E2F1 downregulation promotes lipid droplet accumulation and endometriosis development through impaired MGLL-mediated lipid mobilization

Endometriosis is a common gynecological disease in which lipid metabolic dysregulation has been increasingly implicated. However, the specific metabolic changes in ectopic lesions and stromal cells remain poorly understood. It is also unclear whether these changes contribute to lipid droplet accumulation or how this process is controlled at the transcriptional level. Here, we report that ectopic stromal cells exhibit broad lipid remodeling, showing changes in phosphatidylcholines, lysophosphatidylcholines, sphingomyelins, and acylcarnitines. Both ectopic lesions and ectopic stromal cells showed increased triacylglycerol and total cholesterol levels, lipid droplet accumulation, and reduced E2F1 expression. Integrated epigenomic and transcriptomic analyses of patient-derived ectopic stromal cells, together with mechanistic validation, revealed that E2F1 transcriptionally activates MGLL, which encodes monoacylglycerol lipase, a lipolytic enzyme involved in lipid mobilization. Both in vitro and in vivo experiments showed that downregulation of E2F1 increased lipid droplet accumulation, whereas restoring MGLL expression partially reversed this effect. Consistently, targeted lipidomic analysis of ectopic stromal cells following MGLL knockdown showed increased levels of several diacylglycerol species and alterations in sphingomyelin profiles. In summary, our findings suggest that E2F1 downregulation reduces MGLL expression and impairs lipid mobilization, which may contribute to lipid droplet accumulation and endometriotic lesion growth.