The review, led by Leyu Ai, Huirong Wu, and colleagues, synthesizes a rapidly expanding body of evidence linking lactylation—a posttranslational modification first reported in 2019 by Yingming Zhao’s team—to regulated cell death (RCD), the family of programmed cell death pathways that includes apoptosis, ferroptosis, pyroptosis, PANoptosis, and NETosis. The central thesis is striking: when sepsis forces cells into a glycolytic metabolic state, the resulting lactate surge doesn’t just accumulate harmlessly. It is converted into lactyl-coenzyme A, which competes with acetyl-CoA for the same lysine residues on histones and nonhistone proteins, shifting the entire cellular acylation landscape toward lactylation and away from acetylation.

The mechanistic logic is elegant. Under healthy conditions, oxidative phosphorylation dominates glucose metabolism, generating abundant acetyl-CoA that drives lysine acetylation—the prevailing protein modification. Enzymes like the bifunctional acyltransferase AARS1 show a marked kinetic preference for acetyl-CoA: its Michaelis constant for acetyl-CoA is roughly 80 micromolar, compared with approximately 36 millimolar for lactyl-CoA, meaning the enzyme’s affinity for the acetyl substrate is orders of magnitude higher. But sepsis flips this balance. Hypoxia-inducible factor-1α upregulates lactate dehydrogenase A, while phosphorylation of the pyruvate dehydrogenase complex by PDK1/4 suppresses acetyl-CoA production. The resulting lactyl-CoA flood overwhelms the enzymatic threshold, allowing lactylation to seize dominance at shared modification sites.

Clinical data support this model. In a prospective cohort of 86 critically ill patients, serum lactate levels correlated positively with H3K18la—a histone lactylation mark at lysine 18 of histone H3—while H3K18ac levels fell. The H3K18la/ac ratio correlated with disease severity scores (APACHE II and SOFA), ICU length of stay, and duration of mechanical ventilation, suggesting the modification ratio itself may serve as a biomarker. Earlier work by Chu and colleagues found H3K18la highest in septic shock patients, correlating with inflammatory cytokines and macrophage polarization markers.

But the review’s most provocative contribution lies in mapping how these lactylation marks regulate cell death across organs. In sepsis-associated acute kidney injury—which affects up to 66 percent of septic patients—elevated H3K18la in renal tubular epithelial cells activates the RhoA/ROCK pathway and the Ezrin-MYD88-IRAK1-NF-κB inflammatory cascade, driving apoptosis. Nonhistone lactylation compounds the damage: excessive acetylation and inactivation of PDHA1 leads to lactate overproduction, which then induces lactylation of the mitochondrial fission protein Fis1 at lysine 20, triggering excessive mitochondrial fragmentation and tubular cell death.

In the lung, the picture is equally complex. Histone lactylation at H3K18 promotes alveolar epithelial apoptosis through at least two routes: it upregulates caspase-8, amplifying TNF-α-mediated pro-apoptotic signaling, and it drives EGR1 transcription and nuclear import, degrading the endothelial glycocalyx barrier. Meanwhile, lactylation regulates ferroptosis—iron-dependent lipid peroxidation-driven cell death—through multiple histone marks. H3K14la-mediated transcription upregulates the transferrin receptor TFRC and downregulates SLC40A1, creating iron overload that catalyzes reactive oxygen species via the Fenton reaction. H3K18la enriches at the promoters of ACSL4 and LC3, increasing polyunsaturated fatty acid content and promoting ferritinophagy. A protective feedback loop also exists: elevated H3K14la upregulates PARK7, which restores FADS1/2 enzyme activity and activates the NRF2/KEAP1 antioxidant pathway, suppressing ferroptosis.

Pyroptosis—inflammatory cell death executed by gasdermin pore formation—is another major target. Lactate entering macrophages via monocarboxylate transporter 1 is converted by AARS2 into lactyl-CoA, which mediates site-specific lactylation of NLRP3 at lysines 24 and 565. This modification promotes recruitment of the adaptor protein ASC and assembly of the NLRP3 inflammasome, activating caspase-1, cleaving GSDMD, and releasing mature IL-1β. In the brain, H3K18la upregulates YTHDF3, which stabilizes NLRP3 via the deubiquitinase USP9X, triggering microglial pyroptosis and neuroinflammation. In the kidney, H3K18la activates SPHK1, which phosphorylates and degrades SIRT1—disrupting both a delactylase feedback loop and mitochondrial homeostasis, creating a vicious cycle that amplifies pyroptotic injury.

Perhaps most intriguingly, the review documents bidirectional regulation. In macrophages, MCT1-dependent lactylation of ZBP1 disrupts its interaction with RIPK1/TRIF, promoting ZBP1 degradation and blocking ZBP1-mediated PANoptosis—thereby alleviating lung injury. Conversely, lactylation of CIRP promotes its nuclear-to-cytoplasmic translocation and exosomal release, which endothelial cells internalize via TLR4, stabilizing ZBP1 and enhancing PANoptosis in pulmonary epithelial cells. The same modification, acting on different substrates in different cell types, can either protect or destroy.

The authors also highlight autophagy as a newly identified lactylation target with bidirectional effects. During the hyperinflammatory phase, neutrophil-derived lactate drives H3K18la-mediated upregulation of ATG7, initiating nondegradative secretory autophagy that releases IL-1β and damages pulmonary endothelium. During the immunosuppressive phase, impaired glycolytic reprogramming reduces lactate production, lowering H3K18la and attenuating transcription of ATG5 and ATG16L1—crippling macrophage autophagic flux and bactericidal capacity, thereby promoting immune paralysis.

What emerges is a systems-level view: sepsis is not simply a cytokine storm or a circulatory collapse, but a global epigenetic reprogramming event in which metabolic flux dictates protein modification state, which in turn dictates cell fate. The review proposes that glucose metabolic flux distribution serves as a critical regulatory node—determining not only overall levels of acetylation and lactylation but also their spatiotemporal specificity. Multiorgan metabolomic studies showing enhanced metabolic coupling among abdominal organs, with decoupling of heart and skeletal muscle, suggest that systemic metabolic fluctuations may reshape lactylation profiles across organs simultaneously, mediating synchronous multiorgan injury before clinical dysfunction is detectable.

