Abstract Human and Experimental Toxicology 2020, Vol. 39(5) 696–711 ªThe Author(s) 2020 Article reuse guidelines: sagepub.com/journals-permissions DOI: 10.1177/0960327119897759 journals.sagepub.com/home/het Lithium is one of the most powerful and commonly used medications for the treatment of various psychiatric diseases, especially bipolardisorder.However,ithasanarrowtherapeuticindexwithtoxiceffectsonvariousorgans. There are several case reports of lithium-induced arrhythmia and ischemia. The current work aimed to study the toxiceffects oflithium ontheheartofadultalbinoratsanditsmolecularmechanismsandtheamelioratingeffectofNacetyl cysteine (NAC). Sixty adult male Wistar albino rats were classified into four groups; control, NAC-treated receivedNAC500mg/kg/weekdissolvedin1ml0.9%sodiumchlorideintraperitoneal,lithium-treatedreceived52.5 mg/kg/day of lithium carbonate dissolved in 1 ml 0.9% sodium chloride orally by gavage, and lithium-and-NACtreated (group IV) received lithium and NAC in the previous doses. After 12 weeks, the rats of group III showed a significant accumulation of ascites and a decrease in the mean arterial blood pressure and electrocardiographic (ECG) findings of ischemia and arrhythmia. In addition, there was an elevation in cardiac biomarkers creatine kinase MB(CK-MB),cardiactroponinI(cTnI),andseveralhistological lesionswith a significant increase in the area % of Van Gieson, endothelial nitric oxide synthase (eNOS), and 8-hydroxy-20-deoxyguanosine (8-OHdG) immunoreaction. There was significant upregulation of microRNA-1, microRNA-21 (miRNA-21), and microRNA-29 (miRNA-29). MiRNA-21 was strongly positively correlated to the area % of 8-OHdG, while miRNA-29 was strongly positively correlatedtothearea%ofVanGiesonstaining.NACsignificantlyimprovedthecardiotoxiceffectsoflithium.Beinga nontoxic and safe antioxidant, NAC can be used to ameliorate lithium-induced cardiac injury.