Fluvoxamine and lycopene alleviate cisplatin-induced kidney fibrosis by modulating miR-21 and fibrotic signaling pathways

Abstract

Cisplatin (Cis) is a widely utilized chemotherapy drug for managing various cancers, but its efficacy is limited by nephrotoxicity, which frequently results in kidney fibrosis. Oxidative stress, inflammation, and the fibrotic transforming growth factor beta/small mothers against decapentaplegic (TGF-β/SMAD) pathway are among the underlying mechanisms. Long-term exposure to Cis causes apoptosis, extracellular matrix deposition, and fibrosis. Fluvoxamine (FLV), a selective serotonin reuptake inhibitor and sigma‑1 receptor agonist, lycopene (LYC), a carotenoid antioxidant, and their combination showed a novel protective influence on kidney fibrosis in male albino rats induced by administering Cis (7 mg/kg) by intraperitoneal (IP) injection once weekly for 4 weeks. FLV (5 mg/kg), LYC (10 mg/kg), and their combination were administered orally (PO) once daily for four weeks. Treatment reduced blood urea nitrogen (BUN), serum creatinine (S.cr), nuclear factor kappa B (NF-κB), microRNA-21 (miR-21) levels, and the pro-apoptotic response reflected by decreased Bcl-2-associated X protein (Bax) immunoreactivity while enhancing antioxidant activity. They also attenuated fibrosis markers, including TGF-β1, SMAD3, collagen I (Col-I), and alpha-smooth muscle actin (α-SMA). FLV and LYC effectively attenuated Cis-induced kidney fibrosis through antioxidant, antiapoptotic, and antifibrotic mechanisms. These findings may provide a new therapeutic approach to counter Cis-induced nephrotoxicity in clinical settings.