Polydatin Alleviated Ischemia–Reperfusion Induced Kidney Injury by Inhibiting SETD2‐Mediated Ferroptosis

ABSTRACT Ferroptosis, an iron‐ and reactive oxygen species (ROS)‐dependent cell death process, plays a key role in acute kidney injury (AKI). Inhibiting ferroptosis has been shown to mitigate AKI severity, highlighting its potential as a therapeutic target. Lysine methyltransferase SETD2 regulates ferroptosis‐related proteins and may serve as a novel target for ferroptosis inhibitors. Polydatin, a resveratrol glucoside derived from Polygonum cuspidatum , has demonstrated protective effects in septic‐induced AKI, but its role in ischemia–reperfusion‐induced AKI remains unclear. This study investigates whether Polydatin protects against ischemia–reperfusion‐induced AKI in mice and explores the underlying mechanisms. A mouse AKI model was established by clamping renal pedicles for 30 min, followed by Polydatin (40, 80 mg/kg) administration 1 h before injury. Renal function was assessed via serum creatinine (SCr) and blood urea nitrogen (BUN) levels, alongside histopathological analyses. RNA sequencing identified potential mechanisms, and molecular docking examined Polydatin's interaction with SETD2. ChIP‐qPCR was used to assess SETD2‐mediated regulation of ACSL4 via H3K36me3 modification. SETD2 knockout mice were utilized to validate Polydatin's protective mechanism. Polydatin significantly improved renal function, reducing SCr, BUN, and injury biomarkers (NGAL, KIM‐1). In vitro, it alleviated hypoxia/reoxygenation injury in HK‐2 cells. Mechanistically, Polydatin inhibited ferroptosis by targeting SETD2, as confirmed by RNA sequencing and molecular docking. SETD2 overexpression negated Polydatin's benefits, while knockout enhanced protection. Polydatin protects against ischemia–reperfusion‐induced AKI by inhibiting ferroptosis through SETD2 modulation, highlighting its potential for AKI treatment.