Exogenous ATP Attenuates Biochemical and Histological Markers of Osimertinib-Associated Myocardial Injury in Rats

(1) Background: Osimertinib is an effective third-generation EGFR tyrosine kinase inhibitor, but its clinical use may be limited by cardiotoxicity. This study investigated the relationship between reduced measured cardiac ATP levels and osimertinib-associated cardiac injury and examined whether exogenous ATP administration attenuates the associated biochemical and histopathological alterations. (2) Methods: Twenty-four male Wistar rats were randomly allocated to healthy control (HG), osimertinib (OSM), ATP 5 mg/kg + osimertinib (AOSM-5), and ATP 10 mg/kg + osimertinib (AOSM-10) groups (n = 6). ATP was administered intraperitoneally once daily, followed 1 h later by osimertinib (50 mg/kg, oral gavage) for three weeks. Cardiac tissue ATP, MDA, and tGSH levels, SOD and CAT activities, and plasma TPI levels were measured, together with histopathological and immunohistochemical evaluation of COX-1, COX-2, and 8-OHdG. (3) Results: Osimertinib significantly decreased ATP and tGSH levels and SOD and CAT activities, and increased MDA and TPI levels (p < 0.001), accompanied by increased COX-2 and 8-OHdG, reduced COX-1, hemorrhage, and mononuclear cell infiltration. Exogenous ATP attenuated these alterations, with generally greater effects observed at 10 mg/kg. (4) Conclusions: These findings indicate that ATP co-administration attenuated biochemical, histopathological, and immunohistochemical alterations associated with osimertinib-induced myocardial injury in rats, with these effects being associated, at least in part, with reduced oxidative stress. However, the functional cardiac effects, underlying mechanisms, and potential influence of ATP administration on the antitumor efficacy of osimertinib require further investigation.