Mitophagy in cisplatin-induced kidney injury: regulatory mechanisms and therapeutic targets

BACKGROUND: Cisplatin is a first-line chemotherapeutic agent widely used in clinical oncology, but its clinical utility is severely limited by cisplatin-induced acute kidney injury (Cis-AKI). Renal tubular epithelial cells (RTECs) are the main target of cisplatin-induced damage, and the pathogenesis involves oxidative stress, inflammatory response, and multiple types of programmed cell death. As a core mitochondrial quality control mechanism, mitophagy is closely related to the above pathological processes, but its overall regulatory network in Cis-AKI remains to be systematically clarified. MAIN BODY: This review systematically summarizes the core pathological mechanisms of cisplatin-induced nephrotoxicity, including mitochondrial dysfunction, oxidative stress, inflammation, apoptosis, pyroptosis, and ferroptosis. It focuses on the molecular pathways of mitophagy (PINK1/PARKIN-dependent and -independent pathways), the bidirectional crosstalk between mitophagy and the aforementioned pathological events, and the dual role of mitophagy in Cis-AKI. In addition, this review collates preclinical progress of mitophagy regulators and their renoprotective effects, and analyzes the current obstacles to clinical translation. CONCLUSION: Mitophagy serves as a key regulatory node in Cis-AKI and can simultaneously ameliorate multiple injury pathways by clearing damaged mitochondria and reducing mtROS. Moderate mitophagy plays a renoprotective role, while excessive mitophagy aggravates renal injury. Targeted and precise regulation of mitophagy is expected to become a new strategy for the prevention and treatment of cisplatin-induced nephrotoxicity.