The clinical implications are substantial but preliminary. Existing lactylation research remains largely confined to single-center observational biomarker studies with small cohorts. No interventional clinical trials targeting the lactylation pathway have been reported. The enzyme kinetic data supporting the acylation competition model derive from in vitro purified systems; subcellular compartmentalization and cofactor microenvironments may reshape actual catalytic preferences in vivo. The lactate concentration threshold that drives modification preference shifts in bifunctional acyltransferases has not been systematically defined.

Artificial intelligence may accelerate the field. Deep learning tools like DeepKla can predict lysine lactylation sites with 93.22 percent accuracy. AI-driven multiomics frameworks have stratified patients into LDHA-high and LDHA-low subtypes with distinct prognoses, achieving sensitivity of 0.922 and precision of 0.955 in predicting lactylation-driven therapeutic responses. In pyroptosis research, a Transformer model trained on 40,000 protein interface data points generated the SK56 peptide, which specifically blocks the GSDMD-NT pore, delaying pyroptosis and alleviating inflammation. The review proposes an integrated multimodal model combining early sepsis warning, lactylation site identification, and RCD pathway intervention—a full-chain system spanning early detection through precision targeting.

Ultimately, the lactylation–RCD axis offers a fundamentally new therapeutic logic for sepsis. Rather than nonspecifically lowering systemic lactate, future strategies may target cell-selective metabolic intervention: modulating lactate synthesis or lactyl-CoA generation in specific cell subtypes to restore intracellular lactylation to physiological homeostatic range, thereby blocking RCD-mediated parenchymal organ injury while preserving myeloid pathogen clearance and immune defense. The field remains in its infancy, but the convergence of epigenetics, cell death biology, and artificial intelligence suggests that the humble lactate molecule—long dismissed as a metabolic dead end—may hold the key to rewriting the outcome of one of humanity’s deadliest syndromes.

Subject of Research: Sepsis, lactylation, regulated cell death, epigenetics, metabolic reprogramming

Article Title: Recent advances in research on the association between lactylation and regulated cell death in sepsis

Article References: Ai, L., Wu, H., Huang, W., Zhang, Y., Ma, Y., Wu, D., Chen, J., Fang, X., Liu, C., Wang, P., Cheng, W., Fu, H., Yin, W., Shen, K., & Li, J. (2026). Recent advances in research on the association between lactylation and regulated cell death in sepsis. Journal of Advanced Research. https://doi.org/10.1016/j.jare.2026.10.026

Image Credits: AI Generated

DOI: 10.1016/j.jare.2026.10.026

Keywords: sepsis, lactylation, regulated cell death, apoptosis, ferroptosis, pyroptosis, PANoptosis, NETosis, epigenetics, metabolic reprogramming, H3K18la, lactate

Wilms tumor, also known as nephroblastoma, arises in the developing kidney and accounts for the vast majority of pediatric renal malignancies. More than 90 percent of children are diagnosed with the favorable-histology form, but outcomes vary considerably across patient cohorts. The picture is far grimmer for the 5 to 10 percent of cases classified as high-risk—including metastatic blastemal-type tumors, diffuse anaplastic disease, chemotherapy-refractory tumors, and multiply relapsed cancers—which carry survival rates below 50 percent even after aggressive multimodal therapy. Survivors of intensive radiochemotherapy frequently endure severe long-term side effects that diminish their quality of life. These realities have long motivated researchers to search for molecular vulnerabilities that could enable more individualized and less toxic treatments.

The new study began with a well-known hallmark of cancer: metabolic reprogramming. Tumor cells preferentially break down glucose into lactate even when oxygen is abundant, a phenomenon called the Warburg effect, leading to lactate buildup in the tumor microenvironment. Previous metabolomics work had already flagged elevated lactate as a signature distinguishing Wilms tumor tissue from normal kidney tissue, and a retrospective cohort study showed that higher lactate dehydrogenase activity independently predicts increased recurrence risk in pediatric patients. The research team confirmed these patterns directly, analyzing 52 pairs of Wilms tumor specimens and matched adjacent normal tissues collected at Qilu Hospital of Shandong University. Tumor tissues contained significantly less glucose and significantly more lactate than their normal counterparts, consistent with hyperactive glycolysis.

Lactate, once dismissed as a mere metabolic waste product, is now understood to be a versatile molecule that serves as an energy substrate, a signaling agent, and—critically—an epigenetic regulator. In 2019, researchers first identified histone lactylation as a novel epigenetic modification that directly modulates gene transcription on chromatin. Since then, histone lactylation has been implicated in immune evasion, metabolic reprogramming, and therapeutic resistance across many cancers. The process is enzyme-dependent: the acetyltransferase p300 acts as a writer that deposits lactyl groups onto histones, while HDAC1-3 and sirtuins serve as erasers that remove them. Because these same enzymes also manage histone acetylation, the two modifications share overlapping machinery, raising the possibility that lactylation plays an important but overlooked role in Wilms tumor biology.

Using immunohistochemistry and western blotting on the clinical specimens, the team found that pan-lysine lactylation and H3K18 lactylation were the most prominently elevated modifications in tumor tissue. Survival analysis showed that only high levels of these two marks correlated with significantly poorer event-free survival among the 52 patients studied. To probe function, the researchers manipulated lactylation levels in two Wilms tumor cell lines, WiT49 and WT-CLS1, using sodium lactate to raise intracellular lactate and the glycolysis inhibitors 2-deoxy-D-glucose and oxamate to lower it. The results were striking: boosting lactylation enhanced cell proliferation and migration in a dose-dependent manner, while suppressing lactylation markedly reduced these malignant behaviors.

