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In Vitro Assessment of Drug-Induced Liver Injury Using Three-Dimensional Cultured HepaSH Cells Derived From Chimeric

Xingming Liu1, Yuichiro Higuchi2, Yuta Sakamoto1

  • 1Division of Pharmacology, National Institute of Health Sciences, Kawasaki, Japan.

Journal of Applied Toxicology : JAT
|July 21, 2025
PubMed
Summary

HepaSH cell-derived spheroids show promise for assessing drug-induced liver injury (DILI) risk in vitro. These 3D cultures offer a consistent and predictable alternative to primary human hepatocytes for nonclinical DILI assessments.

Keywords:
HepaSH cellsdrug‐induced liver injuryhuman hepatocyteshumanized liver chimeric micein vitro assessmentsafety pharmacologyspheroidsthree‐dimensional culture

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Area of Science:

  • Hepatology and Toxicology
  • Drug Safety and Development
  • In Vitro Toxicology Models

Background:

  • Drug-induced liver injury (DILI) is a significant cause of drug withdrawal, necessitating improved nonclinical risk assessment methods.
  • Primary human hepatocytes (PHHs) and their 3D cultures predict hepatotoxicity but suffer from variability and limited availability.
  • HepaSH cells, derived from humanized liver chimeric mice, offer consistent availability and similar drug-metabolizing gene expression to PHHs.

Purpose of the Study:

  • To investigate the utility of HepaSH cell-derived spheroids for assessing DILI risk in vitro.
  • To compare the hepatic characteristics of HepaSH cells cultured in 2D versus 3D conditions.
  • To evaluate the sensitivity of HepaSH spheroids to known DILI-associated drugs.

Main Methods:

  • HepaSH cells were cultured in 2D and 3D (spheroid) formats for up to 21 days.
  • Gene expression and phenotypic analyses were performed to assess hepatic development.
  • Cytotoxic assessments were conducted using drugs from the DILIrank dataset.

Main Results:

  • 3D-cultured HepaSH cells demonstrated enhanced development of hepatic characteristics compared to 2D cultures.
  • HepaSH spheroids cultured in chemically defined media showed high sensitivity to high-risk DILI drugs.
  • The HepaSH cell model exhibited minimal variation, ensuring consistent results.

Conclusions:

  • HepaSH cell-derived spheroids represent a viable in vitro model for DILI risk assessment.
  • This model offers a more consistent and available alternative to PHHs for nonclinical drug safety evaluations.
  • Further large-scale screening is recommended to confirm the predictability of human DILI using HepaSH cells.