Pterostilbene attenuates cisplatin-induced acute kidney injury by suppressing TLR4/MyD88/NF-κB signaling.

Abstract

Cisplatin-induced acute kidney injury (Cis-AKI) is a common and severe dose-limiting complication of cisplatin-based chemotherapy, and effective preventive or therapeutic strategies remain limited. Pterostilbene (PTE), a naturally occurring polyphenolic compound, exhibits potent anti-inflammatory and antioxidant properties; however, its protective effects and underlying mechanisms in Cis-AKI are not fully understood. In this study, we investigated the renoprotective effects of PTE in cisplatin-induced injury using HK-2 cells and a mouse model of Cis-AKI. In vitro, PTE significantly alleviated cisplatin-induced cytotoxicity, improved cell viability, and attenuated tubular epithelial cell injury. In addition, PTE reduced oxidative stress, suppressed pro-inflammatory cytokine production, and inhibited apoptosis in cisplatin-treated HK-2 cells. In vivo, PTE improved renal function, alleviated tubular histopathological injury, and preserved renal tubular mitochondrial ultrastructure in cisplatin-treated mice. Exploratory transcriptomic screening highlighted TLR4/NF-κB-related signaling as a candidate pathway for further validation. Mechanistically, PTE inhibited TLR4/MyD88/NF-κB activation, whereas both pharmacological activation of TLR4 with Kdo2-Lipid A (KLA) and genetic restoration of TLR4 expression partially reversed the protective effects of PTE against cisplatin-induced inflammation, oxidative stress, apoptosis, and tubular epithelial damage. Collectively, these findings indicate that PTE protects against Cis-AKI, at least in part, through suppression of the TLR4/MyD88/NF-κB signaling cascade, thereby mitigating inflammation, oxidative stress, and apoptosis. These results suggest that PTE represents a promising therapeutic candidate for the prevention and treatment of Cis-AKI.