Paroxetine attenuates doxorubicin-induced cardiotoxicity: Integrated network pharmacology, molecular modeling, and in vivo evidence consistent with modulation of GRK2/iNOS-related pathways.

Doxorubicin is a potent chemotherapeutic agent whose clinical utility is compromised by dose-dependent, irreversible cardiotoxicity. Given the limitations of current cardioprotective strategies regarding efficacy and safety, repurposing approved medications presents a feasible therapeutic option. This study investigated the cardioprotective potential of paroxetine (PARX), a selective serotonin reuptake inhibitor, against doxorubicin-induced cardiotoxicity (DIC). We employed a multi-disciplinary approach combining network pharmacology, molecular docking, and 300 ns molecular dynamics simulation to identify biologically plausible PARX-associated targets. These in silico predictions were further examined in a murine model of acute DIC (single 15 mg/kg DOX i.p.), where mice received PARX pretreatment (20 mg/kg p.o.) for five days. Network pharmacology identified AKT1 and iNOS as key intersecting targets, while GRK2 was included based on supporting evidence from the literature. Computational modeling suggested that PARX maintains favorable in silico interaction within the ATP-binding region of GRK2 and engages the heme-propionate region of iNOS with a more favorable predicted interaction profile for iNOS. In vivo, PARX pretreatment attenuated biochemical and histopathological markers of cardiac injury, evidenced by reduced serum CK-MB and LDH activities and lower cardiac Troponin and NT-proBNP levels. Mechanistically, PARX reversed the doxorubicin-induced suppression of AKT1 expression, downregulated GRK2 and iNOS overexpression, and mitigated oxidative stress by restoring SOD/CAT activity. Furthermore, PARX alleviated inflammation (reduced NF-κB) and attenuated maladaptive autophagy (reduced LC3-II and Beclin-1). Histological and morphometric analyses confirmed that PARX effectively prevented cardiomyocyte necrosis and interstitial fibrosis. In conclusion, PARX ameliorates DIC via modulation of GRK2/iNOS-related pathways, restoration of AKT1 signaling, and suppression of oxidative stress and maladaptive autophagy. These findings strongly support the cardioprotective potential of PARX and warrant its further investigation during doxorubicin chemotherapy.