The Impact of Hydrogen Sulfide-Mediated Protein Sulfhydration on the Cancer Metabolism

In this study, we investigated the role of H₂S in modulating glucose metabolism in cancer cells through post-translational modification of PKM2. Our results demonstrate that H₂S destabilizes the active PKM2 tetramer, converting it into monomeric and dimeric forms through sulfhydration at Cysteine 326. This modification leads to reduced PKM2 enzymatic activity while enhancing its non-metabolic, transcriptional regulatory functions that contribute to tumor progression. Importantly, we found that blocking PKM2 sulfhydration at C326 via amino acid substitution (C326S) stabilizes the PKM2 tetramer, as confirmed by structural analysis, and prevents the H₂S-induced shift in glucose metabolism. Cancer cells expressing the PKM2-C326S mutant exhibited a metabolic shift from aerobic glycolysis back to mitochondrial respiration, resulting in significantly suppressed tumor growth both in vitro and in vivo. These findings reveal a novel mechanism by which H₂S promotes tumorigenesis through the sulfhydration-dependent inactivation of PKM2. Furthermore, our study highlights the therapeutic potential of targeting PKM2 sulfhydration as a strategy to disrupt cancer-specific metabolic reprogramming.