NAT10 exacerbates aortic valve calcification via PCSK9 mRNA ac4C acetylation.

N4-acetylcytidine (ac4C) is an epitranscriptomic regulator involved in diverse pathological processes. This study investigates the role of N-acetyltransferase 10 (NAT10), the primary enzyme responsible for ac4C deposition, in aortic valve calcification (AVC). NAT10 expression and global ac4C levels are upregulated in calcified aortic valves from human patients and murine models. Clinically, elevated NAT10 expression correlates with increased disease severity. Functionally, NAT10 promotes human valvular interstitial cells (hVICs) osteogenic differentiation. In high-cholesterol diet (HCD)-fed ApoE -/- mice, pharmacological NAT10 inhibition (via remodelin) or targeted degradation (via PROTAC NP1192) ameliorates AVC. Mechanistically, we identified the pro-calcific gene proprotein convertase subtilisin/kexin type 9 (PCSK9) as a downstream target of NAT10. NAT10 catalyzes the ac4C modification of PCSK9 mRNA, thereby enhancing its transcript stability. Collectively, our findings reveal a NAT10-ac4C-PCSK9 regulatory axis that amplifies AVC, establishing the NAT10/ac4C machinery as a promising therapeutic target for calcific aortic valve disease (CAVD).