CircZFR/YTHDF3 axis drives lymph node metastasis in cervical cancer via FASN translation

Lymph node metastasis is a key driver of poor outcomes in cervical cancer. However, the molecular mechanisms of circular RNAs (circRNAs) driving cervical cancer lymph node metastasis remain unclear.

We identified circZFR, fatty acid synthase (FASN) and YTH N6-methyladenosine RNA binding protein F3 (YTHDF3) protein expression in the cervical cancer patients with long and short disease-free survival (DFS). Functional experiments were performed to investigate the function of circZFR, FASN and YTHDF3 on cell migration and invasion. MeRIP-qPCR, RNA pulldown, RNA Immunoprecipitation (RIP), and Co-Immunoprecipitation (Co-IP) assays were executed to investigate the mechanism of circZFR regulating FASN protein expression.

Our study reveals that elevated FASN protein is closely linked to metastasis and reduced survival, and identified a regulatory mechanism involving circular RNAs. We identified circZFR as a crucial regulator, significantly enhancing FASN protein expression. CircZFR overexpression was significantly correlated with accelerated lymph node metastasis and shortened DFS. Mechanistically, circZFR binds to the m⁶A reader protein YTHDF3, facilitating m⁶A recognition on FASN mRNA and recruiting the translation initiator eIF4A3, thereby boosting FASN translation.

These findings establish circZFR as a pivotal driver of cervical cancer progression and highlight its inhibition as a promising therapeutic strategy.