β‐lapachone protects against doxorubicin‐induced hepatotoxicity through modulation of NAD⁺/SIRT‐1/FXR/p‐AMPK/NF‐kB and Nrf2 signaling axis

Abstract

Doxorubicin (DOX) is a widely used antineoplastic drug, but its clinical use is limited by significant toxicities, such as hepatotoxicity. In this study, we evaluated the effects of β‐lapachone (β‐LAP), a natural quinone‐containing compound, in a mouse model of DOX‐induced hepatotoxicity. β‐LAP was orally administered at 1.25, 2.5, and 5 mg/kg for 4 days, and a single dose of DOX (20 mg/kg) was injected intraperitoneally on the second day. Histopathological changes, liver function markers, antioxidant and inflammatory markers were assessed. β‐LAP ameliorated liver injury and liver function markers evoked by DOX. β‐LAP also downregulated the mRNA expression of nuclear factor‐kB‐corresponding genes including interleukin‐6, interleukin‐1β, and tumor necrosis factor‐α. Moreover, β‐LAP increased the nuclear factor erythroid 2‐related factor 2 target genes heme oxygenase‐1 and NAD(P)H: quinone oxidoreductase 1, along with antioxidant enzymes including reduced glutathione, catalase, and superoxide dismutase with simultaneous reduction in the lipid peroxidation product malondialdehyde. Meanwhile, it recovered NAD+/NADH ratios and subsequently elevated the protein levels of sirtuin‐1 (SIRT‐1), farnesoid X receptor (FXR), and phosphorylated AMP‐activated protein kinase (p‐AMPK). Collectively, these findings suggest a protective role of β‐LAP against DOX‐induced hepatotoxicity by partly regulating the NAD+/SIRT‐1/FXR/p‐AMPK axis.

NSUN2 relies on ALYREF to regulate Nrf2-mediated oxidative stress and alleviate Dox-induced liver injury

“…The mechanism of doxorubicin-induced hepatotoxicity is complex, with several systems at work. Recent studies have revealed that oxidative stress play an impartment role in Dox-induced hepatotoxicity [ 2 ]. Post-transcriptional RNA modification has been linked to the regulation of oxidative stress.…”