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<p>The senescence of intestinal epithelial cells (IECs) is closely associated with the development of ulcerative colitis (UC), but the underlying regulatory mechanism remains unclear. Although mitogen activated protein kinase 15 (MAPK15) has been shown to inhibit cellular senescence, its specific role in UC has not yet been clarified. This study investigates the role of MAPK15 in modulating IEC senescence during UC and explores the molecular mechanisms involved in this regulatory process. The senescence phenotype and MAPK15 expression in colon tissues from UC patients, dextran sodium sulfate (DSS)-induced UC mice, and DSS-induced NCM460 cells were detected by SA-β-Gal staining, immunohistochemistry (IHC) staining, and Western blot analysis. To further determine the molecular mechanism of the MAPK15/Suz12/Drp1 axis in UC, MAPK15 was overexpressed and Suz12 was silenced, and the underlying regulatory interactions were assessed using techniques including Co-immunoprecipitation (Co-IP), RIP-qPCR, and RNA pull-down. The results showed that the expressions of senescence-associated markers (p53, p16, and p21) and senescence-associated secretory phenotype (SASP) factors (IL-6, IL-8, and MMP-3) in IECs from UC patients and DSS-induced mice were upregulated, whereas the expression of MAPK15 was downregulated. Functional experiments further demonstrated that overexpression of MAPK15 alleviated DSS-induced intestinal inflammation, reduced cellular senescence-like phenotype, and suppressed Drp1-dependent mitochondrial fission. Mechanistically, MAPK15 enhanced the binding of Suz12 to Drp1 mRNA through phosphorylation of Suz12, which reduced the stability of Drp1 mRNA, and thereby inhibited Drp1-mediated mitochondrial fission damage. However, silencing of Suz12 reversed the protective effect induced by MAPK15 overexpression. In conclusion, these findings indicated that MAPK15 contributed to the inhibition of mitochondrial fission through regulation of the Suz12/Drp1 axis, thereby mitigating IEC senescence-like phenotype and suppressing the progression of UC. These results suggested that MAPK15 might serve as a potential therapeutic target for UC.</p><p>Clinical Trial Number: Not applicable.</p>

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MAPK15 Attenuates Intestinal Epithelial Cell Senescence-Like Phenotype to Regulate Gut Homeostasis and Inflammation by Phosphorylating Suz12 to Suppress Drp1-Mediated Mitochondrial Fission Damage

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月24日

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  • Juan Li,
  • Gang Chen,
  • Xinyi Bao

摘要

The senescence of intestinal epithelial cells (IECs) is closely associated with the development of ulcerative colitis (UC), but the underlying regulatory mechanism remains unclear. Although mitogen activated protein kinase 15 (MAPK15) has been shown to inhibit cellular senescence, its specific role in UC has not yet been clarified. This study investigates the role of MAPK15 in modulating IEC senescence during UC and explores the molecular mechanisms involved in this regulatory process. The senescence phenotype and MAPK15 expression in colon tissues from UC patients, dextran sodium sulfate (DSS)-induced UC mice, and DSS-induced NCM460 cells were detected by SA-β-Gal staining, immunohistochemistry (IHC) staining, and Western blot analysis. To further determine the molecular mechanism of the MAPK15/Suz12/Drp1 axis in UC, MAPK15 was overexpressed and Suz12 was silenced, and the underlying regulatory interactions were assessed using techniques including Co-immunoprecipitation (Co-IP), RIP-qPCR, and RNA pull-down. The results showed that the expressions of senescence-associated markers (p53, p16, and p21) and senescence-associated secretory phenotype (SASP) factors (IL-6, IL-8, and MMP-3) in IECs from UC patients and DSS-induced mice were upregulated, whereas the expression of MAPK15 was downregulated. Functional experiments further demonstrated that overexpression of MAPK15 alleviated DSS-induced intestinal inflammation, reduced cellular senescence-like phenotype, and suppressed Drp1-dependent mitochondrial fission. Mechanistically, MAPK15 enhanced the binding of Suz12 to Drp1 mRNA through phosphorylation of Suz12, which reduced the stability of Drp1 mRNA, and thereby inhibited Drp1-mediated mitochondrial fission damage. However, silencing of Suz12 reversed the protective effect induced by MAPK15 overexpression. In conclusion, these findings indicated that MAPK15 contributed to the inhibition of mitochondrial fission through regulation of the Suz12/Drp1 axis, thereby mitigating IEC senescence-like phenotype and suppressing the progression of UC. These results suggested that MAPK15 might serve as a potential therapeutic target for UC.

Clinical Trial Number: Not applicable.