Ameliorative effect of betanin on experimental cisplatin‐induced liver injury; the novel impact of miRNA‐34a on the SIRT1/PGC‐1α signaling pathway

Abstract The anticancer agent, cisplatin (CIS), is associated with hepatotoxic effects related to activation of oxidative stress and inflammation pathways. CIS‐induced oxidative DNA damage reduces sirtuin 1 (SIRT1) activity, which in turn, modulates the activity of peroxisome proliferator‐activated receptor‐gamma coactivator 1‐alpha (PGC‐1α). Moreover, microRNA‐34a (miRNA‐34a) was shown to hinder both SIRT1 and nuclear factor erythroid 2‐related factor 2 (Nrf2) activity. Thus, targeting such a pathway can alleviate CIS‐induced hepatotoxicity. Betanin (BET) is a natural red glycoside food dye obtained from beets, which is reported to exhibit antioxidant function. However, its role in CIS‐induced liver injury and the molecular mechanism has not been fully elucidated. Thus, the aim of this study was to investigate the ameliorative effect of BET on CIS‐induced acute hepatotoxicity through the SIRT1/PGC‐1α signaling pathway and illustrate the impact of miRNA‐34a. Seventy‐two rats were divided into six equal groups: (1) Control, (2) BET, (3) CIS, (4) CIS/BET, (5) CIS/EX527, and (6) CIS/BET/EX527. CIS‐induced liver injury was evidenced by deregulated BAX and BCL2 levels, decreased levels of AMP‐activated protein kinase and PGC‐1α expression, and decreased SIRT1 activity. Consequently, reduced levels of Nrf2 and the expression of associated heme oxygenase‐1 and glutamate‐cysteine ligase modifier subunit were observed. Intriguingly, BET succeeded in reducing the CIS‐induced liver injury through reducing miRNA‐34a expression and enhancing the SIRT1/PGC‐1α pathway. These findings coincide with the molecular docking results and the histopathological picture. In conclusion, the current research provided novel findings of the BET ameliorative effect on CIS‐induced liver injury through modulating miRNA‐34a expression and the SIRT1/PGC‐1α signaling cascade.