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

ABSTRACT 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.