Vitamin D Modulates Doxorubicin‐Induced ACE2 Expression and Pro‐Inflammatory Cytokines in the Rat Tongue

PURPOSE: Doxorubicin (DOX) is a widely used chemotherapy drug, but its severe toxic effects, including inflammation and taste disturbances, limit its clinical use. This study examined the protective effects of vitamin D on DOX-induced changes in tongue tissue and systemic inflammation in rats. METHODS: Twenty-eight adult male Wistar Albino rats (10-12 weeks old) were divided into four groups: Control, DOX, Vitamin D 5000 + DOX, and Vitamin D 60 000 + DOX. Vitamin D3 was administered intraperitoneally either daily (5000 IU/kg) or 3 days a week (60 000 IU/kg) for 21 days. DOX (18 mg/kg, intraperitoneally) was administered on days 19-21. Tongue tissues were analyzed for angiotensin-converting enzyme 2 (ACE2) expression via immunohistochemistry, and serum cytokine levels (TNF-α, IL-1β, and IL-6) were measured using enzyme-linked immunosorbent assay (ELISA). RESULTS: DOX treatment significantly increased ACE2 expression in tongue tissue compared with controls (p < 0.001), accompanied by elevated serum inflammatory cytokine levels and reduced body weight. Vitamin D supplementation significantly attenuated DOX-induced ACE2 upregulation and inflammatory cytokine elevations (p < 0.05). However, no clear dose-dependent difference was observed between the two vitamin D regimens, as ACE2 expression did not differ significantly between the 5000 IU/kg and 60 000 IU/kg groups. CONCLUSION: DOX administration is associated with increased ACE2 expression in tongue tissue and systemic inflammation in a rat model. Vitamin D supplementation mitigates these DOX-induced alterations; however, within the tested dose range, no additional benefit of the higher vitamin D dose was demonstrated. These findings suggest a potential modulatory role of vitamin D on chemotherapy-associated inflammatory and molecular changes, while highlighting the need for further mechanistic and functional studies.