Hypoxia-induced miR-21-5p promotes autophagy by downregulating CDC25A in endometriosis

Endometriosis is a common gynecological disorder affecting women of reproductive age, often leading to chronic pain, reduced quality of life, and infertility. It is characterized by ectopic endometrial growth within a hypoxic peritoneal environment. Autophagy, a cellular recycling pathway, is elevated in ectopic lesions. However, how hypoxia regulates autophagy to drive lesion development remains unclear. We found that inhibition of autophagy with chloroquine reduced stromal cell growth under hypoxia. The microRNA miR-21-5p, previously shown to be elevated by hypoxia in ectopic lesions, was examined and found to target cell division cycle 25A (CDC25A). Overexpression of miR-21-5p suppressed CDC25A. Under hypoxia, yes-associated protein 1 (YAP1) nuclear accumulation increased miR-21-5p, which in turn further reduced CDC25A expression. Silencing CDC25A enhanced autophagic flux, whereas pharmacologic inhibition of YAP1 with verteporfin restored CDC25A and p62 in mouse lesions and reduced lesion size. Collectively, these findings demonstrate that hypoxia activates YAP1-driven miR-21-5p, which represses CDC25A to promote autophagy and sustain lesion survival, highlighting the miR-21-5p/CDC25A axis as a potential therapeutic target.