Heat stress suppresses keratinocyte inflammation in psoriasis via HSF1-METTL14-mediated m6A regulation of CRYAB

Keratinocyte-driven inflammation plays a central role in the pathogenesis of psoriasis. Although hyperthermia therapy has demonstrated clinical benefits, its underlying molecular mechanisms remain incompletely understood. Here, we show that local hyperthermia at 41 °C significantly alleviates imiquimod-induced psoriasiform inflammation and suppresses NF-κB signaling. The small heat shock protein CRYAB, which is downregulated in psoriatic lesions and inversely associated with disease severity, is markedly upregulated in response to heat stress. Elevated CRYAB expression inhibits IKKβ-dependent NF-κB activation and mitigates inflammatory responses in psoriatic skin. Heat exposure also enhances the expression of the m 6 A methyltransferase METTL14 in keratinocytes. Mechanistically, heat-activated HSF1 contributes to METTL14 upregulation and exhibits increased enrichment at a predicted HSF1-binding region within the METTL14 promoter. Consistent with previous observations, METTL14 is reduced in psoriatic lesions, and its overexpression suppresses NF-κB–mediated inflammation. Bioinformatic analysis predicts multiple m 6 A sites in CRYAB mRNA, and mechanistic studies confirm that METTL14 facilitates CRYAB m 6 A methylation under heat stress, thereby promoting its expression and anti-inflammatory function. IGF2BP2 further facilitates CRYAB expression as an m6A reader. Together, these findings identify an HSF1–METTL14–m 6 A–CRYAB–NF-κB regulatory axis underlying the anti-inflammatory effects of hyperthermia and provide mechanistic insights into its therapeutic effects in psoriasis.