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Lactate-derived lactylation, a novel post-translational modification, has been implicated in various pathological processes by modulating gene transcription. However, the molecular mechanisms by which lactate and lactylation contribute to the pathogenesis of AP remain incompletely understood. An in vivo model of AP was established by intraperitoneal injection of L-arginine. Changes in both Pan- and histone-specific lysine lactylation levels were assessed using western blotting and immunofluorescence. The effects of exogenous lactate supplementation or inhibition of lactate production on pancreatic injury, inflammation, and ferroptosis were evaluated. Target genes regulated by H3K18 lactylation (H3K18la) during ferroptosis were identified through CUT&amp;Tag, RNA sequencing (RNA-seq), ChIP-qPCR, and luciferase reporter assays. For NCOA4 knockdown, AAV-sh-NCOA4 and NCOA4-specific siRNA were utilized. In an in vitro AP model using AR42J pancreatic acinar cells treated with various drugs and siRNA, mitochondrial membrane potential (MMP), intracellular ferrous iron, and reactive oxygen species (ROS) levels were measured. Lactate levels in AP were significantly elevated and positively correlated with inflammation and pancreatic tissue injury. Both Pan- and histone lysine lactylation, particularly H3K18la, were significantly increased. H3K18la was markedly enriched at the NCOA4 promoter region. Exogenous lactate increased H3K18la expression, elevated ferrous iron and ROS levels, reduced MMP in pancreatic acinar cells, thereby promoting ferroptosis, exacerbating inflammation, and aggravating pancreatic tissue injury. However, lactate production inhibition exerted the opposite effects. The activity of NCOA4 promoter was enhanced by Lac-Na, but suppressed by si-EP300 and oxamate. Knockdown of NCOA4 using either AAV-sh-NCOA4 or si-NCOA4 effectively alleviated lactate-promoted ferroptosis, inflammation, and pancreatic injury. Our findings suggest that lactate and H3K18la exacerbate inflammation and tissue injury in AP by modulating NCOA4-mediated ferroptosis. These findings provide novel insights into the molecular mechanisms underlying AP pathogenesis.<\/jats:p>","DOI":"10.1007\/s10753-025-02361-x","type":"journal-article","created":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T18:04:44Z","timestamp":1767031484000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Lactate and H3K18 Lactylation Contribute To the Exacerbation of Acute Pancreatitis by Modulating NCOA4-mediated Ferroptosis"],"prefix":"10.1007","volume":"49","author":[{"given":"Zi-Yu","family":"Han","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue-Ying","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shi-Ya","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhao-jian","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhong-Hua","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-Li","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,29]]},"reference":[{"key":"2361_CR1","doi-asserted-by":"publisher","first-page":"382","DOI":"10.1001\/jama.2020.20317","volume":"325","author":"MA Mederos","year":"2021","unstructured":"Mederos, M.A., H.A. 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