N⁶-methyladenosine modification-tuned lipid metabolism controls skin immune homeostasis via regulating neutrophil...

Disrupted N⁶-methyladenosine (m⁶A) modification modulates various inflammatory disorders. However, the role of m⁶A in regulating cutaneous inflammation remains elusive. Here, we reveal that the m⁶A and its methyltransferase METTL3 are down-regulated in keratinocytes in inflammatory skin diseases. Inducible deletion of Mettl3 in murine keratinocytes results in spontaneous skin inflammation and increases susceptibility to cutaneous inflammation with activation of neutrophil recruitment. Therapeutically, restoration of m⁶A alleviates the disease phenotypes in mice and suppresses inflammation in human biopsy specimens. We support a model in which m⁶A modification stabilizes the mRNA of the lipid-metabolizing enzyme ELOVL6 via the m⁶A reader IGF2BP3, leading to a rewiring of fatty acid metabolism with a reduction in palmitic acid accumulation and, consequently, suppressing neutrophil chemotaxis in cutaneous inflammation. Our findings highlight a previously unrecognized epithelial-intrinsic m⁶A modification-lipid metabolism pathway that is essential for maintaining epidermal and immune homeostasis and lay the basis for potential therapeutic targeting of m⁶A modulators to attenuate inflammatory skin diseases.