Hydrogen sulfide (H₂S) is a gasotransmitter with broad physiological activities, including protecting cells against stress, but little is known about the regulation of cellular H₂S homeostasis. We have performed a high-content small-molecule screen and identified genotoxic agents, including cancer chemotherapy drugs, as activators of intracellular H₂S levels. DNA damage-induced H₂S in vitro and in vivo. Mechanistically, DNA damage elevated autophagy and upregulated H₂S-generating enzyme CGL; chemical or genetic disruption of autophagy or CGL impaired H₂S induction. Importantly, exogenous H₂S partially rescued autophagy-deficient cells from genotoxic stress. Furthermore, stressors that are not primarily genotoxic (growth factor depletion and mitochondrial uncoupler FCCP) increased intracellular H₂S in an autophagy-dependent manner. Our findings highlight the role of autophagy in H₂S production and suggest that H₂S generation may be a common adaptive response to DNA damage and other stressors.

硫化氢 (H _{2 S) 是一种具有广泛生理活性的气体递质，包括保护细胞免受压力，但对细胞 H 2} S 稳态的调节知之甚少。我们进行了高内涵小分子筛选，并确定了基因毒性药物（包括癌症化疗药物）作为细胞内 H ₂ S 水平的激活剂。体外和体内DNA 损伤诱导的H ₂ S。从机制上讲，DNA 损伤会增加自噬并上调 H ₂ S 生成酶 CGL；自噬或 CGL 的化学或遗传破坏会损害 H ₂ S 的诱导。重要的是，外源性 H ₂S 部分地从遗传毒性应激中拯救了自噬缺陷细胞。此外，主要不是遗传毒性的应激源（生长因子耗竭和线粒体解偶联剂 FCCP）以自噬依赖性方式增加细胞内 H ₂ S。我们的研究结果强调了自噬在 H ₂ S 产生中的作用，并表明 H ₂ S 的产生可能是对 DNA 损伤和其他应激源的常见适应性反应。