FTO/SOCS6-m6A axis epigenetic modification links obesity to atopic dermatitis by regulating keratinocyte function.

Atopic dermatitis (AD) is characterized by epidermal barrier dysfunction and immune dysregulation. Notably, metabolic disorders such as obesity can influence AD susceptibility; however, the specific molecular drivers underlying this association, particularly those involving dysregulated RNA metabolism, remain incompletely understood. Our study demonstrates that obesity-associated upregulation of the N6-methyladenosine demethylase FTO (fat mass and obesity-associated) in lesional epidermis, specifically in keratinocytes, drives AD pathology. Integrated transcriptomic and epitranscriptomic sequencing analyses identified SOCS6 (suppressor of cytokine signaling 6) as a key FTO target. Mechanistically, FTO selectively binds and demethylates N6-methyladenosine modifications within the coding sequence of SOCS6 mRNA, reducing SOCS6 mRNA stability and protein expression. This site-specific epigenetic silencing activates inflammatory programs in keratinocytes. We further identified IL-1β, S100A8, and S100A9 as major downstream effectors of this FTO/SOCS6-N6-methyladenosine axis, promoting keratinocyte apoptosis, barrier impairment, and inflammation. Critically, topical FTO knockdown in vivo ameliorated AD-like pathology and restored SOCS6 expression, confirming FTO's causative role. Collectively, we elucidate the FTO/SOCS6-N6-methyladenosine epigenetic axis as a fundamental obesity-AD link, highlighting its components as promising therapeutic targets for precision AD management.