Defective m⁶A RNA Modification in Macrophages Exacerbates Inflammation and Promotes Colitis-Associated Carcinogenesis...

Chronic inflammation resulting from unresolved tissue injury is a potent driver of tumorigenesis. Macrophages are essential for efferocytosis, the clearance of apoptotic cells, which prevents secondary necrosis and promotes inflammation resolution. However, the epigenetic mechanisms regulating this process under inflammatory stress remain incompletely understood. Here, we identify the m6A methyltransferase METTL3 as a critical regulator of macrophage efferocytosis. Using various models of tissue injury, METTL3 expression was significantly downregulated in macrophages under inflammatory conditions and was associated with defective efferocytosis, the accumulation of apoptotic cells, and exacerbated chronic inflammation. Mechanistically, we reveal that METTL3-mediated m⁶A modification promotes IGF2BP2/3-dependent stabilization of MFGE8 mRNA, a process that is compromised upon METTL3 deficiency. In a colitis-associated cancer model, the efferocytosis defect associated with Mettl3 deficiency exacerbated chronic inflammatory tissue injury and increased susceptibility to colitis-associated cancer. Ultimately, external administration of recombinant MFGE8 protein effectively rescued the efferocytosis defect, mitigated inflammation, and reduced tumor burden in the AOM/DSS model. Collectively, our findings identify the METTL3-m⁶A-IGF2BP2/3-MFGE8 pathway as an important regulator of macrophage efferocytosis that may contribute to inflammation-associated carcinogenesis. These results suggest that targeting the METTL3-MFGE8 axis may represent a strategy for restoring efferocytosis and promoting inflammation resolution in chronic inflammatory diseases and inflammation-associated malignancies.