The Effects of Metformin-Related Ligand CXCL13 in Myofibroblast Remodeling and Ovarian Fibrosis Mitigation

Abstract

Background/rationale: Reproductive aging accelerates ovarian dysfunction, with fibrosis being a key contributor to age-related infertility. Metformin reduces ovarian fibrosis, potentially by promoting CXCL13-mediated signaling between macrophages and myofibroblasts. This study investigates the downstream role of CXCL13 and its receptors, Grm7 and Adra2a, in fibroblast activation and ECM remodeling.

Hypothesis/research questions: CXCL13 attenuates ovarian fibrosis by reducing fibroblast activation and ECM remodeling through Grm7 and Adra2a signaling.

Objective/purpose of the study: To examine the effects of CXCL13 and TGF-β1 on fibroblast activity and to assess the roles of Grm7 and Adra2a receptors.

Materials and methods: NIH/3T3 fibroblasts were treated with CXCL13 and GRM7/ADRA2A agonists. Proliferation was measured using the MTT assay, and gene expression was analyzed via RNA sequencing and RT-qPCR.

Results: CXCL13 and Grm7 agonists reduced fibroblast proliferation under inflammatory conditions. All treatments trended toward reduced activation, with CXCL13 suggesting fibrotic remodeling effects, potentially through pathways independent of the target receptors.

Conclusion/significance interdisciplinarity: This study identifies CXCL13-associated signaling as a potential target to mitigate ovarian fibrosis and improve reproductive health outcomes.