In vitro cell-based models of drug-induced hepatotoxicity screening: progress and limitation

Drug-induced liver injury (DILI) is one of the major causes of post-approval withdrawal of therapeutics. As a result, there is an increasing need for accurate predictive in vitro assays that reliably detect hepatotoxic drug candidates while reducing drug discovery time, costs, and the number of animal experiments. In vitro hepatocyte-based research has led to an improved comprehension of the underlying mechanisms of chemical toxicity and can assist the prioritization of therapeutic choices with low hepatotoxicity risk. Therefore, several in vitro systems have been generated over the last few decades. This review aims to comprehensively present the development and validation of two-dimensional (2D) and three-dimensional (3D) culture approaches on hepatotoxicity screening of compounds and highlight the main factors affecting predictive power of experiments. To this end, we first summarize some of the recognized hepatotoxicity mechanisms and related assays used to appraise DILI mechanisms and then discuss the challenges and limitations of in vitro models.

Automated summary

Drug-induced liver injury (DILI) is a major cause of post-approval withdrawal of therapeutics, highlighting the need for reliable in vitro assays to predict hepatotoxic drug candidates and reduce drug discovery time, costs, and animal experiments. Hepatocyte-based research has improved understanding of chemical toxicity mechanisms and can aid in prioritizing therapeutic choices with low hepatotoxicity risk. This review comprehensively presents the development and validation of 2D and 3D culture approaches for hepatotoxicity screening, discussing the factors affecting predictive power and the challenges and limitations of in vitro models.