Polyphenol-Rich Citrullus lanatus Rind Extract Mitigates Doxorubicin-Induced Cardiotoxicity: HPLC Profiling and In Vivo Evaluation

<b>Background/Objectives</b>: Cardiovascular diseases (CVDs) remain a major cause of mortality globally, driven in part by oxidative stress and inflammation. The present study investigated the polyphenolic composition and cardioprotective potential of polyphenol-rich <i>Citrullus lanatus</i> (PRCL) rind extract against doxorubicin-induced cardiotoxicity in rats; <b>Methods:</b> High-performance liquid chromatography (HPLC) was employed to identify and quantify the major bioactive compounds present in the extract. Total 30 healthy male <i>Wistar Kyoto</i> rats were recruited and divided into 6 groups and various cardiovascular markers and antioxidant were measured in vivo and in vitro methods; <b>Results:</b> Ethanolic extraction of <i>Citrullus lanatus</i> rind yielded 19.58 g extract per 100 g of dry plant material. HPLC analysis identified five phenolic acids, i.e., gallic acid, <i>p</i>-hydroxybenzoic acid (PHBA), chlorogenic acid, caffeic acid, and vanillic acid, and two flavonoids, i.e., catechin and hesperetin, with PHBA (163.66 mg/g of extract) being the most abundant. Total phenolic and flavonoid content was determined to be 35.6 mg GAE/g and 12.8 mg CE/g, respectively. In vitro antioxidant assays showed moderate free radical scavenging, reducing power, and 86.9% inhibition of linoleic acid peroxidation. In vivo, Wistar rats were treated with doxorubicin (10 mg/kg) to induce cardiotoxicity, followed by PRCL extract administration (21 days at 250 and 500 mg/kg/day). The extract significantly improved body weight, serum lipid profile, and reduced cardiovascular risk indices. Antioxidant biomarkers (SOD, CAT, GPx, GSH) were restored, while lipid peroxidation (MDA) and inflammatory cytokines (TNF-α, IL-6) were significantly reduced in treated groups. The 500 mg/kg dose demonstrated superior efficacy, comparable to the standard quercetin group. Histopathological examination revealed notable protection of cardiac tissue architecture in the high-dose PRCL-500 group; <b>Conclusions:</b> These findings suggest that PRCL rind extract contains potent compounds having antioxidant and cardioprotective properties and may be used as a natural therapeutic agent against cardiotoxicity.