Drug-Induced Liver Injury Mechanisms and Therapeutic Interventions

Drug-induced liver injury (DILI) encompasses a spectrum of hepatic damage arising from both predictable, dose-dependent toxicity and unpredictable, idiosyncratic reactions. Central to many cases is the metabolic conversion of drugs to reactive intermediates that provoke oxidative stress and mitochondrial dysfunction, leading to oncotic necrosis and secondary activation of sterile inflammation. In parallel, adaptive and innate immune pathways may be engaged in idiosyncratic DILI, sometimes manifesting as an autoimmune-like hepatitis phenotype. Genetic predispositions, including human leucocyte antigen (HLA) alleles and polymorphisms affecting drug metabolism enzymes, modulate susceptibility. Biomarker discovery has improved early detection, while causality assessment methods refine diagnosis. Therapeutic strategies encompass antidotes such as N-acetylcysteine for acetaminophen overdose, emerging small-molecule inhibitors targeting stress kinases, and immunomodulatory approaches for immune-mediated phenotypes. A growing emphasis on mechanism-based interventions and personalised risk assessment promises to transform clinical management, reducing morbidity and guiding safe drug development worldwide.

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Drug-Induced Liver Injury Mechanisms and Therapeutic Interventions publication trend

The graph below shows the total number of articles in drug-induced liver injury mechanisms and therapeutic interventions across all publications each year (not limited to Nature Index journals).

Technical terms

Idiosyncratic DILI: Unpredictable, dose-independent liver injury mediated by host factors and immune responses.

Oncotic necrosis: Passive form of cell death characterised by cell swelling, membrane rupture and release of intracellular contents.

Mitochondrial permeability transition: Sudden increase in inner mitochondrial membrane permeability, leading to loss of membrane potential and cell death.

Autophagy: Regulated process of intracellular degradation of damaged organelles and proteins via lysosomal pathways.

Sterile inflammation: Immune activation in response to tissue injury in the absence of pathogens, driven by damage-associated molecular patterns.

References

1. Acetaminophen Hepatotoxicity: Paradigm for Understanding Mechanisms of Drug-Induced Liver Injury. Annual Review of Pathology Mechanisms of Disease (2024).
2. Nomenclature, diagnosis and management of drug-induced autoimmune-like hepatitis (DI-ALH): An expert opinion meeting report. Journal of Hepatology (2023).
3. RUCAM in Drug and Herb Induced Liver Injury: The Update. International Journal of Molecular Sciences (2015).
4. Mechanistic biomarkers provide early and sensitive detection of acetaminophen‐induced acute liver injury at first presentation to hospital. Hepatology (2013).
5. Role of JNK Translocation to Mitochondria Leading to Inhibition of Mitochondria Bioenergetics in Acetaminophen-induced Liver Injury*. Journal of Biological Chemistry (2008).
6. Role of CYP2E1 in the Hepatotoxicity of Acetaminophen (∗). Journal of Biological Chemistry (1996).
7. Association of Liver Injury From Specific Drugs, or Groups of Drugs, With Polymorphisms in HLA and Other Genes in a Genome-Wide Association Study. Gastroenterology (2016).