Regulation of sepsis-associated acute kidney injury by ELAVL1 through USP14/NCOA4-mediated ferroptosis in renal tubular epithelial cells.

Sepsis-associated acute kidney injury (SA-AKI) is a serious complication of sepsis, characterized by elevated morbidity and mortality rates. Understanding the underlying mechanism is essential for the development of effective therapies. The aim of this study was to investigate the role and mechanism by which ELAVL1 modulates SA-AKI. The cecal ligation and puncture (CLP) mouse model and LPS-induced HK-2 cells were utilized to investigate the regulatory role of ELAVL1 in ferroptosis and kidney damage. RNA immunoprecipitation (RIP) and RNA pull-down assays were performed to analyze the interaction between ELAVL1 and USP14. Additionally, Co-IP and IP/ubiquitination assays were conducted to investigate the interaction between USP14 and NCOA4. Knockdown of ELAVL1 significantly reduced serum creatinine and BUN levels, and histological analysis revealed less tubular damage in septic mice. Moreover, the knockdown of ELAVL1 decreased lipid peroxidation (MDA), intracellular iron (Fe²⁺), LDH, and 4-HNE levels, while increasing GSH and GPX4 levels in CLP mice. In LPS-treated HK2 cells, ELAVL1 knockdown also inhibited ferroptosis. Mechanistically, ELAVL1 bound to USP14 mRNA, enhancing its stability and expression, which in turn stabilized NCOA4 via deubiquitination. Overexpression of USP14 or NCOA4 partially mitigated the inhibitory effects of ELAVL1 knockdown on ferroptosis-related markers in LPS-stimulated HK2 cells, including MDA, Fe²⁺, GSH, LDH, GPX4, lipid ROS, and cell viability. Targeting the ELAVL1/USP14/NCOA4 axis effectively reduces ferroptosis and alleviates SA-AKI, offering a promising therapeutic strategy for sepsis-induced kidney damage.