CO-CHAPERONE P23 INHIBITS FERROPTOSIS IN SEPSIS-ASSOCIATED ACUTE KIDNEY INJURY BY REGULATING GPX4 STABILITY

Ferroptosis, an iron-dependent form of regulated cell death, has been implicated in severe kidney diseases, particularly those characterized by the depletion of GPX4. Despite its clinical significance, the molecular mechanisms driving GPX4 reduction in SA-AKI remain poorly understood. In this study, we uncover a novel regulatory axis involving the RNA-binding protein P23 and GPX4 mRNA stability in SA-AKI pathogenesis. Using integrated in vivo and in vitro models, we demonstrate that P23 expression is significantly upregulated during SA-AKI and functions as a critical suppressor of ferroptosis. Mechanistically, pharmacological inhibition of P23 with celastrol exacerbated renal dysfunction and amplified ferroptotic damage, as evidenced by elevated lipid peroxidation, iron overload, and GPX4 downregulation. Conversely, P23 overexpression robustly attenuated ferroptosis by stabilizing GPX4 mRNA, thereby preserving GPX4 protein levels and redox homeostasis. Crucially, RIP and Co-immunoprecipitation assays revealed that P23 directly binds to GPX4 mRNA and protein, forming a protective complex that impedes mRNA degradation and ferroptotic cascades. These findings establish P23 as a multifunctional regulator of ferroptosis and highlight its RNA-binding activity as a therapeutically targetable mechanism for mitigating SA-AKI. Our work provides a foundation for developing P23-centric interventions to combat ferroptosis-driven kidney injury in sepsis.