Beyond Hydrogen Sulfide and Cysteine Metabolism: Reframing Cystathionine γ-Lyase as a Potential Translational Regulator of Hypoxia-Inducible Factor-1α in Clear Cell Ovarian Carcinoma.

The canonical transsulfuration (TSS) pathway enzymes cystathionine β-synthase (CBS) and cystathionine γ-lyase (CTH) are traditionally recognized for their roles in the sequential conversion of homocysteine to cysteine and in endogenous hydrogen sulfide (H2S) production. Increasing evidence, however, suggests that these enzymes may also exhibit non-canonical ("moonlighting") functions that extend beyond metabolic regulation. In this review, we evaluate the hypothesis that CTH may participate in translational regulation, particularly in the control of hypoxia-inducible factor-1α (HIF-1α) expression in clear cell ovarian carcinoma (CCOC). We first highlight limitations of the prevailing H2S- and cysteine-centric view of the TSS pathway, which may not fully explain emerging context-dependent functions of CTH in cancer biology. Current evidence suggests that CTH enhances HIF-1α protein expression through mechanisms independent of transcription, protein stability, or H2S production, implicating a potential role in translational regulation, although direct mechanistic evidence remains limited. To critically evaluate this emerging hypothesis, we categorize evidence according to its level of experimental support, ranging from direct experimental evidence to indirect mechanistic observations and computational predictions. Within this framework, we examine three non-mutually exclusive models: (1) regulation through PI3K/AKT/mTOR-dependent translational signaling; (2) modulation of translational control through interaction with translation-associated proteins and RNA-binding proteins (RBPs) involved in HIF1A mRNA regulation; and (3) the more speculative possibility of direct interaction between CTH and HIF1A mRNA. Collectively, these observations support a model in which CTH contributes to selective translational regulation beyond its canonical metabolic functions, potentially linking sulfur metabolism to stress-adaptive gene expression in cancer.