MiR ‐146a‐5p Suppresses M1 Polarization of Tumor‐Associated Macrophages via IRAK1 / NF ‐ κB Signaling in Colorectal Polyps

Background: Tumor-associated macrophages (TAMs) play a pivotal role in shaping the inflammatory microenvironment of colorectal polyps. MiR-146a-5p has been implicated in innate immune regulation, but its function in TAM polarization and polyp pathogenesis remains unclear. Methods: Forty paired colorectal polyp and adjacent normal tissues were analyzed for miR-146a-5p, IRAK1, and macrophage markers (CD86/CD206) by qRT-PCR and immunohistochemistry. THP-1-derived macrophages were polarized to M1 or M2 phenotypes, transfected with miR-146a-5p mimic/inhibitor, si-IRAK1, or IRAK1 overexpression plasmids, and treated with polyp-conditioned medium (Polyp-CM) where indicated. Macrophage polarization was evaluated by flow cytometry, qRT-PCR, ELISA, and Western blot. Dual-luciferase reporter assays in HEK293T cells validated direct targeting of IRAK1 by miR-146a-5p. Rescue experiments assessed the functional contribution of IRAK1 and NF-κB signaling to M1 polarization. Results: MiR-146a-5p was significantly downregulated in polyp tissues, whereas IRAK1 and M1 macrophage markers (CD86, iNOS) were upregulated, with a strong negative correlation between miR-146a-5p and IRAK1. Overexpression of miR-146a-5p in macrophages suppressed M1 polarization, decreased pro-inflammatory cytokines (TNF-α, IL-6), and reduced NF-κB activation, while miR-146a-5p inhibition enhanced these responses. Dual-luciferase assays confirmed IRAK1 as a direct target of miR-146a-5p. Silencing IRAK1 or inhibiting NF-κB rescued the pro-M1 effects induced by miR-146a-5p loss. Conversely, IRAK1 overexpression promoted M1 polarization, which was attenuated by miR-146a-5p co-expression. Polyp-CM experiments corroborated these effects under tumor-mimicking inflammatory conditions. Conclusion: These findings suggest that the miR-146a-5p/IRAK1/NF-κB axis may represent a potential therapeutic target for modulating macrophage-mediated inflammatory responses in colorectal polyps.