Xanthenone Orchestrates the Renin–Angiotensin System/Ferroptosis Crosstalk: A Novel AT2R‐Dependent Strategy Against Lower Limb Transient Ischemia‐Induced Liver Injury

Abstract

ABSTRACT Lower limb transient ischemia (LLTI)‐induced hepatic injury is intricately linked to redox disequilibrium, inflammation, and emerging modalities of regulated cell death, including ferroptosis. The renin–angiotensin system (RAS), particularly its non‐canonical arm, has been implicated in tissue protection, yet its crosstalk with ferroptosis remains underexplored. This study investigated the hepato‐therapeutic potential of xanthenone (XNT), an ACE2 activator, in a LLTI‐induced liver injury model, with a focus on the Ang‐(1–9)/AT2R axis and ferroptosis regulation. Accordingly, male Wistar rats were subjected to LLTI and treated with XNT, with or without the AT2R antagonist PD123319. Hepatic function, oxidative stress markers, ferroptotic signals, and RAS components were assessed using molecular modeling, biochemical, and histopathological techniques. XNT improved liver architecture and reduced ALT/AST levels to confer hepatoprotection. Mechanistically, XNT shifted RAS signaling to the protective ACE2/Ang‐(1–9)/AT2R pathway, leading to suppression of Ang‐II and enhancement of Ang‐I/Ang‐(1–9) contents. This shift activated the AKT/Nrf2/HO‐1 antioxidant cascade and restored homeostasis of the central anti‐ferroptotic system SLC7A11/GSH/GPX4, inhibited ACSL4 expression, thereby reducing ROS, and lipid peroxidation. Importantly, XNT also mitigated ferroptosis by downregulating Fe 3+ /TfR1, Fe 2+ , and ferritin accumulation, while modulating the ferritinophagy axis through upregulation of HERC2 and suppression of NCOA4. These effects were largely abolished by PD123319, indicating AT2R dependency. In conclusion, XNT protects against LLTI‐induced hepatic injury by orchestrating a dual antioxidant and anti‐ferroptotic response via the Ang‐(1–9)/AT2R axis. These findings unveil a novel crosstalk between RAS modulation and ferroptosis regulation, positioning AT2R activation as a promising therapeutic strategy for ischemia/reperfusion‐related liver damage.