Metformin protects against cyclophosphamide-induced ovarian fibrosis by MIF/CD74-mediated macrophage polarization

  • J Transl Med. 2025 Nov 12;23(1):1273. doi: 10.1186/s12967-025-07294-5.
Ping Nie  1 ,  Bo Yao  1 ,  Zhejun Zhang  2 ,  Jingling Li  1 ,  Minghua Wang  3 ,  Gendie E Lash  4 ,  Bihui Guo  5 ,  Ping Li  6
Affiliations
  • 1. Department of Pathology, Jinan University School of Medicine, Guangzhou, 510632, China.
  • 2. Department of Pathology, Jinan University First Affiliated Hospital, Guangzhou, 510632, China.
  • 3. Department of Pathology, Longgang District People's Hospital, The Second Affiliated Hospital of The Chinese University of Hong Kong, Shenzhen, 518172, China.
  • 4. Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China.
  • 5. Department of Obstetrics and Gynecology, Huizhou Second Maternal and Child Health Hospital, Huizhou, 516001, China. [email protected].
  • 6. Department of Pathology, Jinan University School of Medicine, Guangzhou, 510632, China. [email protected].
PMID: 41225611 DOI: 10.1186/s12967-025-07294-5
Abstract

Background: Cyclophosphamide (CTX) -induced ovarian fibrosis is involved in premature ovarian failure (POF). While metformin has demonstrated anti-fibrotic properties, the mechanism by which it regulates fibroblast activation, the primary effector cells in fibrosis, remains unclear in POF.

Methods: The therapeutic effects of metformin were investigated in CTX-treated mice and further explored its interaction with macrophage-fibroblast crosstalk using an in vitro co-culture system.

Results: RNA Sequencing revealed that metformin suppressed the MIF/CD74 signaling pathway, which was significantly activated by CTX in ovarian tissues. In vitro, CTX increased the CD86+/CD206 + macrophage ratio via NF-κB pathway activation, indicating altered macrophage polarization. Metformin or the MIF inhibitor ISO-1 reversed this polarization imbalance, thereby attenuating fibroblast activation and extracellular matrix (ECM) production in co-culture models. Additionally, CD74 knockdown in fibroblasts downregulated ECM-related genes and inhibited MAPK/JNK signaling, whereas CD74 overexpression exacerbated the fibrotic responses.

Conclusion: These findings highlight a novel mechanism by which metformin alleviates CTX-induced ovarian fibrosis by targeting the MIF/CD74 axis to reprogram macrophage-fibroblast communication, suggesting metformin as a protective Adjuvant to improve ovarian health during chemotherapy.

Keywords
CD74; Fibroblasts; Fibrosis; MIF; Premature ovarian failure.
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