survival figures were comparable to those reported in prior studies conducted in better-resourced settings, a finding they describe as reassuring for centers operating under similar constraints. In other words, despite the higher complication rates and intensive care utilization, carefully selected patients with renal impairment can still derive meaningful benefit from autologous transplantation even outside the world’s wealthiest medical systems.

The analysis also identified predictors of poorer survival that may guide future patient selection. Dialysis dependence at the time of transplant was significantly associated with worse progression-free survival, with a p-value of 0.035, as were advanced disease stage by the International Staging System, with stage 2 and stage 3 disease each independently linked to shorter progression-free survival. For overall survival, the decisive factor was the comorbidity burden: patients with a higher accumulation of coexisting health conditions died more frequently, with a p-value of 0.015. These findings align with the broader understanding that transplant outcomes reflect not just the cancer itself but the whole patient, and they suggest that in resource-limited settings, where intensive care capacity is finite, prioritizing patients with better organ function, earlier-stage disease, and fewer comorbidities may maximize the benefit derived from each transplant performed.

The study’s conclusions carry practical weight for transplant physicians worldwide. The authors recommend optimizing patient selection for hematopoietic cell transplantation and reducing melphalan doses in patients with renal impairment, strategies that may be particularly warranted where healthcare resources are limited. The finding that full-dose melphalan was associated with increased severe toxicity provides quantitative support for the dose-reduction practices already common in many centers, while the link between deep pre-transplant response and lower toxicity argues for maximizing induction therapy before proceeding to transplant in patients with kidney damage. As novel agents continue to improve myeloma control before transplantation, the population of patients reaching transplant with renal impairment may evolve, but this study provides a valuable benchmark for what can currently be achieved.

Beyond its immediate clinical implications, the research fills an important gap in the global evidence base. Transplant outcomes in low- and middle-income countries are chronically underreported, leaving clinicians in those settings to extrapolate from studies conducted under very different conditions. By documenting both the challenges, including high non-relapse mortality and frequent intensive care utilization, and the achievable successes, with two-year overall survival of 65 percent, the São Paulo team has demonstrated that autologous transplantation remains a viable and defensible option for myeloma patients with renal impairment even where resources are stretched. The study was approved by the local institutional ethics board, all participants provided informed consent, and the work was conducted in accordance with the Declaration of Helsinki, with no external funding supporting the research. For the growing number of myeloma patients worldwide who present with damaged kidneys, the message is one of cautious hope: with careful selection, dose adjustment, and honest counseling about the risks, the transplant pathway remains open.

Subject of Research: Autologous hematopoietic cell transplantation outcomes in multiple myeloma patients with renal impairment

Article Title: Outcomes in patients with multiple myeloma and renal impairment undergoing autologous hematopoietic cell transplantation

Article References: Martins, L., Ribeiro, C., Gasparini, J., Otuyama, L., Mariano, L., Atanazio, M., Seguro, F., Martinez, G., Rocha, V., & Fatobene, G. (2026). Outcomes in patients with multiple myeloma and renal impairment undergoing autologous hematopoietic cell transplantation. Annals of Hematology. https://doi.org/10.1007/s00277-026-07152-4

Image Credits: AI Generated

DOI: 10.1007/s00277-026-07152-4

Keywords: multiple myeloma, renal impairment, autologous transplantation, melphalan, dialysis, non-relapse mortality, progression-free survival, overall survival, toxicity, intensive care, Brazil, hematopoietic stem cells

The stakes of the review are considerable. Organ fibrosis, the end result of chronically dysregulated tissue repair, is estimated to account for roughly 45 percent of all deaths worldwide, spanning conditions as diverse as idiopathic pulmonary fibrosis, cirrhosis, chronic kidney disease, and post-infarction cardiac scarring. Despite its enormous clinical burden, there are currently no treatments that reliably reverse established fibrosis; existing therapies such as nintedanib, pirfenidone, and resmetirom slow progression at best. By mapping the immune landscape of fibrosis at single-cell and single-cell-location resolution, the review’s authors argue that macrophages represent the most promising lever for precision interventions—and that the field’s failure to exploit their heterogeneity has been a key reason anti-fibrotic drug development has repeatedly stalled.

