Research on the Mechanism of Cisplatin-induced Apoptosis and Methods to Alleviate Its Toxicity

Cisplatin is used as a first-line chemotherapy drug in the treatment of various malignancies, but its clinical application is severely limited by dose-limiting toxicities that affect the kidneys, gastrointestinal tract, lungs, and auditory system. Current studies have elucidated the multifactorial mechanisms behind these toxicities, including mitochondrial dysfunction mediated by oxidative stress, DNA damage-induced apoptosis, and dysregulated cell death crosstalk (such as ferroptosis and necroptosis), as well as organ-specific accumulation regulated by transporters such as OCT2 and CTR1. However, the synergy between multi-organ toxicity mechanisms remains to be fully elucidated. This review systematically analyzed the molecular pathways driving cisplatin-induced organ damage, identified risk factors, and provided target ideas for subsequent research on emerging protective strategies. The main findings showed that targeted inhibition of uptake transporters (OCT2), activation of cytoprotective pathways (PPARagonists), and regulation of cell death nodes (MLKL/RIPK3 inhibitors) can significantly reduce toxicity without affecting efficacy. This study provides a mechanistic basis for the design of personalized cisplatin regimens and provides a reference for clinical risk stratification. Key unanswered questions include optimizing organ-selective drug delivery systems and defining biomarkers of toxicity susceptibility. Future studies should prioritize combinatorial approaches that simultaneously target oxidative stress and cell death cascades in affected organs to expand the therapeutic window.