METTL3/ALKBH5‐Mediated N6‐Methyladenosine Modification Drives Macrophage M1 Polarization via the SLC15A3‐TASL‐IRF5 Signaling Axis in Psoriasis

Abstract Impaired N6‐methyladenosine (m 6 A) modification has been implicated in regulating various inflammatory diseases, but its role in psoriasis remains unclear. Here, m 6 A modification and its methyltransferase METTL3 are revealed to be upregulated in psoriatic macrophages, while the demethylase ALKBH5 is downregulated. Conditional knockout of Mettl3 in macrophages alleviated psoriasis‐like symptoms in mice, whereas knockout of Alkbh5 exacerbated them. Both in vivo and in vitro, Mettl3 deficiency inhibited IMQ‐induced M1 macrophage polarization, while Alkbh5 deficiency promoted M1 polarization. The regulation of macrophage polarization by m 6 A is likely mediated by targeting Slc15a3 . SLC15A3 enhances the recruitment of TASL, a recently identified endolysosomal IRF5 adaptor, which functions similarly to the IRF3 adaptors STING and MAVS at the endoplasmic reticulum (ER) and mitochondria, respectively, to augment IRF5 signaling via SLC15A4. The findings underscore the critical role of m 6 A RNA modification in psoriasis pathogenesis and unveil a novel regulatory mechanism of TASL‐IRF5 signaling through m 6 A modification, suggesting potential new therapeutic targets for psoriasis treatment.