To identify the genes controlled by H3K18 lactylation, the team integrated public ChIP-seq datasets with RNA-sequencing data from 126 Wilms tumor patients in the TARGET database. Cross-referencing genes bound by the H3K18la mark with genes upregulated in tumors yielded 302 candidates, which were then filtered through Cox regression analyses of patient survival data. Three genes emerged with independent prognostic significance: PSRC1, RFXAP, and GLRX3. Only PSRC1, however, responded specifically to changes in lactylation levels—its mRNA rose with sodium lactate treatment and fell with oxamate. Chromatin immunoprecipitation experiments confirmed that H3K18la was robustly enriched at the PSRC1 promoter in Wilms tumor cells, and that the writer enzyme p300 was required for this deposition. Importantly, the closely related acetylation mark H3K18ac remained unchanged across all treatments, demonstrating that p300 regulates PSRC1 specifically through lactylation rather than acetylation.

PSRC1 itself proved to be a potent oncogenic driver. The protein, also known as DDA3, is a mitotic regulator previously implicated in small cell lung cancer, breast cancer, and hepatocellular carcinoma. In Wilms tumor, high PSRC1 expression predicted poorer overall survival, with area under the curve values of 0.71 to 0.73 for one-, three-, and five-year survival predictions, and multivariate analysis confirmed it as an independent prognostic risk factor. Mechanistically, the team discovered that PSRC1 acts as a molecular competitor: it binds directly to the kinase domain of AKT through its proline-rich P-X-X-P domain spanning amino acids 103 to 246, thereby blocking the tumor suppressor PTEN from binding AKT and dephosphorylating it. Co-immunoprecipitation, mass spectrometry, immunofluorescence, and molecular docking—all supporting a stable interaction with a binding free energy of minus 28.4 kilocalories per mole—confirmed the competitive binding model. The consequence is sustained activation of the AKT/mTOR pathway, which stabilizes the HIF-1α protein, a master transcription factor that promotes glycolysis and tumor growth.

The final piece of the puzzle closed the loop. HIF-1α, stabilized by PSRC1-driven AKT signaling, was found to bind directly to a hypoxia response element within the PSRC1 promoter, further amplifying PSRC1 transcription. Dual-luciferase reporter assays demonstrated that hypoxia increased promoter activity only when the response element was intact, and HIF-1α knockdown blunted this activation. The result is a positive feedback circuit: H3K18 lactylation activates PSRC1, PSRC1 activates AKT/mTOR/HIF-1α signaling, and HIF-1α returns to boost PSRC1 expression, creating an escalating cycle of oncogenic signaling. Animal experiments corroborated the entire axis in vivo. In nude mouse xenograft models, PSRC1 knockdown slowed tumor growth and reduced lung metastatic burden, while PSRC1 overexpression accelerated growth, promoted lung colonization, and partially reversed the tumor-suppressive effects of oxamate, which was administered daily at 500 milligrams per kilogram.

The therapeutic implications are considerable, though tempered by practical challenges. The authors highlight three promising intervention points: inhibiting lactate production with agents such as oxamate, which has shown antitumor activity and low toxicity in preclinical models but suffers from poor membrane permeability that nanoparticle delivery could overcome; targeting the writer enzyme p300 with inhibitors such as CCS1477, which has advanced to phase I/II clinical trials in other cancers; and disrupting the feedback loop itself through AKT/mTOR inhibitors, peptide inhibitors designed to block the PSRC1-AKT interaction interface, or HIF-1α inhibitors. Each strategy faces hurdles, including systemic toxicity, the heightened safety requirements of pediatric oncology, and the risk that single-target inhibition will be undermined by the very feedback loop the study describes. The authors also note limitations: the clinical cohort was relatively small, genetically engineered animal models were not used, and the identity of the eraser enzymes that remove H3K18 lactylation in Wilms tumor remains unknown.

Nevertheless, the study represents the first demonstration of a histone lactylation-driven feedback circuit in Wilms tumor and bridges three previously separate domains—metabolic reprogramming, epigenetic modification, and oncogenic signaling. By showing that a metabolic byproduct can be converted into a durable transcriptional program that fuels cancer progression, the work adds Wilms tumor to the growing list of malignancies shaped by lactylation and provides a molecular rationale for combining metabolic inhibitors with signaling blockade. For the children with high-risk disease who currently face the bleakest odds, such rational combination strategies may ultimately offer a path toward more effective and less toxic therapy.

Subject of Research: Histone H3K18 lactylation and the PSRC1/AKT/HIF-1α feedback loop in Wilms tumor progression

Article Title: Histone H3K18 Lactylation Promotes the Malignant Progression of Wilms Tumor via a PSRC1/AKT/HIF‐1α Positive Feedback Loop

Article References: Wang, Y., Gao, H., Zhang, B., Li, X., Li, D., Cao, A., & Sun, F. (2026). Histone H3K18 Lactylation Promotes the Malignant Progression of Wilms Tumor via a PSRC1/AKT/HIF‐1α Positive Feedback Loop. Advanced Science, 13(56), Article e76579. https://doi.org/10.1002/advs.76579

Image Credits: AI Generated

DOI: 10.1002/advs.76579

Keywords: Wilms tumor, histone lactylation, H3K18la, PSRC1, AKT signaling, HIF-1α, p300, PTEN, Warburg effect, epigenetics, pediatric cancer, metabolic reprogramming

The centerpiece of the new work is a chemical modification called lactylation, a relatively recent addition to the catalog of post-translational modifications that biologists use to describe how proteins are tuned after they are made. Lactylation attaches a lactate-derived group to lysine residues, the same amino acid building blocks that carry many other regulatory marks. What makes this modification special is its origin: lactate is the end product of the fermentation metabolism that cancer cells rely on heavily even when oxygen is plentiful, a phenomenon known as aerobic glycolysis or the Warburg effect. Tumors therefore bathe their surroundings in lactate, and lactylation provides a direct mechanism by which this metabolic byproduct can be converted into epigenetic and proteomic instructions that reshape cell behavior.

