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