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<p>Colonic smooth muscle cell (CSMC) hypertrophy and hyperplasia have been described in both human ulcerative colitis (UC) and animal models. The deletion of smooth muscle (SM) 22α induces the phenotypic switching of SMCs. Here, we report that <i>Sm22α</i>-deficient mice develop spontaneous colitis, which is characterized by radical S-adenosyl-methionine domain-containing 2 (RSAD2)-driven mitochondrial dysfunction and inflammation in CSMCs and ferroptosis in the colonic mucosa. Mechanistically, RSAD2 mediates YTH m<sup>6</sup>A RNA-binding protein 1 (YTHDF1) methylation and activation, thereby increasing the mRNA N6-methyladenosine (m<sup>6</sup>A) modification and translation of dynamin-related protein 1 (DRP1), resulting in mitochondrial fragmentation in CSMCs. Inflammatory CSMC-derived mitochondrial extracellular vesicles trigger intestinal epithelial ferroptosis by inducing ROS production. The ablation of RSAD2 in mice with SMC-specific <i>Sm22α</i> knockout alleviates colitis severity in this experimental model. Importantly, increases in both RSAD2 expression and the ferroptotic signature are observed in serum and/or colonic samples from UC patients. Overall, this study shows a mitochondrial mechanism underlying the ability of dysfunctional smooth muscle to drive colitis and highlights the potential of targeting the RSAD2-YTHDF1 axis as an innovative therapeutic strategy for colitis.</p>

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Activation of the RSAD2-YTHDF1 axis in smooth muscle causes inflammatory bowel disease via intercellular mitochondrial transfer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月14日

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  • Wen-Di Zhang,
  • Dan-Dan Zhang,
  • Xu Wang,
  • Chen-Yang Li,
  • Fan-Qin Li,
  • Xin-Long Liu,
  • Shi-Zhen Zhang,
  • Wei Sun,
  • Li-Jing Li,
  • Han-Bing Wang,
  • Peng Kong,
  • Xiao-Qin Liu,
  • De-Min Liu,
  • Xiao-Lan Zhang,
  • Ya-Bin Liu,
  • Mei Han

摘要

Colonic smooth muscle cell (CSMC) hypertrophy and hyperplasia have been described in both human ulcerative colitis (UC) and animal models. The deletion of smooth muscle (SM) 22α induces the phenotypic switching of SMCs. Here, we report that Sm22α-deficient mice develop spontaneous colitis, which is characterized by radical S-adenosyl-methionine domain-containing 2 (RSAD2)-driven mitochondrial dysfunction and inflammation in CSMCs and ferroptosis in the colonic mucosa. Mechanistically, RSAD2 mediates YTH m6A RNA-binding protein 1 (YTHDF1) methylation and activation, thereby increasing the mRNA N6-methyladenosine (m6A) modification and translation of dynamin-related protein 1 (DRP1), resulting in mitochondrial fragmentation in CSMCs. Inflammatory CSMC-derived mitochondrial extracellular vesicles trigger intestinal epithelial ferroptosis by inducing ROS production. The ablation of RSAD2 in mice with SMC-specific Sm22α knockout alleviates colitis severity in this experimental model. Importantly, increases in both RSAD2 expression and the ferroptotic signature are observed in serum and/or colonic samples from UC patients. Overall, this study shows a mitochondrial mechanism underlying the ability of dysfunctional smooth muscle to drive colitis and highlights the potential of targeting the RSAD2-YTHDF1 axis as an innovative therapeutic strategy for colitis.