Epidermal METTL1-Mediated m7G Modification Drives Psoriatic Inflammation by Stabilizing Bdkrb1 and Orchestrating Neutrophil Recruitment

  • Adv Sci (Weinh). 2026 Jun 9:e75970. doi: 10.1002/advs.75970.
Chang Zhang  1  2  3  4 ,  Jiayi Lu  1  2  3  4 ,  Sihao Yan  1  2  3  4 ,  Yirui Wang  5  6  7  8 ,  Zhuo Li  5  6  7  8 ,  Weiwei Chen  5  6  7  8 ,  Yang Han  5  6  7  8 ,  Ziyan Zhang  5  9 ,  Yafen Yu  10 ,  Qi Zhen  5  6  7  8 ,  Liangdan Sun  1  2  3  4  5  6  7  8  9
Affiliations
  • 1. Department of Dermatology, the First Affiliated Hospital of Anhui Medical University, Hefei, China.
  • 2. Institute of Dermatology, Anhui Medical University, Hefei, Anhui, China.
  • 3. Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, Anhui, China.
  • 4. Collaborative Innovation Center of Complex and Severe Skin Disease, Anhui Medical University, Hefei, Anhui, China.
  • 5. North China University of Science and Technology Affiliated Hospital, Tangshan, China.
  • 6. North China University of Science and Technology, Tangshan, Hebei, China.
  • 7. Hebei Key Laboratory of Medical Engineering and Integrated Utilization of Saline alkali Land, Tangshan, Hebei, China.
  • 8. Hebei Administration of TCM, Key Laboratory of Quality Control of Salt alkali Resistant TCM, Tangshan, Hebei, China.
  • 9. School of Public Health, North China University of Science and Technology, Tangshan, Hebei, China.
  • 10. The Center for Scientific Research, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
PMID: 42261843 DOI: 10.1002/advs.75970
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 (Mettl1fl/flKrt14-CreERT2), the research reveals significantly attenuated psoriasiform inflammation and decreased neutrophil infiltration relative to Mettl1fl/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.

Keywords
Bdkrb1; Mettl1; RNA modifications; chemotaxis; m7G; neutrophil; psoriasis.
Products