Hydrogen sulfide at the intersection of hypoxia and oxidative stress: implications for lung cancer progression and treatment - a narrative review.

Lung cancer remains a leading cause of cancer-related mortality worldwide, with a pathogenesis deeply influenced by the tumor microenvironment. Two central and interrelated factors -hypoxia and oxidative stress - contribute significantly to tumor progression, angiogenesis, metabolic reprogramming, and therapeutic resistance. In recent years, hydrogen sulfide (HS), traditionally viewed as a toxic gas, has gained recognition as a critical gasotransmitter with a regulatory role in both hypoxic and redox signaling pathways in cancer biology. Endogenously produced by enzymes such as CBS, CSE, and 3-MST, HS can promote or inhibit tumorigenesis depending on the context. In lung cancer, HS has been shown to modulate hypoxia-inducible factor activity, support mitochondrial bioenergetics under low oxygen tension, and influence ROS dynamics, thereby maintaining redox balance that favors tumor cell survival. The complex crosstalk between HS, hypoxia, and oxidative stress creates a permissive environment for tumor growth and immune evasion, but also offers potential vulnerabilities that can be therapeutically exploited. Targeting HS signaling has emerged as a promising avenue in lung cancer management. Both inhibition and controlled supplementation of HS are under investigation as strategies to disrupt tumor adaptation to hypoxia and oxidative stress. This review highlights the dualistic nature of HS in lung cancer progression, explores its mechanisms of action in the context of hypoxic and oxidative stress pathways, and discusses the diagnostic and therapeutic potential of modulating the HS axis for improved clinical outcomes.