Bergenin inhibits ferritinophagy and ferroptosis in cisplatin-induced acute kidney injury by activating the p-GSK3(3/Nrf2/PPARγ pathway

Ferroptosis plays a key role in cisplatin-induced acute kidney injury (AKI). Bergenin, which is extracted from Ardisiae Japonicae Herba and has long been used in folk tea and herbal tea drinks, is known to activate Nrf2 and has anti-inflammatory and antioxidant properties, however, its protective influence on CI-AKI has not been elucidated. We used models of cisplatin-induced nephrotoxicity in vitro and CI-AKI models in vivo. In vitro, we found that ferroptosis and ferritinophagy biomarkers were strongly regulated by bergenin treatment. Mechanistic experiments demonstrated that bergenin bound to and phosphorylated GSK3(3, which inhibited its activity, to promote the nuclear translocation of Nrf2 and its subsequent binding to the PPAR gamma promoter sequence to activate PPAR gamma. However, the protective effects of bergenin on ferroptosis and ferritinophagy in cisplatin-exposed HK-2 cells were diminished when Nrf2 or PPAR gamma was inhibited. In vivo, bergenin effectively inhibited renal damage induced by cisplatin. Furthermore, bergenin attenuated ferritinophagy-mediated ferroptosis caused by cisplatin; these effects were abolished in Nrf2 knockout mice. Our findings revealed that bergenin effectively protected against ferritinophagy and ferroptosis in CI-AKI, which was largely dependent on the activation of the p-GSK3(3/ Nrf2/PPAR gamma pathway.