m6A-binding protein YTHDF2 alleviates 3-nitropropionic acid–induced mitochondrial dysfunction of goat granulosa cells

Abstract

3-Nitropropionic acid (3-NP), a mitochondrial complex II inhibitor and prevalent environmental contaminant, has been implicated in female reproductive toxicity, yet its underlying epigenetic mechanisms remain largely unclear. In this study, we investigated the impact of 3-NP on goat granulosa cells (GCs) and the potential protective role of YTH N6-methyladenosine RNA binding protein 2 (YTHDF2). Exposure to 2.5 mM 3-NP markedly suppressed GCs proliferation and triggered apoptosis, accompanied by excessive reactive oxygen species (ROS) accumulation and mitochondrial dysfunction. Transcriptome analysis revealed 3624 differentially expressed genes (DEGs), which were significantly enriched in pathways associated with apoptosis, cell cycle regulation, and oxidative stress. Importantly, 3-NP treatment resulted in downregulation of YTHDF2 at both the transcript and protein levels. Functional experiments demonstrated that YTHDF2 overexpression mitigated 3-NP-induced GCs injury by enhancing cell viability, supporting proliferation, and attenuating apoptosis. Collectively, our findings identify YTHDF2 downregulation as a key epigenetic event mediating 3-NP–induced GC dysfunction and highlight YTHDF2 as a potential biomarker and therapeutic target for reproductive toxicity caused by this widespread environmental toxin.