Work

Insights into the Biochemical and Immune Mechanisms in Drug-Induced Liver Injury Pathogenesis

Year: 2026

Type: article

Abstract: DILI is the leading cause of drug failure in clinical trials and withdrawal from the market. Certain intrinsic mechanisms of injury have been characterized such as the direct cytotoxicity exerted by NAPQI, a reactive metabolite of acetaminophen. However, presentation of DILI is highly heterogeneous with several idiosyncratic presentations being observed in patients. Such manifestations are often linked to aberrant immune activation although the biochemical mechanisms directing such responses currently evade complete understanding. This review consolidates current literature findings into potential mechanisms of immune-mediated DILI as well as risk factors which may polarize both the liver itself and certain individuals toward a drug-reactive phenotype. Current theories implicate neoantigen formation as a result of the generation of drug-protein adducts by both parent drugs and reactive metabolites. Responses to such adducts can be restricted to the presence of certain HLA alleles though these associations are identified through epidemiological means rather than mechanistic investigations. Further, susceptibility to DILI can be linked to nuance in the T-cell responses to HLA displayed antigens where basal levels of effector molecules and inflammation as well as the presence of liver resident immune cells, such as natural killer T-cells, can augment drug-specific immune responses.

Source: Chemical Research in Toxicology

DOI: 10.1021/acs.chemrestox.5c00530

Authors: Eleanor Saville, Georgia Wells, Liam Farrell, Dean John Naisbitt, Xiaoli Meng

Institution: University of Liverpool

Language: English

Topic: Drug-Induced Hepatotoxicity and Protection

Subfield: Pharmacology

Field: Pharmacology, Toxicology and Pharmaceutics

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $4,500