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

Jie Zhang, Li Cen, Xiaofen Zhang, Chenxi Tang, Yishu Chen, Yuwei Zhang, Mengli Yu, Chao Lu, Meng Li, Sha Li, Bingru Lin, Tiantian Zhang, Xin Song, Chaohui Yu, Hao Wu, Zhe Shen

Redox biology 2022 Oct

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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 expression in human IBD samples. In addition, overexpression of AKT rescued IEC apoptosis caused by MPST deficiency, while inhibition of AKT significantly aggravated it. MPST protects the intestines from inflammation most likely by regulating the AKT/apoptosis axis in IECs. Our results may provide a novel therapeutic strategy for the treatment of colitis. Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.

Citation

Jie Zhang, Li Cen, Xiaofen Zhang, Chenxi Tang, Yishu Chen, Yuwei Zhang, Mengli Yu, Chao Lu, Meng Li, Sha Li, Bingru Lin, Tiantian Zhang, Xin Song, Chaohui Yu, Hao Wu, Zhe Shen. MPST deficiency promotes intestinal epithelial cell apoptosis and aggravates inflammatory bowel disease via AKT. Redox biology. 2022 Oct;56:102469