A novel GSH depletor for simultaneous ferroptosis and cuproptosis Activation in hepatocellular carcinoma

Ferroptosis and cuproptosis are two important new forms of ion-dependent cell death, whose processes can be inhibited by high levels of glutathione (GSH) within cells. Therefore, reducing GSH levels is a key strategy for inducing ferroptosis and cuproptosis. Herein, we successfully developed a curcumin (Cur) derivative, bisdemethylcurcumin (bm-Cur), as a novel GSH depletor that simultaneously induces ferroptosis and cuproptosis in hepatocellular carcinoma (HCC). The unique polyphenolic hydroxy structure and double α, β-unsaturated ketone structure of bm-Cur confers its potent GSH scavenging ability, which can effectively deplete GSH by simultaneously inhibiting GSH synthesis and directly consuming GSH levels, ultimately inducing ferroptosis and cuproptosis. Notably, bm-Cur can target mitochondria, induce mitochondrial lipid peroxidation and mitochondrial damage, thereby promoting ferroptosis and cuproptosis-mediated cell death, which demonstrates potential for anti-HCC activity in vitro and in vivo. Moreover, bm-Cur exhibited very low cytotoxicity, excellent biosafety and biocompatibility. In conclusion, this study suggests that bm-Cur may be a novel ferroptosis and cuproptosis activator with significant development potential for further application.