State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, Engineering Research Centre of Molecular Diagnostics of the Ministry of Education, School of Life Sciences, Xiamen University, Xiamen 361102, Fujian, China.
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, Engineering Research Centre of Molecular Diagnostics of the Ministry of Education, School of Life Sciences, Xiamen University, Xiamen 361102, Fujian, China; School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, Fujian, China.
Mol Cell. 2024 Oct 17;84(20):4016-4030.e6. doi: 10.1016/j.molcel.2024.08.035. Epub 2024 Sep 24.
Hydrogen sulfide (H₂S), a metabolite of the transsulfuration pathway, has been implicated in ferroptosis, a unique form of cell death caused by lipid peroxidation. While the exact mechanisms controlling ferroptosis remain unclear, our study reveals that H₂S sensitizes human non-small cell lung cancer (NSCLC) cells to this process, particularly when cysteine levels are low. Combining H₂S with cystine depletion significantly enhances the effectiveness of ferroptosis-based cancer therapy. Mechanistically, H₂S persulfidates the 195 cysteine on S-adenosyl homocysteine hydrolase (SAHH), reducing its enzymatic activity. This leads to decreased homocysteine levels, subsequently lowering cysteine and glutathione concentrations under cystine depletion conditions. These changes ultimately increase the vulnerability of NSCLC cells to ferroptosis. Our findings establish H₂S as a key regulator of homocysteine metabolism and a critical factor in determining NSCLC cell susceptibility to ferroptosis. These results highlight the potential of H₂S-based therapies to improve the efficacy of ferroptosis-targeted cancer treatments for NSCLC.
硫化氢（H₂S）是转硫途径的代谢产物，与脂质过氧化引起的一种独特的细胞死亡形式——铁死亡有关。虽然控制铁死亡的确切机制尚不清楚，但我们的研究表明，H₂S 使人类非小细胞肺癌（NSCLC）细胞对这一过程敏感，尤其是在半胱氨酸水平较低时。将 H₂S 与胱氨酸耗竭相结合，可显著提高基于铁死亡的癌症治疗的效果。从机制上讲，H₂S 可使 S-腺苷同型半胱氨酸水解酶（SAHH）上的 195 号半胱氨酸过硫化，从而降低其酶活性。这导致同型半胱氨酸水平降低，进而在胱氨酸耗竭条件下降低半胱氨酸和谷胱甘肽浓度。这些变化最终增加了 NSCLC 细胞对铁死亡的易感性。我们的发现确立了 H₂S 作为同型半胱氨酸代谢的关键调节剂和决定 NSCLC 细胞对铁死亡易感性的关键因素。这些结果突出了基于 H₂S 的治疗方法在提高 NSCLC 铁死亡靶向癌症治疗效果方面的潜力。
