Cancer cells undergo metabolic rewiring, notably the Warburg effect, relying on aerobic glycolysis to sustain rapid proliferation. Targeting this cancer-specific metabolic adaptation through drugs like lactate dehydrogenase inhibitors is under evaluation. In glycolysis regulation, PKM2 plays a crucial role, with its activity being modulated by various posttranslational modifications. Interestingly, hydrogen sulfide (H2S) has emerged as a key player in cancer metabolism, exhibiting both pro-tumor and anti-tumor effects through protein sulfhydration. Research indicates that H2S-induced sulfhydration of PKM2 leads to a shift in its activity, impacting glucose metabolism and cell proliferation. Specifically, targeting cysteine 326 on PKM2 shows promise in modulating cancer cell growth. By destabilizing PKM2 tetramers, H2S redirects glucose metabolism towards mitochondrial respiration, inhibiting cell proliferation and tumor growth in breast cancer models. These findings highlight the therapeutic potential of targeting H2S-mediated protein sulfhydration for future anticancer drug development, emphasizing the need for further exploration in understanding the intricate interplay between H2S and cancer metabolism.