<scp>TRPML1</scp> in Cisplatin‐Induced Acute Kidney Injury: A New Target for Renal Tubular Epithelial Protection by Regulating Lysosomal Calcium Homeostasis

Acute kidney injury (AKI) is a global health concern with various etiologies, including ischemia-reperfusion injury, sepsis, and nephrotoxic agents such as cisplatin. Cisplatin-induced nephrotoxicity is associated with lysosomal damage, but the underlying mechanisms remain unclear. This study aimed to elucidate the role of lysosomal damage in cisplatin-induced cell death in tubular epithelial cells (TECs). AKI models were induced using cisplatin both in vivo and in vitro. Mouse kidney morphology and function were assessed using biochemical assays, immunohistochemistry, and histological staining techniques such as HE, PAS, and TUNEL. RNA sequencing analysis and pharmacological interventions were used to investigate the specific mechanism in cisplatin-induced TECs injury. The distribution and expression of lysosomes and calcium (Ca²⁺) were measured through immunofluorescence staining, Western blotting, and confocal microscopy. RNA sequencing analysis revealed a notable role of Ca²⁺ signaling pathways in cisplatin-induced nephrotoxicity. We demonstrated that cisplatin exposure induced significant lysosomal abnormalities, including altered distribution, morphology, and increased Ca²⁺ leakage. This dysregulation of lysosomal Ca²⁺ homeostasis was closely correlated with TECs apoptosis. Mechanistically, we show that lysosome Ca²⁺ release activates calcineurin, thereby triggering apoptosis in TECs. Preliminary data indicate that inhibiting lysosomal Ca²⁺ release through targeting TRPML1 may mitigate cisplatin-induced AKI. Our study reveals a lysosomal Ca²⁺-calcineurin pathway that contributes to cisplatin-induced nephrotoxicity and offers potential therapeutic targets.