Puerarin prevents cadmium-induced endoplasmic reticulum stress via SIRT1-dependent PERK-CHOP pathway in HepG2 cells

Cadmium (Cd) is a high-risk heavy metal that induces oxidative stress, endoplasmic reticulum (ER) stress and inflammation, damaging organs such as the liver. Puerarin (PUE) has been shown to treat liver injury and especially prevent Cd-induced hepatic damage via its antioxidant activity. Sirtuin 1 (SIRT1), a histone deacetylase, is a key protector against various stress insults. However, its role in the protection of PUE against Cd-induced liver damage has not been clarified. Thus, this study is designed to elucidate the molecular mechanism in the human hepatoma cell line HepG2. The results first reveal that Cd-induced apoptosis is significantly restored by PUE pretreatment, as confirmed by the CCK-8, flow cytometric, Hoechst 33258 and TUNEL assays. Mechanistically, PUE significantly decreases ROS production and increases SOD levels in Cd-treated HepG2 cells. Moreover, PUE pretreatment alleviates ER stress by inhibiting the PERK-eIF2α-ATF4-CHOP axis and subsequently partially restores ER function as revealed by decreased Ca ²⁺ release from the ER. In addition, further study demonstrates that PUE upregulates SIRT1 expression, which suppresses the PERK signaling cascade and reduces CHOP levels. Collectively, our results first demonstrate that PUE protects HepG2 cells from Cd-induced apoptosis at least partially by inhibiting the PERK-eIF2α-ATF4-CHOP pathway in a SIRT1 expression-dependent manner. Puerarin appears to have great potential as a hepatoprotective agent.