Activating AMPK-p53 Axis Induced by Mitochondrial Impairment: A Novel Anti-Liver Cancer Mechanism of Sulfane Sulfur

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer and remains refractory to conventional chemotherapy. Sulfane sulfur-based compounds have a long history in the treatment of HCC, but their efficacy has been disappointing. We recently reported a sulfane sulfur donor PSCP, which exhibits improved chemical stability and allows for greater structural modification. This study aimed to investigate the effects of PSCP on HCC and elucidate the underlying mechanisms. Bioinformatics algorithms, including clustering, function enrichment, feature screening, and survival analysis were employed to analyze the Cancer Proteome Atlas (CPTAC) proteomic data and The Cancer Genome Atlas (TCGA) transcriptomic sequencing data of HCC gene expression. The impact of PSCP on HCC were assessed both in vitro and in vivo. We evaluated 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 the binding interaction was visually analyzed. In HCC, sulfur metabolism was found to be reprogrammed and the downregulation of sulfur-related pathways was associated with poor patient prognosis. PSCP treatment inhibited HCC tumor growth in an allograft model, reduced cell viability and proliferation, but induced apoptosis. Moreover, PSCP promoted p53 expression and AMPK phosphorylation by inhibiting mitochondrial respiratory complex I. Collectively, our findings suggest that reprogramming of sulfur-related metabolic pathways is a key factor in HCC, and PSCP emerges as an effective therapeutic strategy, by activating the mitochondrial-AMPK-p53 signaling axis. KEYWORDS: Metabolic reprogramming; Hepatocellular carcinoma; Sulfane sulfur; Mitochondrial complex; AMPK; p53