To map the full landscape of this modification in liver cancer, the team carried out global lactylome profiling, using liquid chromatography-tandem mass spectrometry to identify precisely which proteins in hepatocellular carcinoma tissue carry lactylation marks and at which lysine positions. This unbiased survey was complemented by RNA sequencing, lipidomics to quantify the repertoire of fats and sterols inside tumors, and single-cell RNA sequencing to place the molecular findings within the complex cellular ecosystem of the tumor. The researchers also generated customized site-specific antibodies, tools that recognize lactylation at a single defined amino acid position on a single protein, allowing them to detect and manipulate one specific mark among thousands.

Two distinct lactylation events emerged as the critical nodes of the pathway. The first occurs on histone H3, one of the spool-like proteins around which DNA is wound. When lysine 18 of histone H3 is lactylated, a mark known as H3K18la, it acts on chromatin the way an open sign acts on a shop door: it makes nearby genes accessible for transcription. In this case, the gene switched on by H3K18 lactylation encodes METTL3, methyltransferase-like 3, the catalytic engine of the cell’s N6-methyladenosine machinery. m6A is the most abundant internal chemical modification of messenger RNA in mammals, and METTL3 is the enzyme that installs it. By raising METTL3 production through histone lactylation, the tumor effectively turns up the dial on RNA methylation across the cell.

The second event is more unusual and more conceptually striking. METTL3 itself, a protein rather than a stretch of DNA, is lactylated at lysine 27. This non-histone lactylation of METTL3 enhances its enzymatic activity, so the very methyltransferase whose production was boosted by histone lactylation is simultaneously activated by lactylation of its own structure. The result is a feed-forward arrangement in which lactate amplifies the m6A-writing apparatus at two independent levels. Once supercharged, METTL3 deposits m6A marks onto the messenger RNA of a specific target: FDFT1, farnesyl-diphosphate farnesyltransferase 1, the enzyme that catalyzes the first committed step of the cholesterol biosynthesis pathway, converting farnesyl pyrophosphate into squalene.

m6A marks on RNA do not act alone. They are read by a family of recognition proteins that determine the fate of the tagged transcript. The study identified IGF2BP2, insulin-like growth factor 2 mRNA-binding protein 2, as the reader that recognizes the METTL3-installed marks on FDFT1 messenger RNA. Rather than destroying the transcript, IGF2BP2 stabilizes it and promotes its translation into protein. The net effect of the entire cascade is a surge in FDFT1 protein, a surge in de novo cholesterol synthesis, and, as the lipidomics data confirmed, enhanced cholesterol efflux from the tumor cells into the surrounding microenvironment. Cholesterol, in this scenario, is not merely a building block for membranes; it functions as a signaling metabolite that reprograms neighboring immune cells.

The destination of that cholesterol signal is the tumor-associated macrophage, one of the most influential cell types in the tumor microenvironment. Macrophages are plastic cells that adopt distinct functional states: M1-like macrophages tend to attack tumors and rally anti-tumor immunity, whereas M2-like macrophages suppress immune responses, promote tissue remodeling, and support tumor growth. Using spontaneous orthotopic hepatocellular carcinoma mouse models, in which tumors arise in the liver and grow in their natural anatomical location, together with humanized orthotopic models carrying human immune cells, the researchers demonstrated that the cholesterol-rich environment driven by the lactylation cascade pushes tumor-associated macrophages toward the immunosuppressive M2 phenotype. Flow cytometry confirmed the shift in macrophage polarization states within the tumors.

The clinical implications of this mechanism are considerable. An immunosuppressive macrophage population is one of the central reasons why checkpoint inhibitor therapies underperform in liver cancer: even when T cells are unleashed, they enter a microenvironment thick with M2-polarized macrophages and other suppressive elements. By tracing that suppression back to a defined molecular axis, the H3K18la/METTL3-K27la/FDFT1 pathway, the study converts a diffuse problem into a set of addressable targets. Inhibiting lactate production or lactylation enzymes, blocking METTL3 activity, disrupting the IGF2BP2-FDFT1 interaction, or intervening in cholesterol biosynthesis and efflux each represents a potential point of attack, and combining such interventions with existing immunotherapy could theoretically relieve the immunosuppression that currently blunts treatment responses.

Methodologically, the study is notable for the breadth of its toolkit and the rigor of its validation. The investigators moved from unbiased lactylome discovery to mechanistic confirmation using methylated RNA immunoprecipitation to verify m6A deposition on FDFT1 transcripts, RNA immunoprecipitation to confirm the IGF2BP2 interaction, and chromatin-level analyses to establish the H3K18la-driven transcriptional activation of METTL3. The animal work was conducted under institutional ethics approval and in accordance with ARRIVE guidelines 2.0, and the human tissue component, which collected hepatocellular carcinoma specimens and paired peritumoral tissue from surgical patients with written informed consent, was approved by the Ethics Committee of The First Affiliated Hospital of Zhengzhou University. The authors declared no competing interests, and the work received support from the National Natural Science Foundation of China and the Key Scientific Research Projects of Universities in Henan Province.

Beyond its immediate relevance to liver cancer, the research adds an important conceptual layer to a rapidly growing field. Lactylation was first described as a histone mark linking cellular metabolism to gene expression, but evidence has been accumulating that non-histone proteins are also extensively lactylated. This study is among the first to show, in a single connected pathway, how histone lactylation and non-histone lactylation cooperate: one mark turns a gene on, the other activates the protein that gene encodes, and the combined output rewires lipid metabolism to corrupt the immune landscape of a tumor. It is a vivid demonstration that metabolites can act as messengers across entirely different layers of biological regulation, from chromatin to RNA to lipid chemistry to immune cell behavior. For patients with hepatocellular carcinoma, whose options remain limited despite decades of effort, the identification of this lactylation-cholesterol-macrophage axis offers a genuinely new direction, one that treats the tumor’s metabolic exhaust not as waste but as the fuel of a communication network that medicine may now learn to cut.

