Evaluation of the cardiotoxicity of Echinochrome A using human induced pluripotent stem cell-derived cardiac organoids

Echinochrome A (EchA), a marine-derived natural product, has shown promise in treating cardiovascular and inflammatory diseases due to its antioxidant and anti-inflammatory properties. However, its cardiac safety remains underexplored. In this study, we utilized human induced pluripotent stem cell-derived cardiac organoids (hCOs) to validate their ability to model the cardiac safety profile of EchA in a human-relevant system. While EchA's therapeutic effects have been reported, prior studies have not evaluated its cardiotoxicity or arrhythmogenic potential in a high-fidelity 3D human cardiac model. The hCOs, characterized by expression of key cardiac markers (cTnT) and functional ion channels (Cav1.2, Nav1.5, hERG), exhibited structural and electrophysiological properties reflective of human cardiac physiology. Using multi-electrode array (MEA) analysis, we assessed the effects of EchA at concentrations ranging from 0.1 to 30 µM on electrophysiological parameters, including beat period, field potential amplitude, field potential duration, and spike slope. EchA treatment induced no significant changes in these parameters, confirming its non-toxic electrophysiological profile. Cellular viability and lactate dehydrogenase (LDH) assays revealed no cytotoxic effects of EchA across tested concentrations. Contractility assays further demonstrated that EchA did not affect contraction velocity, relaxation velocity, or time to 50 % maximal contraction and relaxation. This study fills a critical gap and highlights the translational relevance of hCOs for cardiotoxicity assessment, demonstrating EchA's cardiac safety and supporting its potential therapeutic and environmental applications.