Vitamin D modulates hepatic microRNAs and mitigates tamoxifen‐induced steatohepatitis in female rats

Tamoxifen (TAM) is a life‐saving and cost‐effective drug widely used in the prevention and treatment of breast cancer. However, the adverse effects of tamoxifen can lead to non‐adherence and poor patient outcomes. Therefore, exploring novel strategies to improve TAM safety profile is crucial. Given the key role that vitamin D (VD) plays in modulating lipid metabolism and inflammation, in addition to its benefits in reducing risk and progression of breast cancer, we evaluated the protective potential of VD against TAM‐induced hepatotoxicity focusing on lipid metabolism and microRNAs (miRNAs) regulation. Female rats were pretreated with VD as cholecalciferol (500 IU/kg/day, po) for 4 weeks before receiving TAM (40 mg/kg/day, po) concurrently with VD during the fifth and sixth weeks. Liver histology, lipid profile and expression of genes, proteins, and miRNAs involved in lipid metabolism and inflammation were examined. TAM‐induced steatohepatitis was evidenced by elevated liver triglycerides and cholesterol contents, increased serum miRNA‐122 level, and ALT activity, in parallel with accumulation of lipid droplets, focal necrosis, and inflammatory cells infiltration in hepatocytes. Prophylactic use of VD mitigated TAM‐induced steatohepatitis by modulating key transcription factors in the liver: PPAR‐α, Srebf1, and NF‐κB and their downstream genes/proteins Fas, CPT‐1A, and TNF‐α resulting in reduced hepatic lipids and suppressed pro‐inflammatory signaling. Notably, VD pretreatment mitigated TAM‐induced alterations in the expression of serum miRNA‐122, hepatic miRNA‐21, and miRNA‐33. The combination therapy of VD and TAM has complementary benefits in terms of safety and not only efficacy and should be further investigated clinically.