Subject of Research: Lactylation-regulated cholesterol metabolic reprogramming and macrophage polarization in hepatocellular carcinoma

Article Title: Lactylation-regulated METTL3-mediated cholesterol metabolic reprogramming via FDFT1 facilitates macrophage polarization in hepatocellular carcinoma

Article References: Zhai, Y., Zhao, H., Wang, Z., Zhang, Y., Zhao, S., Wang, C., Liu, Y., Cao, J., Lin, C., Wu, Y., Liang, R., Zhu, R., Wang, W., Li, J., & Sun, Y. (2026). Lactylation-regulated METTL3-mediated cholesterol metabolic reprogramming via FDFT1 facilitates macrophage polarization in hepatocellular carcinoma. Journal of Translational Medicine. https://doi.org/10.1186/s12967-026-08870-z

Image Credits: AI Generated

DOI: 10.1186/s12967-026-08870-z

Keywords: hepatocellular carcinoma, lactylation, METTL3, m6A methylation, FDFT1, cholesterol metabolism, macrophage polarization, tumor microenvironment, IGF2BP2, H3K18la, immunosuppression, tumor-associated macrophages

Ulcerative colitis is a chronic inflammatory bowel disease characterized by relentless damage to the colonic epithelium, the single-cell-thick barrier that separates the body from the trillions of microbes in the gut lumen. When this barrier fails, bacterial products flood the underlying tissue, immune cells respond, and a vicious cycle of inflammation and tissue erosion follows. For years, researchers have known that ulcerative colitis involves profound metabolic reprogramming, but the question of how those altered metabolic fluxes actually translate into epithelial injury has remained frustratingly incomplete. The new work, led by Daowei Yang, Tiantian Wang, and Jianwei Zhu with senior authors Rong Wang, Xiaolei Zhu, Sheng Zhou, and Jianhua Zou, set out to close that gap by interrogating the axis connecting metabolism, epigenetics, and ferroptosis directly in human tissue, mouse models, and cultured intestinal epithelial cells.

The team began with transcriptomic profiling of biopsy samples from ulcerative colitis patients, comparing them against healthy donor tissue, and then extended the analysis to mice given dextran sulfate sodium, a chemical that induces colitis and is a standard model of the human disease. Across both systems, a consistent picture emerged: the inflamed epithelium had undergone a glycolytic shift, the metabolic pivot in which cells ramp up glucose fermentation even in the presence of oxygen. A hallmark of this shift was elevated expression of hexokinase-2, or HK2, the enzyme that commits glucose to the glycolytic pathway, accompanied by a striking accumulation of lactate, the end product of fermentation. Lactate, once dismissed as a mere metabolic byproduct, has in recent years been recast as a signaling molecule, and this study adds a dramatic new chapter to that story.

The central molecular player in the new findings is ACSS2, short for acyl-CoA synthetase short-chain family member 2. This enzyme is best known for its role in converting acetate into acetyl-CoA, but the researchers demonstrated that in the lactate-rich environment of the inflamed colon, ACSS2 also converts lactate into lactyl-CoA. That metabolite is the essential substrate for histone lactylation, a chemical modification of histone proteins, the spools around which DNA is wound. Using CUT&Tag, a technique that maps where specific histone modifications sit across the genome, along with immunodetection methods, the team showed that lactate-derived lactyl-CoA drives lactylation of histone H3 at lysine 18, a mark abbreviated H3K18la, on the promoters of specific genes in the epithelial cells.

Here is where the feedback loop closes with almost engineered precision. The genes upregulated by the H3K18 lactylation mark include HK2, the very enzyme that fuels glycolysis and lactate production; ACSS2 itself, the enzyme that converts lactate into the epigenetic substrate; and ACSL4, acyl-CoA synthetase long-chain family member 4, an enzyme long recognized as a decisive driver of ferroptosis because it channels polyunsaturated fatty acids into membrane phospholipids, the raw material that iron-catalyzed peroxidation attacks. In other words, lactate produced by glycolysis activates an epigenetic program that commands the cell to make more glycolytic machinery, more lactate-processing enzyme, and more ferroptosis-sensitizing lipid chemistry. Each turn of the loop amplifies the next, progressively raising the epithelium’s susceptibility to lipid peroxidation and ferroptotic death.

The pathological consequences of this loop were visible throughout the disease models. Increased ferroptotic markers coincided with disruption of tight junctions, the protein seals between adjacent epithelial cells that give the gut barrier its integrity. As epithelial cells succumbed to ferroptosis, the barrier opened, inflammation deepened, and the tissue damage characteristic of ulcerative colitis advanced. The researchers also found support for a ferroptosis transcriptional program in public gene-expression datasets from ulcerative colitis patients, reinforcing the clinical relevance of the mouse and cell findings. The convergence of metabolic shift, epigenetic rewriting, and cell death execution in the same tissue samples makes a compelling case that these processes are not parallel phenomena but causally linked stages of a single disease mechanism.

To test causality directly, the team generated mice lacking Acss2 specifically in the intestinal epithelium, rather than throughout the body. When these animals were subjected to the dextran sulfate sodium colitis model, the results were striking: histone H3K18 lactylation was dampened, ACSL4 expression fell, epithelial cell viability was preserved, and colonic injury was attenuated. Importantly, the epithelium-specific deletion did not cause spontaneous abnormalities in the colon, suggesting that ACSS2 becomes pathologically relevant chiefly under inflammatory, lactate-rich conditions rather than serving an indispensable housekeeping role in healthy gut tissue. The team also traced the loop to its upstream source, identifying c-Myc, a master transcription factor and notorious oncogene, as a common activator of the program, and showed that pharmacological inhibition of c-Myc similarly suppressed the ACSS2/H3K18la/ACSL4 axis and protected the epithelium.

Perhaps the most translationally exciting element of the study is the delivery technology. Systemic administration of small interfering RNA against ACSS2 faces an obvious obstacle: getting RNA drugs into the right cells without collateral effects. The researchers engineered a butyrate-modified lipid nanoparticle, or BLNP, a delivery vehicle decorated with butyrate, a short-chain fatty acid that is naturally consumed by intestinal epithelial cells and is known to be beneficial for colonic health. When administered systemically in the colitis mice, these nanoparticles delivered ACSS2 siRNA to the epithelium, effectively knocked down the enzyme, reversed colitis pathology, restored tight junction integrity, and reduced ferroptotic injury, all without overt toxicity as judged by standard biosafety measures including liver and kidney function markers. Using the gut’s own preferred fuel as a homing beacon for a therapeutic nanoparticle is an elegant design choice that could influence how RNA drugs are targeted to the intestine more broadly.

