Activation of MTCH2 by Momordin Ic Prevents Colitis and Colitis-Associated Colorectal Cancer Through Rescuing the...

Inflammation is associated with various cancers, including colorectal cancer. Momordin Ic (MIc) has anti-tumor and anti-inflammatory properties, but its effects on colitis-associated 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&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 vitro studies with RAW264.7 and BMDMs explored MIc's effects on macrophage polarization and mitochondrial function. Flow cytometry assessed CD86+ macrophages, and qRT-PCR measured inflammatory cytokines. Mitochondrial function was assessed using Mito-tracker, JC-1, and DCFH-DA dyes. Proteomics and GO analysis identified downstream pathways. Flow cytometry and CCK-8 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-inflammatory polarization. Proteomics revealed that MIc affected proteins related to mitochondrial function. MIc restored mitochondrial function impaired by M1 polarization through upregulation of MTCH2. Co-IP analysis showed a direct interaction between Sentrin-specific protease 1 (SENP1) and MTCH2. SENP1 levels increased in M1 macrophages but decreased with MIc, an effect blocked by NFκB 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.