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Mechanism Research and Disease Assessment of Drug-Induced Liver Injury

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (20 March 2025) | Viewed by 5616

Special Issue Editor


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Guest Editor
UMass Chan Medical School, Worcester, MA 01605, USA
Interests: liver injury; DILI liver toxicity; MASH; immunology; oncology; computational pathology; spatial transcriptomics; computational genomics; artificial intelligence
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Drug-induced liver injury (DILI) or hepatotoxicity is a disease of the liver and a common cause of acute liver failure with unknown etiology. DILI is a rare disease responsible for the withdrawal of drugs from the market due to its late detection, which poses a great concern for the FDA and the pharmaceutical industry. The high cost of the drug development pipeline and longer time to reach the market creates disappointment and a waste of scientific effort when drugs are withdrawn. It is very hard to detect a DILI drug and challenging to assess injury levels when multiple drugs are taken by patients. DILI is a growing concern in the drug development research community because of the increasing number of drugs used in medical care and the increasing number of individuals who take these drugs routinely. Hepatotoxicity is the highest concern of adverse drug reactions. DILI injury is induced by prescription drugs taken together with over-the-counter drugs and alternative medicines, such as herbal products and supplements.

DILI-related injury is still poorly understood today. There is no treatment available to cure an injured liver other than the discontinuation of drugs and the removal of offending agents, which can be helpful to avoid risk involved in pre-existing liver disease patients. DILI is classified as intrinsic and idiosyncratic. Intrinsic DILI is predictable and dose-dependent, whereas idiosyncratic DILI is unpredictable, dose-independent and has a variable latency period. The etiology of DILI remains complex and unclear. There is no clear categorization recommended for the classification of DILI.

Therefore, it is important to understand the mechanism of DILI. This special issue welcomes the use of in vitro models, animal models, computer studies, and human studies to explore the mechanisms of DILI that may shed light on its mechanisms and potential therapeutic targets. These findings may help further shed light on future management of DILI.

Dr. Munish Puri
Guest Editor

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Keywords

  • DILI
  • hepatotoxicity
  • DILI drugs
  • liver injury

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Published Papers (5 papers)