The implications reach well beyond a single enzyme in a single disease. Histone lactylation has been implicated in macrophage polarization, tumor biology, and fibrosis, but this study is among the clearest demonstrations that the mark can function as a metabolic feedback amplifier that actively worsens tissue injury rather than merely reporting on metabolic state. By linking a disease-associated metabolic shift to a specific epigenetic mark and then to a specific mode of cell death, the work provides a template for dissecting how metabolic intermediates sculpt chromatin in other inflammatory conditions. It also elevates ACSS2 from a metabolic housekeeping enzyme to a mechanistically central and druggable node in inflammatory bowel disease. The authors conclude that targeting the lactate-fueled ACSS2/H3K18la axis represents a promising strategy to restore mucosal homeostasis, and with a working nanoparticle delivery system already validated in vivo, the path from this feedback loop to a clinical candidate may be shorter than usual. For the millions of people living with ulcerative colitis, a disease in which current therapies suppress immunity without always halting barrier destruction, the idea that a metabolic waste product can be disarmed before it rewrites the genome of gut cells is a genuinely new and hopeful direction.

Subject of Research: The role of ACSS2-dependent histone lactylation in a metabolic feedback loop driving ferroptotic epithelial injury in ulcerative colitis

Article Title: ACSS2-dependent histone lactylation amplifies ferroptotic injury via a metabolic feedback loop in ulcerative colitis

Article References: Yang, D., Wang, T., Zhu, J., Lu, Y., Shen, R., Chen, Y., Zou, J., Zhou, S., Zhu, X., & Wang, R. (2026). ACSS2-dependent histone lactylation amplifies ferroptotic injury via a metabolic feedback loop in ulcerative colitis. Genome Medicine. https://doi.org/10.1186/s13073-026-01786-9

Image Credits: AI Generated

DOI: 10.1186/s13073-026-01786-9

Keywords: ulcerative colitis, histone lactylation, ferroptosis, ACSS2, H3K18la, lactate, metabolic feedback loop, intestinal epithelial cells, lipid nanoparticles, inflammatory bowel disease, HK2, ACSL4

The story begins with lactate, a molecule long dismissed as little more than a metabolic waste product. Cancer cells famously consume enormous amounts of glucose and ferment it into lactate even in the presence of oxygen, a phenomenon known as aerobic glycolysis or the Warburg effect. In 2019, researchers discovered that lactate is not merely discarded; it can be chemically attached to lysine amino acids on proteins, including the histones around which DNA is wound. This modification, called lactylation, can loosen chromatin and activate gene expression, effectively allowing a metabolic byproduct to rewrite the instructions a cell follows. Since that discovery, scientists have raced to determine which lactylation marks matter most in which cancers, and whether blocking them could stall tumor progression.

In the new study, a research team led by Chuang Fu and Zhi-Zhou Shi of Kunming University of Science and Technology focused on a specific mark: lactylation at lysine 18 of histone H3, abbreviated H3K18la, in head and neck squamous cell carcinoma, or HNSCC. The team first showed that hypoxia, the oxygen-starved conditions typical of solid tumors, increased both H3K18la levels and the abundance of EGFR, the epidermal growth factor receptor that is a major therapeutic target in this disease. Single-cell RNA sequencing analysis of patient-derived data revealed a high-lactylation state within HNSCC cells, confirming that the modification is a prominent feature of the tumor landscape rather than a laboratory artifact.

To test whether this mark actually drives malignant behavior, the researchers manipulated lactylation pharmacologically. When they treated HNSCC cells with 2-deoxyglucose, a compound that blocks glycolysis, or with oxamate, an inhibitor of lactate dehydrogenase that prevents lactate production, the cells proliferated more slowly and formed fewer colonies. Critically, adding lactate back into the culture medium reversed these effects, restoring the cells’ growth advantage. This gain-and-loss evidence established that lactate availability, funneled into histone lactylation, directly supports the proliferative engine of the cancer cells, rather than being an incidental byproduct of their altered metabolism.

The next challenge was identifying which genes the mark actually controls. The team combined RNA sequencing, which measures gene expression, with CUT&Tag, a technique that maps where specific histone modifications sit along the genome. The integrated analysis revealed that H3K18 lactylation was strongly enriched at the locus encoding GLI2, a transcription factor best known as a downstream effector of the Hedgehog signaling pathway. The lactylation mark at the GLI2 locus was associated with transcriptional activation, meaning the epigenetic tag was literally switching on a potent pro-growth gene. Functional experiments confirmed the point: knocking down or inhibiting GLI2 suppressed HNSCC cell proliferation and colony formation, while overexpressing GLI2 promoted those same malignant phenotypes.

Having identified the mark and one of its key targets, the researchers asked which enzyme writes it. Attention turned to CBP, a well-known histone acetyltransferase that had previously been implicated as a lactyltransferase in other contexts. Molecular docking simulations predicted a binding interaction between CBP and the lactylated H3K18 mark, and co-immunoprecipitation experiments confirmed that the two proteins physically associate. When the team knocked down CBP, or treated cells with the CBP inhibitor SGC-CBP30 or the compound C646, H3K18la levels fell, GLI2 expression dropped, and HNSCC cells lost much of their capacity to proliferate and form colonies. In short, CBP emerged as the writer of the lactylation mark that sustains the GLI2 program.

