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Momordin Ic (MIc) has anti\u2010tumor and anti\u2010inflammatory properties, but its effects on colitis\u2010associated colorectal cancer (CAC) are not well understood. This study explores MIc's influence on macrophage mitochondrial dysfunction, macrophage polarization, and tumor development in CAC. Mouse colitis and CAC models were established to assess MIc's therapeutic potential. H&amp;E staining and immunohistochemistry evaluated inflammation and mucosal damage in colonic tissues. Flow cytometry analyzed immune cell proportions, while Western blot analyzed inflammatory protein expression. In\u00a0vitro studies with RAW264.7 and BMDMs explored MIc's effects on macrophage polarization and mitochondrial function. Flow cytometry assessed CD86+ macrophages, and qRT\u2010PCR measured inflammatory cytokines. Mitochondrial function was assessed using Mito\u2010tracker, JC\u20101, and DCFH\u2010DA dyes. Proteomics and GO analysis identified downstream pathways. Flow cytometry and CCK\u20108 assessed colon cancer cell proliferation and apoptosis, confirmed in the CAC mouse model. MIc significantly reduced intestinal inflammation and mucosal damage by decreasing macrophage infiltration and pro\u2010inflammatory polarization. Proteomics revealed that MIc affected proteins related to mitochondrial function. MIc restored mitochondrial function impaired by M1 polarization through upregulation of MTCH2. Co\u2010IP analysis showed a direct interaction between Sentrin\u2010specific protease 1 (SENP1) and MTCH2. SENP1 levels increased in M1 macrophages but decreased with MIc, an effect blocked by NF\u03baB inhibitors. MIc promoted apoptosis in CT26 and HCT116 cells and inhibited CAC progression. MIc effectively suppresses CAC development by regulating macrophage mitochondrial function via the SENP1\/MTCH2 pathway, reducing M1 polarization and promoting apoptosis in colorectal cancer cells.<\/jats:p>","DOI":"10.1002\/ptr.70348","type":"journal-article","created":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T11:40:02Z","timestamp":1776685202000},"page":"3936-3954","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Activation of\n                    <scp>MTCH2<\/scp>\n                    by Momordin Ic Prevents Colitis and Colitis\u2010Associated Colorectal Cancer Through Rescuing the Mitochondrial Dysfunction of Macrophage"],"prefix":"10.1002","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3764-7847","authenticated-orcid":false,"given":"Fang","family":"Xianjun","sequence":"first","affiliation":[{"name":"Department of Pharmacy The First Affiliated Hospital of Anhui Medical University  Hefei China"},{"name":"School of Pharmacy, Anhui Medical University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhai","family":"Chi","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Anhui Medical University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Haixia","sequence":"additional","affiliation":[{"name":"Department of Pharmacy The First Affiliated Hospital of Anhui Medical University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Yu","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Anhui Medical University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Kanghui","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Anhui Medical University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huang","family":"Wan","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Anhui Medical University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhang","family":"Xingjian","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Anhui Medical University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang","family":"Zude","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Anhui Medical University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liu","family":"Yunxin","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Nanjing First Hospital, Nanjing Medical University  Nanjing China"},{"name":"School of Basic Medicine &amp; Clinical Pharmacy, China Pharmaceutical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cao","family":"Xi","sequence":"additional","affiliation":[{"name":"Department of Pharmacy The First Affiliated Hospital of Anhui Medical University  Hefei China"},{"name":"School of Pharmacy, Anhui Medical University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,4,20]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-07519-w"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.trsl.2018.07.014"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21834"},{"key":"e_1_2_11_5_1","article-title":"Strategies for Detecting Colon Cancer in Patients With Inflammatory Bowel Disease","volume":"9","author":"Bye W. 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