Using gene-deficient mice and methylated RNA immunoprecipitation (meRIP) sequencing (meRIP-seq), an in-depth mechanistic exploration revealed that piENOX2 regulated macrophage polarization by modulating ALKBH5-mediated Itga4 m6A modification and inhibiting the PI3K–AKT signaling pathway, thereby contributing to RA progression. Here, ITGA4 is linked to rheumatoid arthritis.