NAT10 enzyme drives follicular atresia through ac4C modification of Tnc mRNA

A new study in Cell Death Discovery reports that the RNA-modifying enzyme N-acetyltransferase 10 (NAT10) promotes follicular atresia, the degeneration of ovarian follicles, by stabilizing the mRNA of the extracellular matrix glycoprotein Tnc through N4-acetylcytidine (ac4C) modification. The researchers found that both ac4C RNA levels and NAT10 expression were significantly increased in atretic follicles, linking this chemical RNA tag to the programmed death of granulosa cells that underlies ovarian dysfunction and infertility or subfertility in mammals.

Follicular atresia mediated by programmed granulosa cell death directly contributes to ovarian dysfunction-related disorders and infertility or subfertility in mammals, according to the study. Although NAT10-catalyzed ac4C modification has previously been identified as a driver of multiple biological processes, its role in granulosa cell death and follicular atresia had remained unclear until now.

Functionally, the team showed that NAT10 promotes oxidative stress in granulosa cells by inhibiting mitophagy, the cellular process that clears damaged mitochondria, in vitro.

At the mechanistic level, the researchers identified Tnc mRNA, which encodes an important extracellular matrix glycoprotein, as a direct target of NAT10-catalyzed ac4C modification. This modification enhances the stability of Tnc mRNA, which in turn inhibits mitophagy and promotes oxidative stress in granulosa cells, thereby contributing to the progression of follicular atresia.

The study also uncovered how Tnc interferes with mitochondrial quality control. Tnc protein was found to directly bind Parkin, a key mediator of mitophagy, and to accelerate the ubiquitination and proteasomal degradation of Parkin. This degradation inhibits the Parkin-mediated mitophagy pathway, completing a chain of events that runs from an RNA chemical modification to mitochondrial dysfunction and cell death.

Notably, the NAT10 inhibitor Remodelin promoted mitophagy and inhibited oxidative stress of granulosa cells in vitro. In vivo, the compound hindered follicular atresia and ameliorated impaired reproductive efficiency caused by granulosa cell oxidative stress, acting through the NAT10-ac4C-Tnc pathway the authors describe.

These findings suggest that NAT10 drives follicular atresia progression through regulation of Tnc mRNA stability, and that Remodelin could be a promising therapeutic candidate for targeting NAT10 in follicular atresia and in infertility or subfertility treatment, according to the authors.

The work, published open access on 25 October 2026, is being shared early as a peer-reviewed, accepted manuscript that is citable and carries a permanent DOI, subject to further edits before the final version of record. As with any preclinical study, the in vitro findings and the in vivo results on reproductive efficiency will require further validation before any clinical application, and the reported effects of Remodelin remain experimental rather than established treatments.

Subject of Research: The role of NAT10-catalyzed ac4C modification of Tnc mRNA in granulosa cell oxidative stress and follicular atresia

Article Title: Targeting NAT10 alleviates granulosa cells oxidative stress and follicular atresia by disrupting ac4C acetylation of Tnc

Article References: Zhou, X., Wang, Y., Liu, Y., Zhao, X., Zhao, Y., Niu, L., Chen, L., Gan, M., Zhu, L., & Shen, L. (2026). Targeting NAT10 alleviates granulosa cells oxidative stress and follicular atresia by disrupting ac4C acetylation of Tnc. Cell Death Discovery. https://doi.org/10.1038/s41420-026-03423-1

Image Credits: AI Generated

DOI: 10.1038/s41420-026-03423-1

Keywords: NAT10, ac4C, Tnc, granulosa cells, follicular atresia, mitophagy, Parkin, oxidative stress, Remodelin, ovarian dysfunction, infertility, RNA modification