Urolithin C Exerts Anti-Endometrial Cancer Effects by Inducing Autophagy Through Specific Stimulation of ATF3

Urolithin C (UC), a natural compound derived from the metabolism of ellagitannins by gut microbiota, exhibits diverse pharmacological and biological activities. However, its therapeutic potential and underlying mechanisms in endometrial Cancer (EC) remain unclear. Functional assays were used to determine the effects of UC on the viability, proliferation, cell cycle, Apoptosis, migration, and Autophagy in EC cells. RNA Sequencing was used to investigate the effect of UC on total gene expression in EC cells. The expression level of activating transcription factor 3 (ATF3) was evaluated using western blotting, Real-Time PCR, and immunofluorescence staining. Organoids and a mouse model of EC were used to analyze the anti-tumor effects of UC. UC significantly inhibited the malignant behavior of EC cells. High-throughput transcriptome Sequencing revealed a close association between Autophagy and UC treatment, and identified ATF3 as a key downstream factor. UC treatment increased the expression of ATF3, which was primarily localized to the nucleus. Elevated ATF3 levels positively correlated with the survival of patients with EC. ATF3 knockdown rescued the effects of UC on cell viability, migration, and Autophagy. Furthermore, EC Organoid and in vivo experiments showed that UC markedly reduced Organoid viability and EC tumor growth. UC exerts anti-EC activity by promoting ATF3 expression, thereby inhibiting the malignant behavior of EC cells and promoting autophagic cell death.