DDX3x Regulates NINJ1 Transcription via Histone Lactylation in Sepsis Associated‐Acute Kidney Injury

Abstract

Sepsis associated-acute kidney injury (SA-AKI), a severe complication of sepsis, is characterized by impaired tubular injury that can ultimately cause renal failure and patient mortality. Both histone and non-histone lactylation and cellular PANoptosis have been implicated in the pathogenesis of SA-AKI. In this study, we investigated how lactylation in histone H3 at lysines 9, 18, and 27 (H3K9/18/27la) modulates PANoptosis in SA-AKI. Our findings revealed that lactate triggers PANoptosis by promoting H3K9/18/27la through the activation of Ninjurin-1 (NINJ1) gene transcription in SA-AKI. Notably, NINJ1, a membrane protein, is also lactylated at residues K111 (K111la) and K114 (K114la) in lipopolysaccharides (LPS)-induced HK-2 cells. NINJ1-K111la mediates plasma membrane localization, thereby promoting cell death. Notably, we identified DEAD (Asp-Glu-Ala-Asp)-box 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 ligation and puncture (CLP) mice or LPS-induced HK-2 cells significantly reduced H3K9/18/27la levels, inhibited NINJ1 transcription and PANoptosis, and alleviated SA-AKI 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-AKI.