NAT10 aggravates psoriasis by promoting keratinocytes fatty acid synthesis via stable FASN transcription.

Abstract

RNA modifications have emerged as critical regulators of cellular function and disease pathogenesis; however, their contribution to psoriasis remains unclear. Here, we report that N-acetyltransferase 10 (NAT10) expression is markedly elevated in the epidermis of patients with psoriasis and in imiquimod (IMQ)-induced lesions. Single-cell RNA sequencing further identifies NAT10 upregulation in hyperproliferative and basal keratinocyte subsets. Keratinocyte-specific deletion of NAT10 attenuates IMQ-induced psoriatic phenotypes in mice. Integrative profiling of RNA sequencing and N4-acetylcytidine (ac4C) immunoprecipitation sequencing reveals fatty acid synthase (FASN) as a direct downstream target of NAT10. Mechanistically, NAT10 catalyzes ac4C RNA modification to enhance the stability of FASN mRNA, thereby driving fatty acid metabolic reprogramming and promoting keratinocyte proliferation. This metabolic shift contributes to epidermal hyperplasia and inflammation in psoriasis. Notably, pharmacological inhibition of NAT10 with remodelin alleviates disease severity in vivo and in vitro. Together, these findings identify a NAT10-dependent ac4C regulatory axis that links epitranscriptomic control to metabolic dysregulation in keratinocytes and highlight NAT10 as a promising therapeutic target for psoriasis.