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Background Hypoxic inflammation is a hallmark of ulcerative colitis (UC). Intestinal epithelial cells, serving as the first line of the mucosal barrier and immune defense, play a pivotal role in the pathogenesis of UC. Hypoxia-inducible factor-2 α (HIF-2α), a central regulator of hypoxia-responsive transcription, is upregulated in UC. However, the role of HIF-2α in colitis remains unclear.Methods HIF-2 α levels were measured in UC patients and murine colitis models, and their association with disease activity was analyzed. The role of HIF-2α in UC progression was then evaluated using intestinal epithelial cell–specific knockout mice and in vitro pharmacological inhibition. Next, lactate, histone lactylation, and related regulatory enzymes were quantified in samples from UC patients and epithelial HIF-2α–deficient mice. CUT&Tag and RNA-seq were performed to identify histone lactylation–regulated target genes and pathways, with ChIP-qPCR validation. Finally, candidate HIF-2α–targeting small molecules were screened by integrating traditional Chinese medicine databases with molecular docking, and their in vivo anti-colitis efficacy was compared with a selective HIF-2α inhibitor.Results We identify a previously unrecognized role for histone lactylation in colitis driven by HIF-2 α–dependent lactate accumulation. HIF-2α is markedly upregulated in colonic tissues from patients with UC and in experimental colitis models, and its expression level was positively correlated with disease severity (IDDF2026-ABS-0082 Figure 1). Functionally, intestinal epithelial cell–specific ablation or pharmacological inhibition of HIF-2α significantly ameliorates colitis, whereas HIF-2α activation or exogenous lactate supplementation exacerbates disease progression (IDDF2026-ABS-0082 Figure 2). Mechanistically, intestinal epithelial HIF-2α deficiency reduces lactate dehydrogenase A (LDHA) and lactate levels, thereby decreasing global histone lactylation and histone H3 lysine 27 lactylation (H3K27la). Multi-omics integration shows that loss of HIF-2α markedly diminishes H3K27la enrichment at the MAP3K6 promoter and dampens p38 MAPK inflammatory signaling, resulting in reduced cytokine expression and alleviated inflammation. Likewise, LDHA inhibition lowers lactate and suppresses the inflammatory response (IDDF2026-ABS-0082 Figure 3). Moreover, high-throughput virtual screening identifies (-)-alkannin as a natural HIF-2α inhibitor. (-)-Alkannin disrupts H3K27la-driven inflammatory signaling and effectively attenuates colitis (IDDF2026-ABS-0082 Figure 4).Conclusions Collectively, our findings establish the HIF-2 α-H3K27la-p38 MAPK axis as a critical driver of UC progression and provide a novel potential therapeutic target (IDDF2026-ABS-0082 Figure 5. Mechanism diagram).Abstract IDDF2026-ABS-0082 Figure 1Abstract IDDF2026-ABS-0082 Figure 2Abstract IDDF2026-ABS-0082 Figure 3Abstract IDDF2026-ABS-0082 Figure 4Abstract IDDF2026-ABS-0082 Figure 5