The most clinically consequential part of the study concerns EGFR-targeted therapy. Drugs such as gefitinib and cetuximab, which block EGFR signaling, are standard options for subsets of HNSCC patients, but resistance frequently develops and limits their long-term benefit. The researchers found that EGFR itself sits upstream of the lactylation machinery: knocking down EGFR, or treating cells with gefitinib or cetuximab, reduced global protein lactylation, lowered H3K18la, and suppressed GLI2 expression. EGFR inhibition also decreased intracellular lactate concentrations and reduced glucose uptake, suggesting that EGFR signaling feeds the glycolytic flux that generates the lactate substrate for histone modification. Mechanistically, the team showed that EGFR binds to and stabilizes GLUT3, a glucose transporter, thereby helping the cancer cells maintain their sugar supply and, by extension, their lactylation program.

This wiring suggested a strategy: if the lactylation-GLI2 axis helps tumors survive EGFR blockade, then disabling that axis should resensitize them to the drugs. That is precisely what the experiments showed. Inhibitors acting on the H3K18la-GLI2 axis made HNSCC cells more vulnerable to both gefitinib and cetuximab in culture. More strikingly, in mouse xenograft models derived from CAL27 HNSCC cells, combining the CBP inhibitor SGC-CBP30 with gefitinib greatly improved the anti-tumor effects of the EGFR drug compared with either agent alone. The team also established gefitinib-resistant HNSCC cell lines and found that the H3K18la-GLI2 axis was activated in the resistant cells, and that blocking the pathway overcame that resistance. Together, these results position histone lactylation not just as a marker of aggressive disease but as an actionable driver of therapeutic failure.

The implications extend beyond head and neck cancer. Histone lactylation has now been implicated in multiple tumor types and in inflammatory and fibrotic diseases, and the identification of a defined writer-enzyme, mark, and target-gene cascade gives researchers a concrete axis to interrogate in other settings where EGFR inhibitors are used, including lung cancer. The study also highlights the value of pairing metabolic interventions with epigenetic drugs: because the lactylation mark depends on glycolysis-derived lactate, combinations that attack both the metabolic supply line and the epigenetic reader-writer machinery may prove more effective than either approach alone. Compounds such as 2-deoxyglucose and SGC-CBP30 are experimental tools rather than approved therapies, so translating these findings into the clinic will require careful dose-finding, safety evaluation, and biomarker development.

For patients with HNSCC, whose treatment options narrow sharply once EGFR-targeted agents stop working, the research offers a mechanistic explanation for resistance and a rational combination strategy to test in future trials. The work, funded by programs in Yunnan Province, China, and conducted under approved animal ethics protocols, exemplifies a broader shift in cancer biology: the recognition that the chemical state of chromatin is not fixed but is continuously shaped by the metabolic environment of the tumor. As lactylation research matures, the dream of turning a cancer cell’s own waste product against it, by blocking the enzymes that convert that waste into a growth-promoting epigenetic signal, moves one step closer to reality.

Subject of Research: Histone H3K18 lactylation in head and neck squamous cell carcinoma progression and EGFR-targeted therapy resistance

Article Title: CBP-mediated H3K18 lactylation drives GLI2 transcription to promote progression and EGFR-targeted therapy resistance in head and neck squamous cell carcinoma

Article References: Fu, C., Zhang, X.-G., Li, W.-T., Jiang, W., Fan, S.-C., & Shi, Z.-Z. (2026). CBP-mediated H3K18 lactylation drives GLI2 transcription to promote progression and EGFR-targeted therapy resistance in head and neck squamous cell carcinoma. Journal of Translational Medicine. https://doi.org/10.1186/s12967-026-09049-2

Image Credits: AI Generated

DOI: 10.1186/s12967-026-09049-2

Keywords: histone lactylation, H3K18la, head and neck squamous cell carcinoma, EGFR, GLI2, CBP, gefitinib resistance, lactate, GLUT3, epigenetics, targeted therapy, cancer metabolism

Mesenchymal stem cells, or MSCs, are the workhorses of cell-based repair. Harvested from bone marrow or fat, they secrete factors that calm inflammation, encourage angiogenesis, and limit the destructive remodeling that follows a myocardial infarction. Yet clinical trials in ischemic heart disease have produced frustratingly inconsistent results, and the new study points to a likely culprit: senescence. Donor age and the replicative stress of the large-scale expansion needed to produce clinically useful cell numbers both push MSCs into a senescent state, robbing them of the proliferative capacity, migratory behavior, and paracrine output that make them therapeutic in the first place. The harsh, oxygen-starved environment of an infarcted heart can then induce premature senescence in the transplanted cells themselves, further eroding any benefit.

The researchers began with an epidemiological puzzle. Asprosin, encoded by the FBN1 gene that also produces the structural protein fibrillin-1, is known to rise with obesity, driving hepatic glucose release in younger organisms. But when the team measured circulating asprosin in aged mice, they found that despite significant age-related weight gain, levels failed to rise, and aged animals even developed the impaired glucose tolerance that young obese mice display alongside high asprosin. Public transcriptomic datasets revealed why: Fbn1 expression declines with age across a remarkable range of tissues, including white adipose tissue, heart, lung, skeletal muscle, and skin, with the attrition more pronounced in males. Western blotting confirmed matching reductions in asprosin protein in fat, heart, and muscle across young, middle-aged, and old mice.

The human evidence proved equally compelling. In a cohort of 95 normal-weight men, recruited with an a priori power calculation to control for the confounding effect of adiposity, fasting plasma asprosin showed a significant negative correlation with age, with a Spearman coefficient of -0.374. Aging, in other words, appears to override the adiposity-driven regulation that dominates asprosin levels in youth. Single-cell RNA sequencing data from mice, rats, and humans then revealed something unexpected: MSCs, not mature adipocytes, are the dominant FBN1-expressing cell type across fat, muscle, and bone marrow. Pseudotime trajectory analysis showed FBN1 expression falling steadily as multipotent progenitors commit to differentiated lineages, tying the hormone directly to stemness itself. Both chronically aged and acutely senescent MSCs, the latter produced by hydrogen peroxide treatment, showed coordinated declines in Fbn1 transcription, intracellular asprosin, and secreted asprosin.

