Background and purpose
Nonalcoholic fatty liver disease (NAFLD) is a common metabolic disease with a complex pathogenesis. Although epitranscriptomic modifications such as N6-methyladenosine (m6A) are thought to be involved in NAFLD, the role of N1-methyladenosine (m1A) and its regulators is poorly understood. Recently, YTHDF1, a well-characterized m6A reader, was also shown to recognize m1A. However, the functional consequences of this bispecificity are unknown. This study aimed to investigate the role of YTHDF1 in the development of NAFLD and investigate whether its function is mediated through recognition of RNA methylation modifications on specific target mRNAs.
method
The expression of YTHDF1 in NAFLD was analyzed with GEO database. A loss-of-function study of YTHDF1 was conducted alive (mice fed high fat diet) and in vitro in the NAFLD model (free fatty acid-treated HepG2 cells). We used RNA-seq and m1A-MeRIP-seq to identify key targets, followed by biochemical, histological, and mRNA stability assays to validate the mechanism of the YTHDF1–m1A–NUPR1 axis.
result
We identified an important role for YTHDF1 in promoting hepatic steatosis. NUPR1, a stress-inducible transcriptional regulator, undergoes m1A modification. YTHDF1 directly binds to m1A-modified NUPR1 mRNA and increases its stability, thereby leading to increased NUPR1 protein levels. Functionally, upregulated NUPR1 acts as a core driver of NAFLD pathogenesis by activating adipogenic genes and suppressing fatty acid β-oxidation genes, thereby exacerbating hepatic lipid accumulation.
conclusion
Our study revealed a novel epitranscriptomic mechanism in which YTHDF1, acting as a bispecific reader, controls NAFLD progression through the m1A-NUPR1 axis. This not only expands our understanding of RNA modification recognition but also establishes the YTHDF1-m1A-NUPR1 pathway as a promising therapeutic target for metabolic liver diseases.
sauce:
Reference magazines:
Luo, N. others. (2026). m1A epitranscriptomic regulation of NUPR1 by YTHDF1 exacerbates metabolic dysregulation in nonalcoholic fatty liver disease. Journal of Clinical and Translational Hepatology. Doi: 10.14218/JCTH.2025.00570. https://www.xiahepublishing.com/2310-8819/JCTH-2025-00570
