Dietary Caloric Restriction Suppresses Endometriosis by Inhibiting <scp>STAT3</scp> / <scp>ERK</scp> Pathways

Endometriosis is a chronic, estrogen-dependent inflammatory condition that affects approximately 10% of reproductive-age women and is frequently associated with infertility and pelvic pain. Unlike many estrogen-dependent disorders, epidemiologic studies have reported inconsistent associations between obesity, measured by BMI, and endometriosis. Caloric restriction diet (CRD), a dietary regimen that reduces energy intake without malnutrition, has demonstrated anti-inflammatory and anti-proliferative effects in various chronic diseases but remains underexplored in endometriosis. Here, we investigated the effects of CRD on endometriosis using a mouse model with a GFP reporter. Endometriosis was surgically induced by inoculating endometrial fragments, and mice were randomized to receive either ad libitum feeding (regular diet, RD) or CRD. After 90 days, CRD mice exhibited a 24.5% reduction in body weight compared to RD mice, without impairment of female fertility. Notably, both the number and weight of ectopic lesions were significantly reduced in the CRD group compared to the RD group. Immunohistochemical analysis revealed decreased epithelial and stromal cell proliferation, increased apoptosis, and elevated stromal progesterone receptor expression in ectopic lesions from CRD mice. Furthermore, phosphorylation of STAT3 and ERK1/2, key inflammatory and proliferative signaling molecules, was significantly reduced in ectopic lesions from CRD mice. These findings suggest that CRD, without compromising fertility, exerts beneficial effects on endometriosis by targeting cell proliferation, survival, and inflammation. Our results support lifestyle-based dietary interventions as a promising non-hormonal strategy for endometriosis management.