Bazedoxifene Attenuates Isoproterenol-Induced Cardiac Fibroblast Activation and Fibrotic Phenotype via Modulation of...

Bazedoxifene (BAZ), a selective estrogen receptor modulator, has recently been demonstrated to inhibit the IL-6/STAT3 signaling pathway; however, its direct effects on cardiac fibroblasts and the underlying mechanisms remain unclear. Isoproterenol (ISO)-stimulated Sprague-Dawley neonatal rat cardiac fibroblasts (CFs) were employed as an in vitro model. CCK-8 assay, flow cytometry, Transwell migration assay, ELISA, qRT-PCR, and Western blot were applied to evaluate the effects of BAZ on CF activation, proliferation, migration, and collagen synthesis. Additionally, IL-6 overexpression via lentivirus (Lv-IL-6) was used to assess mediation by IL-6/STAT3 signaling. BAZ (5 μmol/L) significantly inhibited ISO-induced CF proliferation by inducing G₀/G₁ cell-cycle arrest; migration and upregulation of α-SMA and Collagen I/III were reduced; IL-6, TGF-β1, and hydroxyproline concentrations in the conditioned medium were decreased; STAT3 phosphorylation was significantly suppressed. Supplementation with Lv-IL-6 partially reversed these effects. The suppression of ISO-induced CF activation and fibrotic phenotype was associated with inhibition of IL-6 expression and blockade of IL-6/STAT3 signaling, suggesting the involvement of this pathway in the anti-fibrotic effects of BAZ. These findings provide in vitro evidence supporting BAZ as a candidate anti-myocardial fibrosis agent.