Epidermal METTL1‐Mediated m7G Modification Drives Psoriatic Inflammation by Stabilizing <i>Bdkrb1</i> and Orchestrating Neutrophil Recruitment

ABSTRACT The functional significance of RNA modifications, specifically N7‐methylguanosine (m7G), in inflammatory conditions such as psoriasis remains not fully elucidated. This study demonstrates that methyltransferase‐like 1 (METTL1), an m7G methyltransferase, is significantly upregulated in epidermal keratinocytes of human psoriatic lesions and imiquimod (IMQ)‐induced murine models. Utilizing mice with an inducible keratinocyte‐specific Mettl1 deletion ( Mettl1 fl/fl Krt14 ‐Cre ERT2 ), the research reveals significantly attenuated psoriasiform inflammation and decreased neutrophil infiltration relative to Mettl1 fl/fl counterparts. Mechanistically, METTL1 drives inflammation by augmenting Bdkrb1 mRNA stability through m7G modification. This stabilization leads to elevated bradykinin receptor B1 (BDKRB1) protein expression, which activates the p38 mitogen‐activated protein kinase (MAPK) pathway in keratinocytes, promoting the secretion of key proinflammatory C‐X‐C motif chemokine ligand (CXCL) chemokines and robust neutrophil chemotaxis. Crucially, both in vivo genetic BDKRB1 overexpression and pharmacological BDKRB1 activation successfully rescue the attenuated inflammatory phenotype in Mettl1 ‐deficient mice, firmly validating this specific signaling cascade. Conversely, pharmacological inhibition of the METTL1–BDKRB1 axis effectively mitigates psoriasiform inflammation. Collectively, these data establish that METTL1 modulates psoriasis by fostering p38‐dependent chemokine production and neutrophil recruitment, identifying the METTL1–BDKRB1 axis as a novel therapeutic target.