2. Academic Validation
  3. Gut microbiota derived butyrate enhances ferroptosis sensitivity in endometriosis through FFAR2/PPAR-γ/PINK1/Parkin mediated mitophagy

Gut microbiota derived butyrate enhances ferroptosis sensitivity in endometriosis through FFAR2/PPAR-γ/PINK1/Parkin mediated mitophagy

  • Free Radic Biol Med. 2025 Oct:238:640-652. doi: 10.1016/j.freeradbiomed.2025.07.019.
Yanling Gou 1,  Jin Ding 2,  Honglin Wang 1,  Ruru Bai 1,  Hongli Wang 1,  Beidi Wang 1,  Yingying Cao 1,  Jinming Liu 1,  Jing Cui 1,  Zongfeng Zhang 3
Affiliations

Affiliations

  • 1 Department Obstetrics & Gynecology, Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China.
  • 2 Department Obstetrics & Gynecology, First Affiliated Hospital of Wannan Medical College, Wuhu, 241001, China.
  • 3 Department Obstetrics & Gynecology, Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China. Electronic address: zongfengzhang@hrbmu.edu.cn.
PMID: 40669572 DOI: 10.1016/j.freeradbiomed.2025.07.019
Abstract

Endometriosis (EMs) is a chronic, estrogen-dependent disease defined by the presence of endometrial-like tissue outside the uterine cavity. Gut microbiota has emerged as potent inducer for chronic inflammatory disease, yet whether its mechanism in EMs remains elusive. In vivo EMs models were established using both microbiota-depleted (MD) and control mice to explore the role of gut microbiota in EMs. Stool samples were also collected from human patients with either endometriosis or benign ovarian cysts for 16S rRNA Sequencing. CCK8, transmission electron microscopy, liperfluo, FerroOrange, MDA, GSH, JC-1, mitotracker, lysotracker, and mitoSOX assays were used to access the function of butyrate in endometriotic stromal cells (ESCs). Furthermore, westen blot was used to detect the signaling pathway involved in the process of butyrate. Results showed that depleting the gut microbiota in MD mice led to a significant increase in the volume and weight of endometriotic lesions. 16S rRNA Sequencing revealed that patients with EMs had lower abundances of butyrate-producing microbiota compared to the control group. Butyrate supplementation in MD mice significantly reduced the growth of lesions. Mechanistically, butyrate was found to enhance the sensitivity of cells to erastin-induced Ferroptosis. This effect was dependent on impaired Mitophagy pathway. Further investigation showed that butyrate enhances Ferroptosis sensitivity by impairing Mitophagy through the FFAR2/PPAR-γ/PINK1/Parkin signaling pathway. The findings suggest that a deficiency in butyrate-producing gut microbiota contributes to the progression of endometriosis. Butyrate appears to counteract this by enhancing Ferroptosis in ESCs via the FFAR2-mediated impairment of Mitophagy. Therefore, butyrate shows potential as a therapeutic agent for the treatment of endometriosis.

Keywords

Butyrate; Endometriosis; Ferroptosis; Gut microbiota; Mitophagy.

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