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Both histone and non\u2010histone lactylation and cellular PANoptosis have been implicated in the pathogenesis of SA\u2010AKI. In this study, we investigated how lactylation in histone H3 at lysines 9, 18, and 27 (H3K9\/18\/27la) modulates PANoptosis in SA\u2010AKI. Our findings revealed that lactate triggers PANoptosis by promoting H3K9\/18\/27la through the activation of Ninjurin\u20101 (NINJ1) gene transcription in SA\u2010AKI. Notably, NINJ1, a membrane protein, is also lactylated at residues K111 (K111la) and K114 (K114la) in lipopolysaccharides (LPS)\u2010induced HK\u20102 cells. NINJ1\u2010K111la mediates plasma membrane localization, thereby promoting cell death. Notably, we identified DEAD (Asp\u2010Glu\u2010Ala\u2010Asp)\u2010box helicase 3x (DDX3x), a previously unreported delactylase capable of regulating H3K9\/18\/27la levels, which influences NINJ1 transcription and PANoptosis. Furthermore, we developed Odetiglucan (Ode), a novel agonist targeting DDX3x delactylase function. Application of Ode in cecum\u00a0ligation\u00a0and\u00a0puncture (CLP) mice or LPS\u2010induced HK\u20102 cells significantly reduced H3K9\/18\/27la levels, inhibited NINJ1 transcription and PANoptosis, and alleviated SA\u2010AKI progression. In summary, DDX3x, function as a delactylase, regulates PANoptosis by influencing H3K9\/18\/27la. Thus, enhancing the delactylase activity of DDX3x may represent a potential therapeutic strategy for SA\u2010AKI.<\/jats:p>","DOI":"10.1002\/advs.76979","type":"journal-article","created":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T12:11:21Z","timestamp":1786968681000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["DDX3x Regulates NINJ1 Transcription via Histone Lactylation in Sepsis Associated\u2010Acute Kidney Injury"],"prefix":"10.1002","author":[{"given":"Hongyu","family":"Liang","sequence":"first","affiliation":[{"name":"Department of Anesthesiology Ruijin Hospital Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jihong","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology Shanghai General Hospital Shanghai Jiao Tong University School of Medicine  Shanghai 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