Bindarit ameliorates doxorubicin-induced ovarian damage by suppressing CCL8-dependent macrophage infiltration and NF-κB-mediated inflammation

Doxorubicin (DOX), a widely used chemotherapeutic agent, induces severe ovarian damage resulting in premature ovarian insufficiency and reduced fertility. In the present study, through transcriptome sequencing and immune cell infiltration analysis, we demonstrated that DOX significantly upregulates ovarian CCL8 expression, thereby activating the CCL8/CCR5 axis to promote the recruitment and polarization of proinflammatory M1 macrophages. Mechanistically, CCL8 exacerbates local inflammation through NF-κB signaling (evidenced by p65 phosphorylation and IκBα degradation), initiating granulosa cell apoptosis and follicular atresia. The CCL8-specific inhibitor Bindarit effectively mitigated this pathological cascade by (1) reducing macrophage infiltration by 90.9% ( P  < 0.01), (2) inhibiting NF-κB activation (99.3% decrease in p65 nuclear translocation, P  < 0.001), and (3) downregulating proinflammatory cytokines (reduction in TNF-α/IL-1β expression: 80–90%, P  < 0.001). Notably, Bindarit treatment restored 54.5% of fertility capacity ( P  < 0.01) in DOX-treated mice (which showed 84.1% fertility loss). These findings illuminate the crucial role of the CCL8/NF-κB axis in DOX-induced ovarian toxicity and propose a novel therapeutic strategy for fertility preservation. Bindarit could serve as a promising CCL8-targeted agent with substantial clinical potential.