<p>This study aimed to investigate the cytotoxic effects of isomalabaricane stellettins Q-V and globostelletins K-N, recently isolated from the Vietnamese marine sponge <i>Rhabdastrella globostellata</i>, against human cervical cancer HeLa, human melanoma SK-Mel-28, murine neuroblastoma Neuro-2a cells, human normal keratinocytes HaCaT, and rat normal cardiomyocytes H9c2, as well as to study the cardioprotective activity of non-toxic compounds. Stellettins Q and R and globostelletins M and N showed moderate cytotoxic activity against HeLa, SK-Mel-28, Neuro-2a cells as well as normal keratinocytes HaCaT and normal cardiomyocytes H9c2. Stellettin U increased the viability of H9c2 cardiomyocytes treated with nutrient deprivation, high concentration of ATP, TNF-α pro-inflammatory cytokine, and CoCl₂-mimicking hypoxia. In an in vitro ischemia model, stellettin U reversed mitochondrial ROS and cardiolipin peroxidation levels. In CoCl₂-induced toxicity, intracellular and mitochondrial ROS production, mitochondrial membrane depolarization, and cardiolipin peroxidation levels were normalized following stellettin U treatment. The effect of stellettin U on ATP-induced Ca²⁺influx led to the assumption that stellettin U protects cardiomyocytes via a P2X7R-dependend pathway. Moreover, the modulation of the NF-κB-dependent anti-inflammatory pathway by stellettin U was confirmed. Thus, it was suggested that stellettin U may protect cardiomyocytes via both canonical NF-κB- and non-canonical P2X7R-dependend pathways.</p> Graphical abstract <p></p>