The technical foundation for this reappraisal is the maturation of single-cell RNA sequencing, single-nucleus RNA sequencing, and spatial transcriptomics. These platforms allow investigators to profile thousands of individual cells from fibrotic tissue, cluster them by their transcriptional identities, and then place those identities back into their anatomical context within the scarred organ. What these tools have revealed is that macrophages within a single fibrotic organ are not a uniform population responding uniformly to inflammation. Instead, they occupy a multidimensional landscape defined by at least four axes: their cellular origin, the stage of disease at which they are sampled, the spatial microenvironment they inhabit, and their ultimate functional output, whether that output is collagen deposition, matrix degradation, or efferocytosis—the clearance of dead cells.

The origin axis is particularly consequential. Tissue-resident macrophages in organs such as the lung, liver, and brain are embryonically derived, seeding tissues during development from yolk sac and fetal liver progenitors and thereafter maintaining themselves locally through self-renewal. In the liver, these resident cells are the Kupffer cells, which patrol the sinusoids and perform surveillance functions honed over a lifetime. By contrast, when injury strikes, bone marrow-derived monocytes flood into the damaged organ in response to chemokine gradients—chiefly the CCL2/CCR2 axis—and differentiate into monocyte-derived macrophages with fundamentally different transcriptional programs. Fate-mapping studies using markers such as Ms4a3 have allowed researchers to distinguish these lineages with precision, and the distinction matters therapeutically: in the lung, monocyte-derived alveolar macrophages have been shown to drive fibrosis and persist in tissue over the lifespan of the animal, whereas resident alveolar macrophages generally perform homeostatic and restorative functions.

Nowhere is the new heterogeneity framework more vividly illustrated than in the identification of SPP1-expressing macrophages. Secreted Phosphoprotein 1, also known as osteopontin, marks a subset of stroma-associated macrophages that the review identifies as a conserved pro-fibrotic end-state across all four organs examined. In the lung, proliferating SPP1/MERTK-expressing macrophages have been documented in idiopathic pulmonary fibrosis. In the kidney, platelet-instructed SPP1-positive macrophages drive myofibroblast activation in a CXCL4-dependent manner. In the heart, spatial multi-omic maps of human myocardial infarction have localized these cells to the infarct border zone, where they sit alongside activated fibroblasts in a self-reinforcing signaling loop. The review’s authors propose that SPP1-positive macrophages, because they recur in fibrotic niches across organ boundaries, could serve as a candidate cross-organ therapeutic axis—meaning a drug developed against this cell type in one organ might conceivably be repurposed for fibrotic diseases elsewhere in the body.

Spatial transcriptomics has been essential to identifying these conserved niches because it reveals not just which cells are present, but where they are relative to their targets. Scar-associated macrophages, for example, are not scattered randomly through fibrotic tissue; they cluster adjacent to myofibroblasts, the collagen-producing workhorses of fibrosis, in spatially restricted niches sustained by growth factors such as macrophage colony-stimulating factor. In the heart, CCR2-positive and CCR2-negative resident macrophages perform distinct roles in orchestrating monocyte recruitment after myocardial injury, and their positioning within the infarct zone versus the border zone correlates with different outcomes for tissue remodeling. The spatial dimension transforms macrophage biology from a cell-autonomous story into an ecological one: macrophages behave differently depending on which neighbors they are talking to.

