MPST deficiency promotes intestinal epithelial cell apoptosis and aggravates inflammatory bowel disease via AKT

作者：Jie Zhang, Cen Li, Xiaofen Zhang, Chenxi Tang, Yishu Chen, Yuwei Zhang, Mengli Yu, Chao Lü, Meng Li, Sha Li, Bingru Lin, Tiantian Zhang, Xin Song, Chaohui Yu, Hao Wu, Zhe Shen · 发表于：Redox Biology · 年份：2022 · DOI：10.1016/j.redox.2022.102469 · 被引用次数：111 · 研究领域：Inflammatory Bowel Disease、Neutrophil, Myeloperoxidase and Oxidative Mechanisms、PI3K/AKT/mTOR signaling in cancer

Excessive inflammatory responses and oxidative stress are considered the main characteristics of inflammatory bowel disease (IBD). Endogenous hydrogen sulfide (H2S) has been reported to show anti-inflammatory activity in IBD. The main aim of this study was to explore the role of 3-mercaptopyruvate sulfurtransferase (MPST), a key enzyme that regulates endogenous H2S biosynthesis, in IBD. Colonic MPST expression was evaluated in mice and patients with IBD. Various approaches were used to explore the concrete mechanism underlying MPST regulation of the progression of colitis through in vivo and in vitro models. MPST expression was markedly decreased in colonic samples from patients with ulcerative colitis (UC) or Crohn's disease (CD) and from mice treated with DSS. MPST deficiency significantly aggravated the symptoms of murine colitis, exacerbated inflammatory responses and apoptosis, and inhibited epithelium stem cell-derived organoid formation in an H2S-independent manner. Consistently, when HT29 cells were treated with TNF-α, inhibition of MPST significantly increased the expression of proinflammatory cytokines, the amount of ROS and the prevalence of apoptosis, whereas overexpression of MPST markedly improved these effects. RNA-seq analysis showed that MPST might play a role in regulating apoptosis through AKT signaling. Mechanistically, MPST directly interacted with AKT and reduced the phosphorylation of AKT. Additionally, MPST expression was positively correlated with AKT...