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

Xiaorong Wang, Wang X, Zhu J, Jingwen Zhu, Li J, Jie Li, Yan Huang, Huang Y, Qing Xue, Xue Q
Clinical science (London, England : 1979) · 2026 · vol. 140(11) , pp. 2387–2409 · doi:10.1042/cs20261535 · PMID:42803692 · W7214614230
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E2F1 downregulation impairs MGLL-mediated lipid mobilization, promoting lipid droplet accumulation and endometriosis development through altered phospholipid and cholesterol levels in ectopic stromal cells.

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Abstract

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 (SMs), and acylcarnitines. Both ectopic lesions and ectopic stromal cells showed increased triacylglycerol and total cholesterol levels, lipid droplet accumulation, and reduced E2F transcription factor 1 (E2F1) expression. Integrated epigenomic and transcriptomic analyses of patient-derived ectopic stromal cells, together with mechanistic validation, revealed that E2F1 transcriptionally activates monoacylglycerol lipase gene (MGLL), which encodes monoacylglycerol lipase, a lipolytic enzyme involved in lipid mobilization. Both in vitro and in vivo experiments showed that down-regulation 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 SM profiles. In summary, our findings suggest that E2F1 down-regulation reduces MGLL expression and impairs lipid mobilization, which may contribute to lipid droplet accumulation and endometriotic lesion growth.

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MeSH descriptors

E2F1 Transcription Factor E2F1 Transcription Factor E2F1 Transcription Factor E2F1 Transcription Factor Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Lipid Droplets Lipid Droplets Lipid Droplets Lipid Mobilization Lipid Mobilization Monoacylglycerol Lipases Monoacylglycerol Lipases Monoacylglycerol Lipases Monoacylglycerol Lipases Animals

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