Powering the liver toxicity assessment in the organoid era

Abstract Hepatotoxicity assessment is paramount in drug development and food safety. Traditional in vitro models suffer from insufficient physiological relevance and poor functional reproducibility. Liver organoids have rapidly emerged as three-dimensional culture models capable of recapitulating multicellular interactions and key hepatic functions, offering unprecedented tools for toxicity assessment. They exhibit broad potential in modeling diverse toxicity phenotypes, including acute liver injury, chronic cumulative toxicity, cholestasis, and fibrosis. Currently, organoids are extensively utilized in drug hepatotoxicity evaluation, environmental contaminant screening, drug-drug interaction profiling, and the determination of personalized safety margins. Despite ongoing challenges in functional maturation and standardized derivation, the integration of multidisciplinary technologies and refined ethical frameworks positions liver organoids as a central platform for future toxicity testing. They will propel the advancement of precision toxicology and precision medicine, serving as a pivotal tool for hepatobiliary disease research. The present review systematically chronicles the developmental trajectory of liver organoids, their versatile applications in toxicity assessment, and recent technological breakthroughs. Furthermore, we explore their translational potential in hepatobiliary surgery, personalized nutritional interventions, and preclinical research, aiming to provide a comprehensive reference for researchers and clinicians in related fields.