Modulation of miR-204 and miR-375 Expression by Flavonoid Chrysin Treatment During Melphalan-Induced Histopathological Damage in Adult Rat Skin and Hair Tissue.

Chemotherapy-induced skin and hair follicle damage, driven in part by miRNAs such as miR-204 and miR-375 that regulate apoptosis and autophagy after alkylating agent exposure, significantly impacts patient quality of life. While chrysin-a common food-derived flavonoid and nutritional bioactive with antioxidant and cytoprotective properties-has shown potential to modulate miRNA activity, its role in melphalan-induced injury and associated miRNA expression remains unclear. This study investigated the effects of melphalan on skin and hair follicle integrity in rats, focusing on miR-204 and miR-375 expression, and evaluated the protective potential of chrysin treatment. Forty-eight male Wistar rats were divided into six groups receiving melphalan (1.5 mg/kg), chrysin (50 or 75 mg/kg), or their combination for 21 days. Dorsal skin samples were analyzed using histological and morphometric assessments. Expression levels of apoptosis-related genes, autophagy markers, and miR-204/miR-375 were quantified by RT-qPCR. Melphalan significantly reduced epidermal thickness and anagen-phase hair follicles while increasing apoptosis markers (BAX, caspase-3) and suppressing autophagy-related genes. It also markedly upregulated miR-204 and miR-375. Chrysin co-administration, particularly at 75 mg/kg, correlates with restored epidermal thickness, improved hair follicle cycling, enhanced autophagy marker expression, suppressed apoptosis, and significantly downregulated miR-204 and miR-375. Chrysin reduces melphalan-induced skin and hair follicle damage, possibly correlating with modulation of apoptosis and autophagy pathways and suppression of miR-204 and miR-375. These findings suggest chrysin as a promising nutraceutical candidate and supportive dietary strategy to help reduce chemotherapy-associated dermatological side effects.