NAT10 deficiency in aging drives impaired liver regeneration by disrupting PARP10 in an ac4C-dependent manner

The age-related decline in liver regenerative capacity worsens outcomes for elderly patients with liver disease or undergoing liver surgery, and therapeutic options are limited. The RNA modification N4-acetylcytidine (ac4C), catalyzed by N-acetyltransferase 10 (Nat10), is implicated in regeneration; however, its role in the aged liver remains unknown.

We quantified Nat10/ac4C levels in human and murine livers across ages and correlated them with regenerative capacity. Function was assessed via hepatocyte-specific knockout, adeno-associated virus (AAV)-mediated gene manipulation, and pharmacological inhibition. Mechanisms were defined using integrated ac4C-specific immunoprecipitation sequencing (ac4C-seq), ribosome profiling (Ribo-seq), and RNA sequencing (RNA-seq).

Hepatic Nat10 and ac4C levels decreased with age. Disruption of Nat10/ac4C impaired liver regeneration, whereas their augmentation enhanced it. Multi-omics integration linked ac4C to coordinated changes in mRNA abundance, stability, and translation. Mechanistically, Nat10 installed ac4C on Parp10 mRNA to enhance its stability and translational efficiency. Upregulated Parp10 inhibited GSK3β, thereby activating pro-regenerative β-catenin signaling. Furthermore, we identified the age-related decline in Nat10 was attributed to loss of its transcriptional driver, ATF3. Pharmacological induction of ATF3 restored Nat10 expression and rescued regeneration in aged liver.

Our study highlights the critical role of Nat10 in liver regeneration via mRNA ac4C-manner and identifies its age-related decline as a reversible impairment. Targeting this presents a promising therapeutic strategy for stimulating regeneration in the aged liver.