Key result
Targeting NAT10 attenuates aortic valve calcification in mice by disrupting the NAT10-ac4C-PCSK9 axis.
Why the study?
The role of NAT10-mediated ac4C acetylation in the pathogenesis of aortic valve calcification and its molecular mechanisms were unclear.
Does NAT10 inhibition or degradation ameliorate aortic valve calcification in preclinical models?
Does NAT10 inhibition or degradation ameliorate aortic valve calcification in preclinical models?
This study identifies the NAT10-ac4C-PCSK9 regulatory axis as a key driver of aortic valve calcification, providing early evidence that targeting the NAT10/ac4C machinery could be a promising therapeutic strategy for calcific aortic valve disease.
Hypothesis-generating for NAT10 inhibition in aortic stenosis; prospective trials needed before clinical adoption.
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).
No takes yet. Share an insight, caveat, or question.
Liu et al. (2026) studied Aortic valve calcification. NAT10 inhibition (remodelin) or targeted degradation (PROTAC NP1192) was evaluated on Aortic valve calcification severity. Pharmacological NAT10 inhibition or targeted degradation ameliorates aortic valve calcification in murine models by disrupting the pro-calcific NAT10-ac4C-PCSK9 regulatory axis.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: