NNMT Enhances Invasive and Migratory Capacity of Keloid Fibroblasts and M2 Macrophage Polarization

Keloid are characterized by fibroblastic proliferation and excessive collagen deposition. Nicotinamide N-methyltransferase (NNMT) belongs to the methyltransferase family and plays an important role in various physiological processes, including keloid formation. However, the role of NNMT in keloid development remains poorly understood. In this study, we investigated the role of NNMT in keloids using a bleomycin (BLM)-induced fibrosis model in vivo and primary human keloid fibroblast (HPKF) in vitro. NNMT expression was upregulated in keloid tissues, and M2 macrophages were significantly increased in keloid tissue. NNMT overexpression reduced the SAM content, while NNMT knockdown increased it. Moreover, overexpression of NNMT enhanced the cell viability of HPKFs, while knockdown of NNMT promoted apoptosis. Additionally, NNMT overexpression promoted HPKF invasion and migration, whereas knockdown effectively inhibited these processes. Overexpression of NNMT also increased the expression of fibrosis-related markers, including FN1, COL1A1, COL3A1, Vimentin, and α-SMA, while NNMT knockdown reversed it. THP-1 cells were induced into THP1-M0 macrophages using PMA and co-cultured with HPKFs. Co-culturing with NNMT-overexpressing HPKFs promoted M2 polarization in M0 cells, while NNMT knockdown inhibited M2 polarization and reduced TGFB1 and Arg-1 expression in M0 cells. Furthermore, NNMT overexpression promoted IGF-1 expression, and treatment with AG1024 (an IGF1R inhibitor) suppressed NNMT-induced M2 polarization and inhibited IGF1B and Arg-1 expression. Taken together, our findings suggest that NNMT enhances the invasive and migratory capacity of keloid fibroblasts and regulates M2 macrophage polarization in keloids through IGF-1 modulation. These results highlight NNMT as a potential therapeutic target for keloid treatment.