Scholarlink

Background <p>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.</p> Methods <p>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.</p> Results <p>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.</p> Conclusion <p>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.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年11月12日

查看全文
  • Ping Nie,
  • Bo Yao,
  • Zhejun Zhang,
  • Jingling Li,
  • Minghua Wang,
  • Gendie E. Lash,
  • Bihui Guo,
  • Ping Li

摘要

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.