TET3-overexpressing macrophages promote endometriosis

Endometriosis is a debilitating, chronic inflammatory condition affecting approximately 10% of women of reproductive age globally, with no known cure. Macrophages play a crucial role in the pathology of endometriosis, but targeting them therapeutically has proven difficult due to their diversity and the dual nature of disease-associated macrophages (DAMs), which can either contribute to or protect against the disease. In this study, we identified a subset of pathogenic macrophages in human endometriosis lesions characterized by the overexpression of TET3. We found that factors within the disease microenvironment upregulated TET3, transforming macrophages into pathogenic DAMs. TET3 overexpression promoted the production of pro-inflammatory cytokines through a feedback mechanism involving the inhibition of let-7 miRNA expression. Notably, these macrophages depended on TET3 overexpression for their survival, making them susceptible to TET3 knockdown. We demonstrated that Bobcat339, a synthetic cytosine derivative, induced TET3 degradation in both human and mouse macrophages. This degradation was mediated by the VHL E3 ubiquitin ligase, which was also upregulated in TET3-overexpressing macrophages. Additionally, depleting TET3-overexpressing macrophages through myeloid-specific Tet3 ablation or treatment with Bobcat339 significantly inhibited endometriosis progression in mice. Our findings establish TET3-overexpressing macrophages as key pathogenic drivers and promising therapeutic targets for endometriosis. These insights may also be relevant for other chronic inflammatory diseases where DAMs play a critical role.