Abstract
Endometriosis is an estrogen-dependent chronic inflammatory disorder. Cholesterol (CHO) has been reported to be closely associated with estrogen synthesis and inflammatory responses. Nevertheless, the mechanisms underlying the effects of cholesterol on endometriosis progression and immune response remain to be elucidated. Our research revealed that cholesterol accumulation in ectopic lesions acts as a crucial catalyst for the progression of endometriosis. Using a co-culture system, we simulated a cholesterol-abundant ectopic milieu and demonstrated cholesterol induced M2 macrophage polarization via the STAT6/PPARγ pathway, connecting cholesterol metabolism to immune response in endometriosis. Notably, cholesterol-induced M2 macrophage polarization accelerated the aggressive behavior of ectopic endometrial stromal cells (EESCs). Furthermore, we identified solute carrier family 25 member 1 (SLC25A1) as a pivotal target for regulating cholesterol metabolism in endometriosis, as it significantly upregulated in ectopic lesions and markedly increased intracellular and extracellular cholesterol content. In vitro and in vivo experiments revealed that cholesterol supplementation reversed the cellular and immune microenvironment alterations caused by SLC25A1 knockdown. Collectively, our results demonstrated that SLC25A1 upregulated the cholesterol metabolism in EESCs and mediated M2 macrophages polarization via the STAT6/PPARγ signaling pathway. Our study on the molecular mechanisms underlying cholesterol accumulation and function may provide potential targets and therapeutic strategies for endometriosis management.