The review also devotes substantial attention to the metabolic reprogramming that underlies macrophage fate decisions—a dimension of immunology that has accelerated dramatically since the recognition that activated immune cells undergo profound shifts in fuel preference. Classically activated pro-inflammatory macrophages rely on aerobic glycolysis, a Warburg-like metabolic state that prioritizes rapid ATP generation and biosynthetic intermediates over mitochondrial efficiency. The glycolysis–PKM2 axis, in which Pyruvate Kinase Isozyme Type M2 acts as both a metabolic enzyme and a transcriptional co-activator of HIF-1α-driven inflammatory genes, has emerged as a central switch in this process. In the kidney, myeloid PFKFB3-mediated glycolysis has been shown to promote fibrosis, and pharmacological inhibition of PFKFB3 attenuates disease in experimental models. In the heart, temporal changes in glucose metabolism reflect polarization shifts in resident and monocyte-derived macrophages after myocardial infarction, offering a metabolic readout of the transition from inflammatory to reparative phases.

Metabolism does not merely fuel macrophages; it determines what they become. The review highlights how succinate, an intermediate of the tricarboxylic acid cycle, functions as a signaling molecule through its receptor SUCNR1 to induce profibrotic M2-like macrophages in the kidney, yet exerts protective effects on hepatocytes in the context of non-alcoholic fatty liver disease. This context-dependence—where the same metabolite promotes pathology in one organ and protects in another—illustrates why the review’s authors caution against oversimplified cross-organ generalizations even as they identify conserved subsets like SPP1-positive macrophages. Similarly, the c-Rel transcription factor has been shown to orchestrate energy-dependent reprogramming in both epithelial cells and macrophages during fibrosis, linking mitochondrial metabolism to the epigenetic regulation of inflammatory gene expression.

On the therapeutic front, the review surveys an expanding toolkit for manipulating macrophages in fibrotic disease. Rather than depleting all macrophages—a strategy that risks impairing essential homeostatic and reparative functions—emerging approaches aim for precision. Selective depletion of profibrotic macrophages using bioactivated in-vivo self-assembly peptides has been shown to ameliorate kidney fibrosis in experimental models while sparing beneficial populations. Therapeutic silencing of Spp1 specifically within TREM2-positive cardiac macrophages has been demonstrated to suppress atrial fibrillation. Nanoengineered immunosuppressive therapeutics, including dendrimer-graphite nanoparticles and endogenous cell-targeting nanoplatforms, are being explored for their ability to modulate the balance of macrophage phenotypes in situ rather than eliminating cells outright. Reprogramming strategies—shifting macrophage polarization away from profibrotic states using agents such as the FXR agonist resmetirom, which recently completed a Phase 3 trial in metabolic dysfunction-associated steatohepatitis—represent another layer of intervention that exploits metabolic vulnerabilities.

Chemokine axis blockade remains a parallel strategy. The CCR2/CCR5 dual inhibitor cenicriviroc, originally investigated for its ability to reduce inflammatory monocyte recruitment to the liver in steatohepatitis, has been re-examined in the context of COVID-19-associated lung injury, while inhibitors targeting PSMP/MSMP through CCR2 represent novel antifibrotic targets identified in hepatology. The review also underscores the significance of macrophage-to-myofibroblast transition, or MMT, in which macrophages themselves acquire collagen-producing characteristics—a phenomenon documented in renal fibrosis via the neural transcription factor Pou4f1 and in kidney disease through myofibroblast-derived exosomal signaling. Blocking these transdifferentiation pathways, rather than simply modulating polarization, adds a third dimension to the therapeutic landscape.

The authors argue that understanding macrophage heterogeneity as a multidimensional phenomenon—shaped simultaneously by origin, disease stage, spatial context, and metabolic state—will be necessary to design interventions that can navigate this complexity rather than being defeated by it. They highlight that organ-specific macrophage biology remains non-uniform despite the identification of conserved subsets, and that therapeutic strategies calibrated to a single axis of heterogeneity risk incompletely modulating disease. In liver fibrosis, for example, splenocyte-derived macrophages traveling through a spleen–liver axis exacerbate scarring independently of bone marrow-derived recruitment, adding yet another anatomical layer to macrophage origins that must be considered. In lung fibrosis, interstitial macrophages and alveolar macrophages represent distinct compartments with distinct functional roles, and treatments must account for both. In cardiac fibrosis, macrophage-derived CCL24 signaling through fibroblast CCR3 has been identified as a driver of pathological remodeling, while MMP-12-producing Ly6C-low macrophages paradoxically extend post-infarction survival by preventing neutrophil influx—underscoring that macrophages cannot be uniformly classified as friend or foe.

