Cardiac Outcomes of Prophylactic and Therapeutic Applications of Hydroxychloroquine and Zinc in a Rat Sepsis Model

Sepsis-induced cardiac dysfunction remains a critical challenge in clinical practice, and effective therapeutic strategies are urgently needed. This study evaluated the cardioprotective potential of hydroxychloroquine (HCQ) and zinc combination therapy as both prophylactic and therapeutic interventions in a Sprague–Dawley rat model of sepsis induced by cecal ligation and puncture (CLP). Rats were assigned to five groups: Sham, Sepsis (SE), Zinc + Sepsis (Cx), HCQ + Sepsis (H), and HCQ + Zinc + Sepsis (HC). HCQ (200 mg/kg), zinc chloride (40 mg/kg), or their combination was administered after sepsis induction. Histological analysis revealed that sepsis induced marked myocardial injury, characterized by edema (p < 0.001), congestion (p < 0.01), necrosis (p < 0.01), and inflammatory infiltration (p < 0.05). Monotherapy with HCQ or zinc partially mitigated these changes; however, the HCQ + Zinc combination therapy significantly attenuated all pathological features, including reduced mononuclear cell infiltration, edema, necrosis, and fibrosis. Immunohistochemical evaluation demonstrated that sepsis caused a decrease in ZO-1 expression (p < 0.001), indicating disruption of myocardial tight junctions, whereas HCQ + Zinc treatment restored ZO-1 levels toward Sham values. TNF-α expression did not differ significantly among groups (p > 0.05). These results indicate that combination therapy not only mitigates structural myocardial damage but also preserves endothelial integrity and modulates inflammatory responses in sepsis.In conclusion, the HCQ and zinc combination offers synergistic cardioprotective effects, providing a potential therapeutic strategy that could be easily translated into clinical practice for managing sepsis-related cardiac injury. Further studies are warranted to determine optimal dosing and clinical applicability.