RNF34 restrains endometriosis through SREBP1-dependent metabolic-immune crosstalk.

Endometriosis is a chronic inflammatory disease with cancer-like features, yet the mechanisms linking metabolic dysregulation to immune remodeling during lesion progression remain poorly understood. Here, we identify the ubiquitin E3 ligase RNF34 as a central suppressor of endometriosis that integrates cell-intrinsic metabolic control with macrophage-mediated immune regulation. Mechanistically, RNF34 directly interacts with SREBP1 and promotes its K48 and K63-linked ubiquitination and proteasomal degradation, thereby restraining lipogenic gene expression and fatty acid synthesis in endometrial stromal cells. Functionally, RNF34 suppresses stromal cell proliferation, clonogenic growth, migration, and invasion in an SREBP1-dependent manner. Loss of RNF34 stabilizes SREBP1, leading to excessive synthesis and extracellular release of monounsaturated fatty acids, particularly oleic acid. Oleic acid acts as a paracrine metabolic cue that drives macrophage polarization toward an immunosuppressive M2-like phenotype, which in turn reinforces endometriotic cell proliferation, migration, and resistance to apoptosis, establishing a feed-forward metabolic-immune circuit. In vivo, genetic ablation of RNF34 markedly accelerates endometriosis development, accompanied by increased accumulation of M2 macrophages within ectopic lesions, whereas pharmacological inhibition of SREBP1 or macrophage depletion using clodronate liposomes significantly suppresses lesion growth. Consistently, human endometriotic tissues exhibit reduced RNF34 expression that inversely correlates with SREBP1 abundance and M2 macrophage markers. Collectively, our findings define an RNF34-SREBP1-oleic acid axis that links lipid metabolism to immune remodeling in endometriosis, revealing a metabolically driven therapeutic vulnerability.