Hepatoprotective potential of 5,4′-dihydroxy-6,8-dimethoxy-7-o-rhamnosylflavone through modulation of oxidative stress and inflammatory responses in doxorubicin-challenged mice

Doxorubicin (DOX) induces hepatotoxicity through oxidative stress, inflammation, and ferroptosis driven by GPX4/SLC7A11 downregulation and dysregulated iron homeostasis (TfR1/ferritin/FPN1). This study evaluated 5,4'-dihydroxy-6,8-dimethoxy-7-O-rhamnosylflavone (DDR), a flavonoid with reported antioxidant/anti-inflammatory activity, against DOX-induced liver injury in mice (n=6/group). DOX (2.5 mg/kg IP weekly ×6 weeks) elevated serum enzymes (ALT/AST/ALP/bilirubin), malondialdehyde (MDA), cytokines (IL-6/TNF-α/IL-1β), while depleting glutathione (GSH)/antioxidant enzymes and downregulating GPX4/SLC7A11 (all p<0.01). 5,4′-dihydroxy-6,8-dimethoxy-7-O-rhamnosylflavone (DDR) co-administration (25/50 mg/kg oral, twice weekly) dose-dependently restored these parameters, upregulating GPX4/SLC7A11 (2.1-3.4-fold), normalizing iron-handling proteins, and improving hepatic architecture that is absent with DDR alone. These findings demonstrate that DDR mechanistically counteracts DOX hepatotoxicity by simultaneously attenuating oxidative stress/inflammation and inhibiting ferroptosis through GPX4/SLC7A11-mediated lipid peroxidation suppression and iron homeostasis restoration, positioning DDR as a promising chemotherapy adjuvant.