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

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. N-acetyltransferase 10 (NAT10) aggravates psoriasis by promoting keratinocytes fatty acid synthesis via stable fatty acid synthase (FASN) transcription. NAT10 regulates keratinocyte proliferation via N4-acetylcytidine (ac4C) modification. The transcriptional and translational levels of NAT10 are significantly increased during the onset of psoriasis. Overexpressed NAT10 directly interacts with its downstream target gene FASN, enhancing the stability of FASN mRNA and promoting fatty acid synthesis. This process, in turn, regulates keratinocyte hyperproliferation. • N-acetyltransferase 10 (NAT10) expression and its ac4C (N4-acetylcytidine) modification are markedly elevated in psoriatic keratinocytes. • NAT10-mediated ac4C enhances fatty acid synthase (FASN) mRNA stability to drive fatty acid metabolic reprogramming, and multi-level validation confirms FASN as a direct NAT10 target. • Genetic or pharmacological inhibition of NAT10 markedly alleviates psoriatic pathology, identifying NAT10 as a promising therapeutic target.