ZNRF2 integrates ubiquitination-driven ferroptosis and mitochondrial quality control in renal ischemia–reperfusion injury

Renal ischemia–reperfusion injury (RIRI) is characterized by a surge of oxidative stress, lipid peroxidation, and mitochondrial dysfunction, leading to ferroptotic tubular cell death and renal impairment. Recent findings implicate ZNRF2, a RING-type E3 ubiquitin ligase localized to the endo‑lysosomal membrane, as a central regulator that integrates ubiquitin-mediated signaling, ferroptosis susceptibility, and mitochondrial quality control (MQC) pathways. In this review, we synthesize current evidence on ZNRF2’s structural features, ubiquitination targets (e.g., GPX4, SLC7A11, NCOA4), and its modulation of key MQC processes—DRP1-driven mitochondrial fission, PINK1–Parkin–mediated mitophagy, and lysosomal clearance via mTORC1/TFEB axis. We propose a temporal model aligning ischemia and reperfusion phases with specific redox and cell-death events, and highlight testable hypotheses such as ZNRF2’s control over GPX4 stability or ferritinophagy dynamics. Moreover, we discuss therapeutic perspectives, including pharmacological modulators of ZNRF2 activity (small‑molecule stabilizers, PROTACs), and timing-based intervention windows. This integrated mechanistic framework advances understanding of RIRI pathogenesis and opens avenues for novel redox-targeted therapeutic strategies.