Abstract

Acute kidney injury (AKI) is a clinically significant syndrome characterized by a rapid decline in renal function, affecting over 50% of patients in intensive care units. Ferroptosis, a recently identified form of regulated cell death, is driven by iron-dependent lipid peroxidation and has been implicated in AKI pathogenesis. Emerging evidence suggests that lipophagy – a selective autophagic degradation of lipid droplets – potentiates ferroptosis, though the upstream regulatory mechanisms remain poorly understood. ESRRA (estrogen related receptor, alpha), a key transcriptional regulator of fatty acid metabolism and macroautophagy/autophagy, may play a critical role in this process. In this study, we identified ESRRA as a pivotal transcription factor in proximal tubular epithelial cells using single-cell transcriptomic analysis. To investigate its functional role, we employed wild-type mice and tubular epithelial cell-specific Esrra deficient mice to establish AKI models. Our findings demonstrated that ESRRA exerted a protective effect by modulating the RAB7-dependent lipophagy-ferroptosis axis. Furthermore, integrating chromatin Immunoprecipitation (ChIP)-seq and JASPAR database analyses, we predicted PIK3CA as a direct transcriptional target of ESRRA. Mechanistically, ESRRA bind to a specific promoter region within Pik3ca, enhancing its expression and subsequently activating the AKT-MTOR signaling pathway, which is required for the suppression of RAB7 mediated lipophagy in renal tubular epithelial cells, thereby attenuating AKI progression.Abbreviations: ACSL4: acyl-CoA synthetase long-chain family member 4; AKI: acute kidney injury; AKT/PKB: Akt serine/threonine kinase; ChIP: chromatin Immunoprecipitation; Cis-AKI: cisplatin-induced acute kidney injury; CI-AKI: contrast-induced acute kidney injury; ER: endoplasmic reticulum; ESRRA: estrogen related receptor, alpha; FFAs: free fatty acids; FA-AKI: folic acids-induced acute kidney injury; GPX4: glutathione peroxida