RNF34 restrains endometriosis through SREBP1-dependent metabolic-immune crosstalk

Abstract 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. Similar content being viewed by others Funding The study was supported by research grants from National Natural Science Foundation of China (Grant no. 81972489 and 82003201), National Natural Science Foundation of Shandong Province (Grant no. ZR2020YQ58), Shandong Province College Science and Technology Plan Project (Grant no. J17KA254). Author information Authors and Affiliations Corresponding authors Ethics declarations Ethics All animal protocols were performed according to the guidelines and approved by the Institutional Animal Care and Use Committee of Shandong Second Medical University (Approval number: 2024SDL697). An informed consent form was signed by all patients in accordance with the Declaration of Helsinki, and the study was approved by the Affiliated Hospital of Shandong Second Medical University (Approval number: wyfy-2024-ky-321). Competing interests The authors declare no competing interests. Additional information Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Supplementary Information Below is the link to the electronic supplementary material. Rights and permissions Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/. About this article Cite this article Yue, C., Li, Z., Wang, M. et al. RNF34 restrains endometriosis through SREBP1-dependent metabolic-immune crosstalk. Cell. Mol. Life Sci. (2026). https://doi.org/10.1007/s00018-026-06290-2 Received: Revised: Accepted: Published: DOI: https://doi.org/10.1007/s00018-026-06290-2