What the review ultimately advances is a conceptual reframing. Fibrosis research has historically sought a single target or a single pathway that could be inhibited across all patients. The single-cell omics era, as synthesized here, argues instead for precision strategies tailored to the specific macrophage subtypes and microenvironmental niches operating in a given patient’s disease at a given stage. The identification of SPP1-positive macrophages as a conserved, targetable, pro-fibrotic end-state across lung, liver, kidney, and heart offers one candidate for such a strategy, while the growing catalog of metabolic checkpoints—PKM2, PFKFB3, SUCNR1, and c-Rel—provides pharmacological handles for shifting macrophage behavior without destroying these essential cells. Whether this framework can be translated into clinical interventions that meaningfully reverse, rather than merely slow, organ fibrosis remains the defining challenge of the next decade of fibrosis research, but the review makes clear that the macrophage, in all its staggering diversity, is now the center of that effort.

The study, led by M.A.J. Morsink, S. Fleischer, T.R. Nash and colleagues, presents what it describes as a practical toolbox for modelling fibrosis outside the body. Rather than treating fibrosis as a single disease, the authors examine the biological features shared across organs while recognizing that each tissue has its own cellular composition, mechanical environment and response to injury. This distinction is critical. A model that reproduces collagen accumulation in a dish may still fail to capture the electrical properties of the heart, the air–liquid interface of the lung, the filtration architecture of the kidney or the specialized immune environment of the liver. Faithful modelling therefore requires more than adding a profibrotic chemical to cultured cells.

At the centre of fibrosis is a complex interaction between injured parenchymal cells, immune cells, vascular cells and fibroblasts. Fibroblasts are connective-tissue cells that normally help maintain the extracellular matrix and support wound healing. During chronic injury, however, they can become activated into myofibroblasts, contractile cells that produce large quantities of collagen and other matrix proteins. Signalling molecules such as transforming growth factor beta are widely associated with this transition, but fibrosis is not controlled by one pathway alone. Cytokines, growth factors, oxidative stress, altered metabolism and signals from damaged cells can all contribute. The review emphasizes that in vitro systems should reproduce this multicellular communication rather than isolate a single cell type from its biological context.

The extracellular matrix itself is not simply a passive scar. Its composition, organization and physical properties can actively direct cell behaviour. As collagen and related proteins accumulate, the tissue becomes stiffer. That mechanical change can activate mechanosensitive pathways, including signalling through integrins and transcriptional regulators such as YAP and TAZ. In turn, cells may produce even more matrix, creating a self-reinforcing cycle in which biochemical and mechanical signals amplify one another. A useful fibrosis model must therefore measure not only the quantity of deposited matrix but also its organization, crosslinking, stiffness and ability to alter cellular function. Techniques such as three-dimensional biomaterials, tunable hydrogels, traction-force measurements and advanced microscopy can help investigators observe these changes in real time.

The authors identify three-dimensional human tissue models as an important bridge between conventional cell culture and animal studies. Two-dimensional cultures are relatively inexpensive and experimentally convenient, but they flatten cells onto artificial surfaces and often expose them to conditions unlike those found in living tissue. Three-dimensional systems can allow cells to adopt more realistic shapes, form tissue-like interfaces and experience gradients of oxygen, nutrients and signalling molecules. Organoids, engineered tissue constructs and organ-on-chip platforms can further introduce fluid flow, vascular-like channels or mechanical stimulation. These features may be especially valuable for modelling organs in which physical forces are central to disease, such as the breathing lung, the beating heart and the continuously perfused kidney.

