Ferulic acid alleviates ionizing radiation-induced developmental and neurobehavioral toxicity in zebrafish via modulation of apoptosis-related genes.

High-dose ionizing radiation (IR), as encountered in radiotherapy-related and radiological emergency contexts, induces severe acute developmental and neurobehavioral toxicity. However, safe and effective natural radioprotective agents remain limited. Ferulic acid (FA), a natural phenolic compound widely found in medicinal and edible plants, possesses well-established antioxidant and anti-inflammatory properties. Nevertheless, its protective effects and underlying mechanisms against high-dose IR-induced acute in vivo injury remain largely unclear. This study aimed to evaluate the in vivo protective effects of FA against acute IR-induced developmental and neurobehavioral toxicity in zebrafish and to investigate the involvement of apoptosis-related pathways. An acute radiation injury model was established in zebrafish embryos subjected to 1-10 Gy IR treatment, and 2.5 Gy was selected for FA intervention based on the dose-response results. Developmental phenotyping, locomotor activity, and social behavioral assays were conducted to assess IR-induced toxicity. Transcriptomic profiling combined with GO and KEGG enrichment analyses, RT-qPCR validation, and acridine orange staining were performed to explore the potential molecular mechanisms. High-dose IR treatment induced dose-dependent developmental defects, increased mortality, and pronounced locomotor and social behavioral abnormalities in zebrafish larvae. FA treatment significantly alleviated IR-induced developmental toxicity and improved locomotor activity and light-dark transition responses. Transcriptomic analysis showed that FA was associated with broad modulation of IR-responsive gene expression changes, with apoptosis, organelle homeostasis, and cell cycle-related processes identified as major transcriptomic features. Four apoptosis-associated candidate genes (chchd10, dmtf1, rcn3, and nr3c2) were identified and validated under irradiated conditions. FA attenuated the aberrant expression of these genes and reduced excessive apoptosis-associated signals in vivo. Collectively, these findings demonstrate that FA confers significant protection against high-dose IR-induced acute in vivo toxicity, at least in part, in association with apoptosis-related transcriptional modulation and attenuation of apoptosis-associated signals. This study provides mechanistic insights supporting FA as a promising natural radioprotective agent for further evaluation in radiotherapy-related and radiological emergency contexts.