Daphnetin alleviates cisplatin-induced acute kidney injury by inhibiting the HIF-1α signaling pathway

Cisplatin-induced acute kidney injury (AKI) limits its clinical use, and effective renoprotective agents are lacking. Daphnetin (DAP), a natural coumarin, exhibits anti-inflammatory and antioxidant properties, but its role and mechanism in cisplatin nephrotoxicity remain unclear. This study investigates whether DAP protects against cisplatin-induced renal tubular injury and elucidates the involvement of the HIF-1α signaling pathway. A rat model of cisplatin-induced AKI and an in vitro HK-2 cell injury model were used. Renal function, histopathology, injury markers (KIM-1, NGAL), inflammatory cytokines (TNF-α, IL-1β, IL-6, TGF-β), cell viability, proliferation, apoptosis, and HIF-1α expression were assessed. Bioinformatics analysis and rescue experiments using the HIF-1α activator ML228 were performed. DAP significantly ameliorated cisplatin-induced renal dysfunction, pathological damage, and inflammatory responses in rats. In HK-2 cells, DAP enhanced viability and proliferation, reduced apoptosis, and downregulated KIM-1, NGAL, and pro-inflammatory cytokines. HIF-1α protein and mRNA level was upregulated by cisplatin, and DAP reversed this effect. Bioinformatics and KEGG analysis identified the HIF-1 pathway as the most enriched. Activation of HIF-1α by ML228 abolished DAP's protective effects, confirming the pathway's critical role. DAP alleviates cisplatin-induced AKI by inhibiting the HIF-1α signaling pathway. This natural compound represents a promising candidate for preventing chemotherapy-related renal injury.