Human cells are another major advantage of these systems. Primary cells obtained from patients can retain disease-associated characteristics, while induced pluripotent stem cells can be differentiated into several human cell types and combined into more complex models. Patient-derived material may reveal why some individuals develop aggressive fibrosis after injury while others recover with limited scarring. It may also expose differences in drug response that are invisible in genetically uniform laboratory animals or immortalized cell lines. Yet the review cautions that human relevance does not automatically guarantee biological accuracy. Cells can lose their identity during expansion, stem-cell-derived populations may remain immature and donor-to-donor variability can make results difficult to compare. Rigorous characterization is therefore essential.

A major design challenge is deciding which hallmarks of fibrosis a model must reproduce. The review proposes that researchers begin with the biology of the target organ and define measurable criteria before selecting a platform. These criteria may include persistent fibroblast activation, pathological extracellular matrix deposition, tissue stiffening, inflammatory signalling, altered vascular behaviour, epithelial or endothelial dysfunction and loss of organ-specific performance. In a lung model, for example, meaningful fibrosis should involve more than collagen production; it should also reflect changes in epithelial integrity, gas-exchange-related functions and the interaction between airway or alveolar cells and immune populations. In a cardiac model, contractility and electrical activity may be as important as matrix accumulation.

The practical value of a model depends equally on how its results are measured. Traditional endpoint assays can quantify collagen or profibrotic gene expression, but they may miss changes that emerge earlier or disappear by the time a sample is collected. The authors highlight the growing importance of live imaging, single-cell and spatial molecular profiling, secreted-protein analysis, mechanical testing and functional readouts. Combining these methods can reveal which cells initiate fibrosis, how signals move through a tissue and whether a treatment reverses disease-associated function rather than merely suppressing one marker. Standardized reporting of cell sources, matrix composition, culture conditions, disease induction methods and analysis pipelines will also be necessary if results from different laboratories are to be compared.

These models could reshape the search for antifibrotic therapies, a field in which promising laboratory findings have often failed to translate into durable clinical benefits. A well-designed human tissue system could be used to test candidate drugs across several stages of disease, from early inflammatory activation to established matrix remodelling. It might also help distinguish compounds that genuinely restore tissue function from those that simply reduce a biomarker. Because fibrosis frequently involves multiple cell types and feedback loops, future platforms may be particularly useful for evaluating drug combinations and identifying patients most likely to respond. The authors ultimately present in vitro fibrosis modelling not as a replacement for clinical or animal research, but as a complementary technology capable of narrowing the gap between molecular discovery and human disease.

The review’s broader message is that the next generation of fibrosis models should be designed as integrated biological systems rather than as collections of isolated measurements. Researchers will need to combine human cells, organ-specific architecture, immune interactions, extracellular-matrix biology, mechanical forces and functional outputs in a manner that remains experimentally manageable. Advances in microfluidics, biomaterials, imaging and computational analysis could make such systems increasingly precise, while shared standards may improve reproducibility and accelerate adoption beyond specialist laboratories. By defining the hallmarks that matter most and translating them into practical design choices, the authors offer a framework for building models that are not only technically sophisticated but clinically informative. For a disease responsible for progressive organ failure across the world, that shift could turn the laboratory dish into a more powerful window on how scarring begins, persists and might finally be stopped.

Subject of Research: Human in vitro models of fibrosis across multiple organs, including the heart, lung, kidney, liver and synovium.

Article Title: A practical toolbox for modelling fibrosis in vitro

Article References: Morsink, M.A.J., Fleischer, S., Nash, T.R. et al. A practical toolbox for modelling fibrosis in vitro. Nature Biomedical Engineering (2026). https://doi.org/10.1038/s41551-026-01749-w

Image Credits: AI Generated

DOI: https://doi.org/10.1038/s41551-026-01749-w

Keywords: Fibrosis, in vitro models, tissue engineering, extracellular matrix, organoids, organ-on-chip, mechanobiology, human disease modelling, drug discovery, regenerative medicine.