Gaudichaudione H Enhances the Sensitivity of Hepatocellular Carcinoma Cells to Disulfidptosis via Regulating NRF2‐SLC7A11 Signaling Pathway

Gaudichaudione H (GH) is a naturally occurring small molecular compound derived from Garcinia oligantha Merr. (Clusiaceae), but the full pharmacological functions remain unclear. Herein, the potential of GH in disulfidptosis regulation, a novel form of programmed cell death induced by disulfide stress is explored. The omics results indicated that NRF2 signaling could be significantly activated by GH. The potential targets are associated with hepatocarcinogenesis and cell death. Moreover, both glutathione (GSH) metabolism and NADP⁺-NADPH metabolism are affected by GH, indicating the potential in disulfidptosis regulation. It is also observed that GH enhanced the sensitivity of hepatocellular carcinoma (HCC) cells to disulfidptosis, which is dependent on the activation of NRF2-SLC7A11 pathway. GH significantly increased the levels of NRF2 and promoted the transcription of NRF2 target gene, SLC7A11, through autophagy-mediated non-canonical mechanism. Under the condition of glucose starvation, GH-induced upregulation of SLC7A11 aggravated uptake of cysteine, disturbance of GSH synthesis, depletion of NADPH, and accumulation of disulfide molecules, ultimately leading to the formation of disulfide bonds between different cytoskeleton proteins and disulfidptosis eventually. Collectively, the findings underscore the potential role of GH in promoting cancer cell disulfidptosis, thereby offering a promising avenue for the treatment of drug-resistant HCC in clinical settings.