Background: Doxorubicin-induced cardiotoxicity (DIC) is a major limitation of anthracycline chemotherapy and is characterized by oxidative stress, apoptosis, and myocardial remodeling. Dysregulation of AMP-activated protein kinase (AMPK) and its downstream effector sirtuin-1 (SIRT1) has been implicated in the molecular pathogenesis of DIC. Vardenafil (Var), a selective phosphodiesterase-5 inhibitor, has shown cardiovascular benefits; however, its impact on AMPK/SIRT1 signaling during DIC remains unclear. Methods: DIC was induced in rats by cumulative doxorubicin administration. Cardiac function, serum injury biomarkers, oxidative stress indices, histopathological alterations, apoptosis, fibrosis, and molecular markers associated with the AMPK/SIRT1 pathway were evaluated. In addition, molecular docking was performed to assess the potential interaction of Var with AMPK. Results: Var significantly improved cardiac function and reduced serum levels of lactate dehydrogenase, creatine kinase, and blood urea nitrogen. Treatment attenuated myocardial oxidative stress, restored glutathione content, reduced lipid peroxidation, and alleviated histopathological damage. Furthermore, Var suppressed caspase-3 and TGF-β1 expression while enhancing HO-1 levels. Var treatment was associated with restoration of cardiac phosphorylated AMPK (p-AMPK) expression and increased SIRT1, Nrf2, and PPARγ levels in doxorubicin-treated rats, consistent with modulation of an AMPK/SIRT1-associated cytoprotective network. Molecular docking demonstrated favorable interactions between Var and AMPK, providing supportive in silico evidence for the observed molecular findings. Conclusions: These findings demonstrate that Var attenuates doxorubicin-induced cardiotoxicity, and its cardioprotective effects are associated with restoration of the p-AMPK/SIRT1/Nrf2/PPARγ signaling pathway, together with reductions in oxidative stress, apoptosis, and fibrosis. Collectively, these findings suggest that Var attenuates early Dox-induced cardiac injury, potentially through modulation of the AMPK/SIRT1 signaling pathway, warranting further validation in long-term and dose–response studies.

Testicular damage is one of the deleterious effects of cadmium (Cd) toxicity. Cadmium is a serious contaminant to the environment that causes severe damage to a variety of tissues and organs including the liver, kidney, and testes. Moreover, cadmium compounds are classified as carcinogenic substances in humans. Acute and chronic cadmium intoxication results in the formation of reactive oxygen species (ROS), attenuation of anti-oxidant enzyme activity and inducing oxidative stress. In addition, inflammation is induced by cadmium toxicity. So, both oxidative stress and inflammation play an important role in the pathogenesis of testicular damage under cadmium exposure. Oxidative stress is triggered by reactive oxygen species (ROS) and an imbalance between ROS and antioxidant enzymes activities. oxidative stress activates the NF-κB signaling pathway, which controls several genes implicated in inflammatory responses such as TNF-α and iNOS. Cd can pass through the blood-testes barrier, causing changes in the hypothalamic-pituitary-testicular axis and DNA damage The harmful effect of cadmium on testes is known to be germ cell degeneration and impairment of testicular steroidogenesis due to damage in testicular Leydig cells.