Schisandrol A induces cardiac developmental toxicity in zebrafish (Danio rerio) via disruption of calcium homeostasis, oxidative stress, and apoptosis.

Schisandrol A (SA) is a major lignan component of Schisandra chinensis with anti-inflammatory and antioxidant activities, yet its developmental and cardiac safety profile remains unclear. In this study, a zebrafish (Danio rerio) embryo model was used to evaluate the toxicity of SA and its underlying mechanisms following exposure to different concentrations of SA (ranging from 0 to 160 μg/mL, with safe concentrations of 10, 20, and 40 μg/mL for mechanistic studies from 6 to 96 h post-fertilization (hpf). SA induced a dose-dependent increase in mortality, with an LC₅₀ of 62.5 μg/mL at 96 hpf. SA induced concentration-dependent developmental abnormalities, characterized by reduced body length, pericardial edema (PE), delayed yolk sac absorption, and spinal curvature, accompanied by decreased heart rate, indicating evident cardiotoxicity. Transcriptomic analysis showed that differentially expressed genes were mainly enriched in pathways related to oxidative stress, apoptosis and calcium signaling. Consistent with this, fluorescence staining and qPCR demonstrated that SA induced Ca2+ accumulation and increased ROS and AO signals in the cardiac region, along with dysregulated expression of genes involved in calcium handling, antioxidant defense and apoptosis. In conclusion, SA induces developmental and cardiac toxicity in zebrafish embryos, at least in part by disrupting calcium homeostasis, promoting oxidative stress and activating apoptotic pathways, suggesting that its potential safety risks should be carefully considered in future development and application.