METTL7A‐Dependent m ⁶ A Methylation Orchestrates CXCR4 ^hi Neutrophil Pathogenicity and NETosis in Skin Inflammation

ABSTRACT Neutrophil extracellular traps (NETs) released by C–X–C motif chemokine receptor 4‐high (CXCR4 hi ) neutrophils are major contributors to skin inflammation in psoriasis, yet the upstream epitranscriptomic mechanisms that regulate NETosis remain poorly defined. Here, we investigated the role of methyltransferase‐like protein 7A (METTL7A) in N 6 ‐methyladenosine (m 6 A)‐mediated neutrophil activation and psoriasis pathogenesis. Using transcriptomic profiling of CXCR4 hi neutrophils from psoriasis patients, m 6 A RNA immunoprecipitation, in vitro functional assays, and in vivo murine models of skin inflammation, along with genetic silencing and adoptive transfer experiments, we demonstrated that METTL7A was preferentially upregulated in pathogenic and aged CXCR4 hi neutrophils and was positively associated with disease severity. METTL7A expression also increased during human promyelocytic leukemia cells(HL‐60 cell differentiation, maturation, and activation. Silencing METTL7A inhibited neutrophil maturation and aging, reduced NETosis, and alleviated psoriasiform inflammation in vivo. Adoptive transfer of METTL7A ‐deficient neutrophils further protected mice from skin inflammation. Mechanistically, METTL7A stabilized phospholipid scramblase 1 ( PLSCR1 ) mRNA through m 6 A‐associated regulation, thereby enhancing reactive oxygen species production and neutrophil extracellular traps (NETs) formation. These findings identify METTL7A as a novel epitranscriptomic regulator of pathogenic CXCR4 hi neutrophils, acting through the METTL7A–PLSCR1 axis to drive NETosis and skin inflammation, thereby providing a rationale for developing m 6 A‐targeted therapies in neutrophil‐associated disorders.