Activating the AMPK-p53 Axis by Mitochondrial Impairment: Unveiling a Novel Anti-Liver Cancer Mechanism of Sulfane Sulfur

Hepatocellular carcinoma (HCC) is the most prevalent form of primary liver cancer, notoriously refractory to conventional chemotherapy. Historically, sulfane sulfur-based compounds have been explored for the treatment of HCC, but their efficacy has been underwhelming. We recently reported a novel sulfane sulfur donor, PSCP, which exhibited improved chemical stability and structural malleability. This study aimed to investigate the effects of PSCP on HCC and elucidate the underlying mechanisms. We utilized bioinformatics algorithms for clustering, function enrichment, feature screening and survival analysis on proteomic data from the Cancer Proteome Atlas (CPTAC) and transcriptomic data from the Cancer Genome Atlas (TCGA). The impact of PSCP on HCC were assessed in vitro and in vivo , focusing on the expression and activity of p53 and AMP-activated protein kinase (AMPK), as well as mitochondrial function. The molecular target of PSCP was identified using Autodock, and binding interactions were visually analyzed. Sulfur metabolism was found to be reprogrammed in HCC, with downregulation of sulfur-related pathways correlating with poor patient prognosis. PSCP treatment significantly inhibited HCC tumor growth in an allograft model, reduced cell viability and proliferation, and induced apoptosis. PSCP potently increased p53 expression and induced AMPK phosphorylation in SNU398 HCC cells. AMPK suppression diminished PSCP-induced p53 upregulation. PSCP also impaired mitochondrial function by inhibiting mitochondrial respiratory complex I. The supplementation of ATP significantly countered PSCP-induced SNU398 cell injury. Our findings suggest that the reprogramming of sulfur-related metabolic pathways is pivotal in HCC. PSCP presents as a promising therapeutic strategy by activating the mitochondrial-AMPK-p53 signaling axis.