The zebrafish model: a versatile platform for uncovering the therapeutic potential of phytochemicals in liver diseases

The search for novel therapeutics for prevalent liver diseases such as metabolic dysfunction-associated steatotic liver disease, alcohol-related liver disease, and drug-induced liver injury is constrained by the methodological gaps in conventional preclinical models, which struggle to balance physiological complexity with screening efficiency. This challenge is particularly acute for natural products, where elucidating multifaceted mechanisms and inherent toxicological risks is paramount for translation. The zebrafish ( Danio rerio ) model, with its unique attributes of optical transparency, genetic tractability, and high-throughput capability, has emerged as a transformative platform to address this bottleneck. This review synthesizes and critically evaluates the integral role of zebrafish in advancing natural product-based hepatology. We provide a systematic analysis of established protocols for modeling key liver pathologies—from diet-induced and ethanol-induced steatosis to chemical hepatotoxicity—and consolidate evidence on how these models have been leveraged to decipher protective mechanisms, including the regulation of lipid metabolism, oxidative stress, and inflammation. Crucially, we integrate the parallel and essential discourse on safety, highlighting how zebrafish models, especially transgenic lines, enable the real-time visualization and mechanistic interrogation of compound-induced hepatotoxicity. By confronting current limitations, such as interspecies metabolic differences and protocol variability, we outline a strategic roadmap for the field. This involves the integration of multi-omics, humanized genetics, and standardized approaches to enhance the predictive validity of zebrafish studies. Ultimately, this review articulates how the zebrafish serves as a unified in vivo system to accelerate the identification and mechanistic validation of plant-derived therapeutics while concurrently de-risking their development, thereby directly contributing to the pipeline for new treatment options in liver disease.