Perilipin 2 drives cisplatin-induced acute kidney injury in young but not aged kidneys.

Cisplatin is a widely used chemotherapeutic agent, but acute kidney injury (AKI) remains its dose-limiting toxicity, particularly in older patients. In recent years, dysregulated lipid metabolism has emerged as a key driver of cisplatin nephrotoxicity; however, the underlying mechanisms and their modulation across ages remain incompletely understood. Here, we demonstrated that the lipid droplet protein perilipin 2 (Plin2) was induced after cisplatin-induced AKI, with markedly greater induction in aged kidneys and distinct organ-specific patterns in the liver and heart. Knockdown of Plin2 protected against cisplatin-induced AKI in young mice, as evidenced by reduced serum creatinine and blood urea nitrogen levels, attenuated morphological injury, decreased tubular cell apoptosis, and diminished inflammation, but failed to confer protection in aged mice. Proteomic profiling identified selective upregulation of 3-hydroxy-3-methylglutaryl-CoA synthase 2 (Hmgcs2), suggesting enhanced ketogenesis in Plin2-knockdown kidneys. Surprisingly, Plin2 knockdown did not significantly alter fatty acid oxidation and glycolytic pathways after AKI. Mechanistically, Plin2 interacts with sirtuin 5 (Sirt5) to regulate Hmgcs2 desuccinylation, impairing ketogenesis and tubular energy homeostasis to exacerbate AKI in an age-dependent manner.NEW & NOTEWORTHY Aging is a major determinant of cisplatin nephrotoxicity, yet the mechanisms underlying age-dependent metabolic vulnerability remain unclear. This study revealed that lipid droplets are not merely lipid storage structures but actively regulate kidney metabolic adaptation during cisplatin-induced AKI. We identified Plin2 as a context-dependent regulator whose knockdown enhanced protective ketogenesis in young kidneys but lost efficacy with aging. These findings uncover age-dependent metabolic plasticity as a critical determinant of AKI susceptibility and therapeutic response.