2. Academic Validation
  3. Stromal cell-derived itaconate promotes endometriosis via macrophage NRF2 and lysosomal pH modulation

Stromal cell-derived itaconate promotes endometriosis via macrophage NRF2 and lysosomal pH modulation

  • Redox Biol. 2026 May:92:104101. doi: 10.1016/j.redox.2026.104101.
Zhaoyang Zhong 1,  Shuang Wang 1,  Qianhui Ren 2,  Xue Jiao 1,  Le Xu 2,  Xiaoyu Dong 2,  Na Li 2,  Hongwei Guan 2,  Ran Chu 2,  Ming Yuan 2,  Jincheng Liu 3,  Yanbo Du 4,  Keke Wei 5,  Lei Yan 6,  Guoyun Wang 7
Affiliations

Affiliations

  • 1 Department of Obstetrics and Gynecology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250000, China; Medical Integration and Practice Center, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250000, China; Shandong Key Laboratory of Reproductive Research and Birth Defect Prevention (Under Construction) Shandong Provincial Health Commission Key Laboratory of Prevention and Treatment for Major Mynecological Diseases (Under Construction), China; JiNan Key Laboratory of Diagnosis and Treatment of Major Gynaecological Disease, Jinan, Shandong Province, 250000, China; Gynecology Laboratory, Shandong Provincial Hospital, Jinan, Shandong Province, 250000, China; Gynecology Laboratory, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong Province, 250000, China.
  • 2 Department of Obstetrics and Gynecology, Shandong Provincial Hospital, Affiliated to Shandong First Medical University, Jinan, Shandong, China; Shandong Key Laboratory of Reproductive Research and Birth Defect Prevention (Under Construction) Shandong Provincial Health Commission Key Laboratory of Prevention and Treatment for Major Mynecological Diseases (Under Construction), China; JiNan Key Laboratory of Diagnosis and Treatment of Major Gynaecological Disease, Jinan, Shandong Province, 250000, China; Gynecology Laboratory, Shandong Provincial Hospital, Jinan, Shandong Province, 250000, China; Gynecology Laboratory, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong Province, 250000, China.
  • 3 State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong University, 250012, China; National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong, 250012, China; Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan, Shandong, 250012, China; Shandong Technology Innovation Center for Reproductive Health, Jinan, Shandong, 250012, China; Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, Shandong, 250012, China; Shandong Key Laboratory of Reproductive Research and Birth Defect Prevention, Jinan, Shandong, 250012, China; Research Unit of Gametogenesis and Health of ART-Offspring, Chinese Academy of Medical Sciences (No.2021RU001), Jinan, Shandong, 250012, China.
  • 4 Medical Integration and Practice Center, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250000, China; State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong University, 250012, China; National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong, 250012, China; Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan, Shandong, 250012, China; Shandong Technology Innovation Center for Reproductive Health, Jinan, Shandong, 250012, China; Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, Shandong, 250012, China; Shandong Key Laboratory of Reproductive Research and Birth Defect Prevention, Jinan, Shandong, 250012, China; Research Unit of Gametogenesis and Health of ART-Offspring, Chinese Academy of Medical Sciences (No.2021RU001), Jinan, Shandong, 250012, China.
  • 5 State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong University, 250012, China; National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong, 250012, China; Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan, Shandong, 250012, China; Shandong Technology Innovation Center for Reproductive Health, Jinan, Shandong, 250012, China; Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, Shandong, 250012, China; Shandong Key Laboratory of Reproductive Research and Birth Defect Prevention, Jinan, Shandong, 250012, China; Research Unit of Gametogenesis and Health of ART-Offspring, Chinese Academy of Medical Sciences (No.2021RU001), Jinan, Shandong, 250012, China. Electronic address: [email protected].
  • 6 Medical Integration and Practice Center, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250000, China; State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong University, 250012, China; National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong, 250012, China; Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan, Shandong, 250012, China; Shandong Technology Innovation Center for Reproductive Health, Jinan, Shandong, 250012, China; Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, Shandong, 250012, China; Shandong Key Laboratory of Reproductive Research and Birth Defect Prevention, Jinan, Shandong, 250012, China; Research Unit of Gametogenesis and Health of ART-Offspring, Chinese Academy of Medical Sciences (No.2021RU001), Jinan, Shandong, 250012, China. Electronic address: [email protected].
  • 7 Department of Obstetrics and Gynecology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250000, China; Medical Integration and Practice Center, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250000, China; Department of Obstetrics and Gynecology, Shandong Provincial Hospital, Affiliated to Shandong First Medical University, Jinan, Shandong, China; Shandong Key Laboratory of Reproductive Research and Birth Defect Prevention (Under Construction) Shandong Provincial Health Commission Key Laboratory of Prevention and Treatment for Major Mynecological Diseases (Under Construction), China; JiNan Key Laboratory of Diagnosis and Treatment of Major Gynaecological Disease, Jinan, Shandong Province, 250000, China; Gynecology Laboratory, Shandong Provincial Hospital, Jinan, Shandong Province, 250000, China; Gynecology Laboratory, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong Province, 250000, China. Electronic address: [email protected].
PMID: 41780193 DOI: 10.1016/j.redox.2026.104101
Abstract

Endometriosis (EM) is driven by immune dysregulation and macrophage dysfunction, yet the underlying mechanisms remain unclear. Here, metabolomic profiling revealed excessive itaconate accumulation in EM lesions, primarily due to elevated cis-aconitate decarboxylase 1 (ACOD1) expression in ectopic stromal cells (ESCs). ESC-derived itaconate was internalized by peritoneal macrophages, where it suppressed pro-inflammatory activity and phagocytosis, thereby facilitating ESC survival and dissemination. Mechanistically, itaconate exerted dual regulatory effects on macrophages: it activated NRF2 signaling to repress the transcription of pro-inflammatory genes, and it enhanced lysosomal acidification, thereby reducing lysosomal calcium release, which in turn inhibited p38-MAPK activation and further attenuated pro-inflammatory gene expression. In vivo, ACOD1 inhibition restored macrophage function and reduced lesion burden, while exogenous 4-octyl itaconate aggravated disease progression. These findings define a novel "ESC-ACOD1-itaconate-macrophage" axis that mediates immunosuppression in EM and identify ACOD1 as potential therapeutic targets.

Keywords

ACOD1; Endometriosis; Itaconate; Lysosome; Macrophage.

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