Diagnosing idiosyncratic drug-induced liver injury: lessons from monocyte-derived hepatocyte-like cells.

INTRODUCTION

Idiosyncratic drug-induced liver injury (iDILI) is an unpredictable adverse drug event that often involves an abnormal immune response. iDILI is a challenge in the development of new drugs and the diagnosis in clinical practice. Hepatocyte-like cells generated from monocytes of iDILI patients are being developed as an ex vivo assay to enhance understanding of underlying molecular mechanisms and to assist in drug causality assessment, especially in cases involving multiple agents.

AREAS COVERED: Following a PubMed literature search from January 2000 to December 2025, protocols for the dedifferentiation of peripheral blood monocytes followed by hepatocyte-like cell transformation are described, and their performance in ex vivo causality assays for iDILI is reported. This review considers the benefits and challenges of exploiting these cell types in advancing our understanding of iDILI.

EXPERT OPINION: Developing in vitro models that incorporate immunological aspects of iDILI susceptibility is essential for advancing hepatotoxicity research as an alternative to animal testing, aligning with the Food and Drug Administration (FDA) Modernization Act 2.0. Peripheral blood monocyte-derived hepatocyte-like cells, particularly when incorporated into multicellular organoid systems, offer a valuable opportunity to mimic the polygenic architecture of drug susceptibility, enabling the investigation of a compound's DILI potential and underlying mechanisms.