Increased xCT and transsulfuration pathway has been associated with metabolic reprogramming of colorectal cancer. However, the correlation between these 2 events and the underlying molecular mechanism remains obscure. xCT expression was determined in tissue microarrays of colorectal cancer. RNA sequencing and functional assays in vitro was adopted to delineate the involvement of transsulfuration pathway in the proper function of xCT in maintaining the chemoresistant phenotype. The synthetic lethality of blocking xCT and the transsulfuration pathway was investigated both in vitro and in vivo. The up-regulation of the transsulfuration pathway after inhibiting xCT in colon cancer cells was evident and exogenous H₂S partially reversed the loss of chemoresistance phenotype after inhibiting xCT. Mechanistically, CTH derived H₂S increased the stability of xCT through persulfidation of OTU domain-containing ubiquitin aldehyde-binding protein 1 at cysteine 91. AOAA and Erastin resulted in synthetic lethality both in vitro and in vivo, which was mediated through increased ferroptosis and apoptosis. Our findings suggest that a reciprocal regulation exists between xCT and the transsulfuration pathway, which is a targetable metabolic vulnerability. Mechanistically, CTH derived H₂S increased the stability of xCT through persulfidation of OTU domain-containing ubiquitin aldehyde-binding protein 1 at cysteine 91.

增加的 xCT 和转硫途径与结直肠癌的代谢重编程有关。然而，这两个事件与潜在分子机制之间的相关性仍然模糊不清。在结直肠癌的组织微阵列中测定 xCT 表达。采用体外RNA 测序和功能测定来描绘转硫途径在 xCT 维持化学抗性表型的适当功能中的参与。在体外和体内研究了阻断 xCT 和转硫途径的合成致死率。结肠癌细胞中抑制xCT后转硫途径上调明显，外源性H ₂S 在抑制 xCT 后部分逆转了化学抗性表型的丧失。机械地，CTH衍生ħ ₂ s到的persulfidation增加XCT的稳定性OTU泛素醛结合在半胱氨酸91蛋白1 AOAA和Erastin导致两个合成致死性结构域的体外和体内，这是通过增加ferroptosis和介导细胞凋亡。我们的研究结果表明，xCT 和转硫途径之间存在相互调节，这是一种可靶向的代谢脆弱性。从机制上讲，CTH 衍生的 H ₂ S 通过半胱氨酸 91 处含有 OTU 结构域的泛素醛结合蛋白 1 的过硫化作用增加了 xCT 的稳定性。