SQOR as a metabolic rheostat of H2S: structure, redox homeostasis, and disease therapy.

Sulfide:quinone oxidoreductase (SQOR) is an inner-mitochondrial-membrane enzyme that couples hydrogen sulfide oxidation to the coenzyme Q pool, thereby linking sulfur metabolism with cellular bioenergetics and redox control. Recent structural and mechanistic advances-most notably the catalytic cysteine trisulfide-clarify how membrane context and substrate availability tune catalytic flux, yet debate persists over the physiological sulfur acceptor (glutathione versus sulfite) and how microenvironments route sulfide. SQOR also shapes ferroptosis: by using hydrogen selenide to reduce ubiquinone, it elevates ubiquinol and suppresses lipid peroxidation independently of glutathione peroxidase-4. We synthesize cross-system disease evidence-brain (hypoxia/ischemia, neuroinflammation), heart (divergent roles in acute ischemia-reperfusion versus chronic failure), kidney (mitochondrial dysfunction and cGAS-STING(cyclic GMP-AMP synthase-stimulator of interferon genes)-driven fibrosis), gastrointestinal tract (stage-specific effects in colorectal cancer and impaired detoxification in ulcerative colitis), bone/metabolic disorders, and the male reproductive system-highlighting SQOR's bidirectional pathology when hydrogen sulfide is excessive or depleted. Viewing SQOR as a "metabolic rheostat" reconciles these paradoxes and underscores therapeutic opportunities: metabolic supplementation (e.g., coenzyme Q10), selective inhibition or activation, and context-matched modulation. We further propose companion diagnostics that quantify sulfur/selenium species and enzyme activity to enable patient stratification and de-risk clinical translation.