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Oxidative stress, inflammation, and the fibrotic transforming growth factor beta\/small mothers against decapentaplegic (TGF-\u03b2\/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\u20111 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\u00a0mg\/kg) by intraperitoneal (IP) injection once weekly for 4 weeks. FLV (5\u00a0mg\/kg), LYC (10\u00a0mg\/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-\u03baB), 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-\u03b21, SMAD3, collagen I (Col-I), and alpha-smooth muscle actin (\u03b1-SMA). FLV and LYC effectively attenuated Cis-induced kidney fibrosis through antioxidant, antiapoptotic, and antifibrotic mechanisms. 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