To test whether asprosin actively governs senescence rather than merely tracking it, the team built CRISPR-Cas9 lentiviral vectors targeting the furin cleavage site within the Fbn1 gene, selectively ablating the hormone while preserving fibrillin-1’s structural role. Asprosin-deficient young MSCs proliferated poorly and, when challenged with hydrogen peroxide, accumulated in the G1 phase of the cell cycle, stained heavily for senescence-associated beta-galactosidase, lost clonogenic potential, and under high oxidative stress underwent increased apoptosis. The mirror-image experiment was more dramatic: overexpressing human asprosin in aged MSCs restored proliferation, pushed cells back into S phase, reduced senescence markers, and enhanced colony formation. Recombinant asprosin produced in human cells, at concentrations from 10 nanograms per milliliter up to 10 micrograms per milliliter without cytotoxicity, reproduced these effects across mouse bone marrow cells, mouse fat-derived cells, and human adipose-derived stem cells.

The mechanism traces through metabolism. Gene set enrichment analysis of asprosin-treated senescent MSCs showed activation of the PI3K-AKT and HIF-1 signaling pathways and a strong enrichment of glycolysis-related gene sets, with no change in oxidative phosphorylation. Seahorse metabolic flux assays confirmed that asprosin raised the extracellular acidification rate, basal glycolysis, and compensatory glycolytic capacity, while lactate production rose and was abolished by the glycolysis inhibitor 2-deoxyglucose. Asprosin upregulated the glucose transporter GLUT1 and rate-limiting enzymes including hexokinase 2 and the phosphofructokinases PFKL and PFKP. Pharmacological inhibition of AKT with MK2206 or of HIF-1alpha with KC7F2 blocked every one of these metabolic shifts, and either inhibitor, or 2-deoxyglucose, erased asprosin’s boosts to proliferation and migration. Notably, mTOR stayed inactive, indicating that asprosin works through a signaling route distinct from classical growth factor pathways. Intriguingly, the proangiogenic paracrine effect, driven by elevated VEGF-A and TIMP-1, depended on AKT-HIF-1 signaling but not on glycolysis itself.

That distinction between bioenergetics and gene regulation is where the study’s most novel layer emerges. Lactate, the end product of glycolysis, is now known to serve as a substrate for histone lactylation, a recently discovered post-translational modification in which lactate is covalently attached to lysine residues on histone proteins. The team showed that asprosin treatment increased global lysine lactylation and, specifically, lactylation of histone H3 at lysine 18, or H3K18la, in senescent MSCs, mirroring the effect of exogenous lactate. Blocking lactate production with sodium oxamate or inhibiting the p300 writer enzyme with A485 abolished both the H3K18la increase and the functional rejuvenation. CUT&Tag sequencing then mapped the epigenetic landscape: asprosin broadened H3K18la deposition genome-wide, and 70 percent of the genes it upregulated carried promoter-associated H3K18la marks. Among the targets were genes governing cell cycle progression and migration, and, critically, a network of DNA repair and replication fidelity genes, including Mcm8, Nucks1, Recql, Grwd1, and Foxp1, whose promoters gained H3K18la enrichment. When asprosin was knocked out, hydrogen peroxide-induced DNA double-strand breaks, marked by gamma-H2AX foci, worsened and repair faltered.

The therapeutic payoff came in a mouse model of acute myocardial infarction. Senescent MSCs transduced with an asprosin-overexpressing lentivirus, or with an empty vector, were injected into the infarct border zone. Immunofluorescent quantification on days 3 and 7 showed significantly higher retention of the asprosin-engineered cells. Over 28 days, mice receiving asprosin-overexpressing MSCs survived at higher rates than untreated infarct controls, while the empty-vector cells conferred no survival benefit. Echocardiography revealed improved left ventricular ejection fraction only in the asprosin group, which also showed reduced heart-to-lung and heart-to-body weight ratios, smaller fibrotic areas on Masson’s trichrome staining, and increased numbers of CD31-positive endothelial and alpha-SMA-positive smooth muscle cells in the peri-infarct zone, indicating robust new vessel formation.

The authors frame their intervention as a third way beyond existing anti-senescence strategies. Senolytics clear damaged cells, and NAD-boosting compounds offer generic metabolic support, but asprosin instead performs what they call functional reprogramming: it directly reverses the senescent state by activating a specific glycolysis-H3K18la axis, restoring a regenerative phenotype without deleting the cells or merely nourishing them. The team also showed that asprosin’s bioactivity depends on post-translational modifications present only in eukaryotic production systems, as bacterially derived protein failed to elicit the same transcriptional response, a caution for any future pharmaceutical development. Significant hurdles remain before clinical translation: the murine infarct model does not capture the comorbidities of human patients, lentiviral overexpression carries a theoretical insertional mutagenesis risk that local, cell-based delivery is designed to minimize, and the MSC-specific asprosin receptor has yet to be identified. Still, with efficacy demonstrated across species, tissue sources, and a broad safe concentration range, asprosin-engineered stem cells now stand as one of the most mechanistically complete rejuvenation strategies yet described, and a promising enhancement partner for the next generation of cardiac cell therapy.

Subject of Research: Asprosin-driven metabolic and epigenetic rejuvenation of senescent mesenchymal stem cells for cardiac repair after myocardial infarction

Article Title: Asprosin-driven metabolic-epigenetic rewiring attenuates mesenchymal stem cell senescence with therapeutic benefits for infarcted hearts

Article References: Zhang, Z., Wang, Z., Zhu, L., Chen, T., Chen, R., Wu, Z., Chen, J., Zhang, H., Wang, M., Liu, J., Hua, N., Hu, S., & Chen, Y. (2026). Asprosin-driven metabolic-epigenetic rewiring attenuates mesenchymal stem cell senescence with therapeutic benefits for infarcted hearts. Journal of Advanced Research, 88, 1055-1075. https://doi.org/10.1016/j.jare.2026.01.073

Image Credits: AI Generated

DOI: 10.1016/j.jare.2026.01.073

Keywords: asprosin, mesenchymal stem cells, senescence, histone lactylation, H3K18la, glycolysis, myocardial infarction, FBN1, epigenetics, cardiac repair, regenerative medicine, HIF-1alpha