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

Abstract

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.