The use of doxorubicin (DOX) to treat various tumors is limited by its cardiotoxicity. This study aimed to investigate and compare the cardioprotective effects of nicotinamide (NAM) and alfacalcidol (1α(OH)D₃), against DOX-induced cardiotoxicity. Sprague Dawley male rats received DOX (5 mg/kg, i.p.) once/week for four consecutive weeks. Treated groups received either NAM (600 mg/kg, p.o.) for 28 consecutive days or 1α(OH)D₃ (0.5 ug/kg, i.p.) once/week for four consecutive weeks. DOX elicited marked cardiac tissue injury manifested by elevated serum cardiotoxicity indices, conduction and histopathological abnormalities. Both NAM and 1α(OH)D₃ successfully reversed all these changes. From the mechanistic point of view, DOX provoked intense cytosolic and mitochondrial calcium (Ca²⁺) overload hence switching on calpain1 (CPN1) and mitochondrial-mediated apoptotic cascades as confirmed by upregulating Bax and caspase-3 while downregulating Bcl-2 expression. DOX also disrupted cardiac bioenergetics as evidenced by adenosine triphosphate (ATP) depletion and a declined ATP/ADP ratio. Moreover, DOX upregulated the Ca²⁺ sensor; calmodulin kinase II gamma (CaMKII-δ) which further contributed to cardiac damage. Interestingly, co-treatment with either NAM or 1α(OH)D₃ reversed all DOX associated abnormalities by preserving Ca²⁺ homeostasis, replenishing ATP stores and obstructing apoptotic events. Additionally, DOX prompted nuclear factor kappa B (NF-κB) dependent inflammatory responses and subsequently upregulated interleukin-6 (IL-6) expression. Co-treatment with NAM or 1α(OH)D₃ effectively obstructed these inflammatory signals. Remarkably, NAM showed superior beneficial cardioprotective properties over 1α(OH)D₃. Both NAM and 1α(OH)D₃ efficiently attenuated DOX-cardiomyopathy mainly via preserving Ca²⁺ homeostasis and diminishing apoptotic and inflammatory pathways. NAM definitely exhibited effective cardioprotective capabilities over 1α(OH)D₃.

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