Inhibition the MAP3K20-mediated ribotoxic stress response pathway downregulates M1 macrophage polarization in ulcerative colitis.

Abstract

To comprehensively investigate driven ribotoxic stress response (RSR) activation of M1 macrophage polarization in ulcerative colitis (UC), Gene Set Variation Analysis (GSVA) of intestinal tissues, weighted gene co-expression network analysis (WGCNA) based identification of RSR hub genes correlated with immune infiltration, and single-cell RNA sequencing were used. The multi-modal approach identified six core RSR hub genes (SNAL1, MDM2, MAPK11, MAP3K20, E2F1, BMP6) and established MAP3K20 as the pivotal kinase coordinating RSR-mediated M1 macrophage polarization in UC pathogenesis. Using DSS-induced UC models, we collectively demonstrated that MAP3K20 concurrent regulation of JNK/p38 signaling drive M1 macrophage polarization and UC inflammation, while pharmacological inhibition with Vemurafenib (MAP3K20 inhibitor) effectively attenuated both pathway activation and pathological damage. Our study provides a potential novel therapeutic target and clue for treating UC.