Lipid Metabolism in Drug-Induced Liver Injury

Lipid metabolism underpins hepatic cellular homeostasis through the coordinated processes of fatty acid uptake, synthesis, storage and degradation. In drug-induced liver injury, this balance is disrupted by xenobiotic compounds that interfere with mitochondrial β-oxidation, alter de novo lipogenesis and impede lipid export, leading to an abnormal accumulation of triglyceride-laden lipid droplets within hepatocytes. Such hepatic steatosis can progress to inflammation and fibrosis in a subset of patients, manifesting as drug-induced steatohepatitis and, ultimately, impaired liver function. Mechanistic studies have highlighted roles for nuclear receptors, transcription factors and transport proteins in modulating fatty acid flux, while oxidative stress and mitochondrial dysfunction emerge as central mediators linking lipid overload to cellular injury. Understanding these interlocking pathways is critical to identifying predictive biomarkers of toxicity, refining adverse outcome pathways and developing therapeutic strategies to prevent or reverse lipid-driven hepatic damage. Recent advances in high-resolution metabolic profiling, in vitro–in silico extrapolation and single-cell methodologies have further elucidated the dynamic interplay between drug challenge and hepatocyte lipid handling across different cellular subpopulations and exposure scenarios.

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Lipid Metabolism in Drug-Induced Liver Injury publication trend

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

Technical terms

Hepatocyte: A liver parenchymal cell responsible for metabolism, detoxification and synthesis activities.

Hepatic steatosis: Accumulation of triglyceride-rich lipid droplets in hepatocytes.

Steatohepatitis: Inflammatory injury of the liver characterised by steatosis, inflammation and often fibrosis.

β-Oxidation: Mitochondrial process of sequential removal of two-carbon units from fatty acids to generate energy.

Xenobiotic: A foreign compound, such as a drug or environmental chemical, metabolised by the liver.

High-content imaging: Automated microscopy technique combining multiple fluorescent markers to quantify cellular events.

Single-cell metabolic profiling: Analysis of metabolic activity and gene expression at the level of individual cells.

Adverse outcome pathway: Structured sequence of molecular and cellular events linking a molecular initiating event to an adverse health effect.

References

1. Single-cell metabolic profiling reveals subgroups of primary human hepatocytes with heterogeneous responses to drug challenge. Genome Biology (2023).
2. In vitro to in vivo extrapolation and high-content imaging for simultaneous characterization of chemically induced liver steatosis and markers of hepatotoxicity. Archives of Toxicology (2023).
3. Drug-Induced Fatty Liver Disease (DIFLD): A Comprehensive Analysis of Clinical, Biochemical, and Histopathological Data for Mechanisms Identification and Consistency with Current Adverse Outcome Pathways. International Journal of Molecular Sciences (2024).