Hydrogen sulfide regulation in redox homeostasis and programmed cell death: mechanistic insights and implications in cancer

Hydrogen sulfide (H₂S), a key endogenous gaseous mediator derived from sulfur-containing amino acid metabolism, exhibits a concentration-dependent duality in cancer. At physiological concentrations, H₂S exerts antioxidant effects by activating the NRF2/Keap1 pathway and suppressing lipid peroxidation, thereby promoting tumor cell survival. In contrast, supraphysiological levels of H₂S induce programmed cell death (PCD) by impairing mitochondrial homeostasis, triggering reactive oxygen species (ROS) bursts, and modifying critical proteins via persulfidation. The complex interplay between H₂S and PCD pathways highlights its potential as a therapeutic target, with emerging strategies focusing on modulating endogenous H₂S production and developing targeted H₂S-releasing compounds. Current pharmacological approaches include inhibiting H₂S-synthesizing enzymes and exogenous administration of H₂S donors, which have shown promise in preclinical models and clinical trials for overcoming therapy resistance and enhancing treatment efficacy. This review establishes the integrative framework bridging H₂S biology with six distinct PCD modalities, focusing on its potential therapeutic applications in cancer therapy. It further investigates the core challenges in clinical translation of H₂S-based therapies, particularly the dual hurdles of achieving targeted delivery and managing concentration-dependent effects. To overcome these challenges, we outline emerging translational strategies that leverage enzyme-targeted inhibitors, repurpose H₂S-modulating drugs already approved by the FDA, and integrate novel nano-theranostic platforms capable of stimulus-triggered and spatially precise release of H₂S. Future research should prioritize developing intelligent delivery systems with precise spatiotemporal control, and deciphering the dynamic regulation of H₂S-mediated PCD, which will be essential for advancing these mechanistic insights into precision oncology therapeutics.