ZXDB Drives Macrophage Inflammatory Programming in Sepsis‐Induced Acute Kidney Injury by Recruiting EIF4A3 to Enhance ACACA Translation

Macrophage-driven inflammation is central to the pathogenesis of sepsis-induced acute kidney injury (SI-AKI), yet the role of RNA-binding proteins (RBPs) in post-transcriptionally regulating this process remains elusive. Here, we identify the RBP zinc finger X-linked duplicated B (ZXDB) as an upstream contributor to SI-AKI by promoting a pathogenic, pro-inflammatory macrophage activation state. We found that ZXDB expression is consistently elevated in M1-like macrophages within the kidney during SI-AKI, where it stimulates pro-inflammatory cytokine secretion and glycolytic reprogramming. Mechanistically, we discovered that ZXDB directly interacts with EIF4A3, a core exon junction complex (EJC) DEAD-box RNA helicase, via its aa151-300 region, thereby enhancing ACACA 5'UTR-dependent translation of ACACA, a metabolic enzyme that mediates downstream pathogenic effects associated with ZXDB activation. Critically, macrophage-specific deletion of Zxdb attenuated disease severity in a mouse model of SI-AKI, preserving renal function and attenuating inflammation. Taken together, our study uncovers a novel ZXDB-EIF4A3-ACACA axis that orchestrates macrophage-mediated kidney injury through translational control of metabolism, thereby suggesting ZXDB as a potential therapeutic candidate for SI-AKI.