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

Ulcerative colitis (UC) is marked by profound metabolic reprogramming and intestinal epithelial barrier breakdown. However, how altered cellular metabolism contributes to epithelial injury remains incompletely understood. Recent evidence suggests that metabolic intermediates can drive epigenetic modifications, but their role in regulating ferroptosis in UC has not been fully elucidated. We integrated transcriptomic profiling of UC patient biopsies, dextran sulfate sodium (DSS)–induced mouse colitis models, and in vitro stimulation of intestinal epithelial cells (IECs) to explore the metabolic/epigenetic/ferroptosis axis. Histone lactylation was assessed via CUT&Tag and immunodetection. Functional studies employed intestinal epithelium-specific Acss2 knockout mice and a butyrate-modified lipid nanoparticle (BLNP) system for targeted delivery of ACSS2 siRNA. Pharmacological inhibition of c-Myc, a common upstream transcriptional activator, was also evaluated. Human UC tissues and DSS-treated mice showed a glycolytic shift with elevated HK2 expression and lactate accumulation. Lactate was converted by ACSS2 into lactyl-CoA, promoting histone H3K18 lactylation (H3K18la). This modification upregulated HK2, ACSS2, and ACSL4, establishing a lactate-responsive feedback program that increased epithelial susceptibility to lipid peroxidation and ferroptotic injury. Increased ferroptotic markers coincided with tight junction disruption in UC models. Genetic ablation of Acss2 or c-Myc inhibition dampened H3K18la, reduced ACSL4 expression, and preserved IEC viability. Moreover, systemic administration of ACSS2 siRNA via BLNPs effectively reversed colitis pathology, restored tight junction integrity, and reduced ferroptotic injury, without overt toxicity. Our findings identify a lactate-fueled ACSS2/H3K18la-associated feedback program as an amplifier of ferroptosis-prone epithelial injury in UC. Targeting this axis represents a promising therapeutic strategy to restore mucosal homeostasis. These results highlight ACSS2 as a mechanistic and translationally relevant target in inflammatory bowel disease.