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Research

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14 pages, 3150 KiB  
Article
Isoquercitrin Attenuates Oxidative Liver Damage Through AMPK-YAP Signaling: An Integrative In Silico, In Vitro, and In Vivo Study
by So-Hyun Kwon, Won-Yung Lee, Young Woo Kim, Kwang Suk Ko, Seon Been Bak and Sun-Dong Park
Int. J. Mol. Sci. 2025, 26(6), 2717; https://doi.org/10.3390/ijms26062717 - 18 Mar 2025
Viewed by 375
Abstract
Isoquercitrin, a flavonoid glycoside found in various plants, has demonstrated antioxidant, anti-inflammatory, and anticancer properties. However, its hepatoprotective effects and underlying mechanisms against oxidative liver injury remain unclear. In this study, we evaluated the antioxidant and hepatoprotective effects of isoquercitrin using integrated in [...] Read more.
Isoquercitrin, a flavonoid glycoside found in various plants, has demonstrated antioxidant, anti-inflammatory, and anticancer properties. However, its hepatoprotective effects and underlying mechanisms against oxidative liver injury remain unclear. In this study, we evaluated the antioxidant and hepatoprotective effects of isoquercitrin using integrated in silico, in vitro, and in vivo approaches. HepG2 cells exposed to arachidonic acid (AA) and iron exhibited oxidative stress-induced apoptosis, which was significantly attenuated by isoquercitrin treatment, as evidenced by increased cell viability and reduced apoptosis-related protein alterations. Isoquercitrin decreased reactive oxygen species (ROS) generation and preserved mitochondrial function in a dose-dependent manner. Molecular docking and Western blot analyses revealed that isoquercitrin activates the LKB1/AMPK pathway, increasing phosphorylation of AMPK and its downstream target ACC, thereby modulating energy metabolism and reducing oxidative stress. This activation was LKB1 dependent, as confirmed in LKB1-deficient HeLa cells. Additionally, isoquercitrin modulated the YAP signaling pathway in hepatic cells. In vivo, isoquercitrin protected mice against carbon tetrachloride-induced liver injury, reducing serum ALT and AST levels and improving histopathological features. These findings suggest that isoquercitrin exerts hepatoprotective effects by activating the LKB1/AMPK pathway and modulating metabolic enzymes, highlighting its potential as a therapeutic agent against oxidative liver damage. Full article
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20 pages, 2123 KiB  
Article
Metabolic Biomarkers of Liver Failure in Cell Models and Patient Sera: Toward Liver Damage Evaluation In Vitro
by Simone Rentschler, Sandra Doss, Lars Kaiser, Helga Weinschrott, Matthias Kohl, Hans-Peter Deigner and Martin Sauer
Int. J. Mol. Sci. 2024, 25(24), 13739; https://doi.org/10.3390/ijms252413739 - 23 Dec 2024
Viewed by 971
Abstract
Recent research has concentrated on the development of suitable in vitro cell models for the early identification of hepatotoxicity during drug development in order to reduce the number of animal models and to obtain a better predictability for hepatotoxic reactions in humans. The [...] Read more.
Recent research has concentrated on the development of suitable in vitro cell models for the early identification of hepatotoxicity during drug development in order to reduce the number of animal models and to obtain a better predictability for hepatotoxic reactions in humans. The aim of the presented study was to identify translational biomarkers for acute liver injury in human patients that can serve as biomarkers for hepatocellular injury in vivo and in vitro in simple cell models. Therefore, 188 different metabolites from patients with acute-on-chronic liver failure before and after liver transplantation were analyzed with mass spectrometry. The identified potential metabolic biomarker set, including acylcarnitines, phosphatidylcholines and sphingomyelins, was used to screen primary and permanent hepatocyte culture models for their ability to model hepatotoxic responses caused by different drugs with known and unknown hepatotoxic potential. The results obtained suggest that simple in vitro cell models have the capability to display metabolic responses in biomarkers for liver cell damage in course of the treatment with different drugs and therefore can serve as a basis for in vitro models for metabolic analysis in drug toxicity testing. The identified metabolites should further be evaluated for their potential to serve as a metabolic biomarker set indicating hepatocellular injury in vitro as well as in vivo. Full article
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14 pages, 4065 KiB  
Article
The Modulation of Phospho-Extracellular Signal-Regulated Kinase and Phospho-Protein Kinase B Signaling Pathways plus Activity of Macrophage-Stimulating Protein Contribute to the Protective Effect of Stachydrine on Acetaminophen-Induced Liver Injury
by Fu-Chao Liu, Huang-Ping Yu, Hung-Chen Lee, Chun-Yu Chen and Chia-Chih Liao
Int. J. Mol. Sci. 2024, 25(3), 1484; https://doi.org/10.3390/ijms25031484 - 25 Jan 2024
Cited by 4 | Viewed by 1582
Abstract
Stachydrine, a prominent bioactive alkaloid derived from Leonurus heterophyllus, is a significant herb in traditional medicine. It has been noted for its anti-inflammatory and antioxidant characteristics. Consequently, we conducted a study of its hepatoprotective effect and the fundamental mechanisms involved in acetaminophen (APAP)-induced [...] Read more.
Stachydrine, a prominent bioactive alkaloid derived from Leonurus heterophyllus, is a significant herb in traditional medicine. It has been noted for its anti-inflammatory and antioxidant characteristics. Consequently, we conducted a study of its hepatoprotective effect and the fundamental mechanisms involved in acetaminophen (APAP)-induced liver injury, utilizing a mouse model. Mice were intraperitoneally administered a hepatotoxic dose of APAP (300 mg/kg). Thirty minutes after APAP administration, mice were treated with different concentrations of stachydrine (0, 2.5, 5, and 10 mg/kg). Animals were sacrificed 16 h after APAP injection for serum and liver tissue assays. APAP overdose significantly elevated the serum alanine transferase levels, hepatic pro-inflammatory cytokines, malondialdehyde activity, phospho-extracellular signal-regulated kinase (ERK), phospho-protein kinase B (AKT), and macrophage-stimulating protein expression. Stachydrine treatment significantly decreased these parameters in mice with APAP-induced liver damage. Our results suggest that stachydrine may be a promising beneficial target in the prevention of APAP-induced liver damage through attenuation of the inflammatory response, inhibition of the ERK and AKT pathways, and expression of macrophage-stimulating proteins. Full article
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10 pages, 4234 KiB  
Article
Lactoferrin Alleviates Ethanol-Induced Injury via Promoting Nrf2 Nuclear Translocation in BRL-3A Rat Liver Cells
by Deming Li, Li Ding, Yilin Yan, Yifei Xing, Jiaying Xu and Liqiang Qin
Int. J. Mol. Sci. 2023, 24(23), 16848; https://doi.org/10.3390/ijms242316848 - 28 Nov 2023
Cited by 4 | Viewed by 1537
Abstract
Our previous animal studies found that the preventive effects of lactoferrin (Lf) on alcoholic liver injury (ALI) are associated with nuclear factor E2-related factor 2 (Nrf2). To further explore the causality, experiments were performed using rat normal liver BRL-3A cells. Lf treatment reduced [...] Read more.
Our previous animal studies found that the preventive effects of lactoferrin (Lf) on alcoholic liver injury (ALI) are associated with nuclear factor E2-related factor 2 (Nrf2). To further explore the causality, experiments were performed using rat normal liver BRL-3A cells. Lf treatment reduced ethanol-induced death and apoptosis; meanwhile, Lf treatment alleviated excessive LDH release. These findings confirmed the protection of Lf against ethanol-induced injury in BRL-3A cells. Mechanistically, Lf treatment reversed the reduction in nuclear Nrf2 induced by ethanol without affecting the cytoplasmic Nrf2 level, which led to antioxidant enzyme activity restoration. However, the blocking of Nrf2 nuclear translocation by ML385 eliminated the protective effects of Lf. In a conclusion, Lf protects BRL-3A cells from ethanol-induced injury via promoting Nrf2 nuclear translocation. Full article
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Review

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19 pages, 1738 KiB  
Review
Liver Sinusoidal Endothelial Cells in the Regulation of Immune Responses and Fibrosis in Metabolic Dysfunction-Associated Fatty Liver Disease
by Munish Puri and Snehal Sonawane
Int. J. Mol. Sci. 2025, 26(9), 3988; https://doi.org/10.3390/ijms26093988 - 23 Apr 2025
Viewed by 268
Abstract
Liver Sinusoidal Endothelial Cells (LSECs) play a crucial role in maintaining liver homeostasis, regulating immune responses, and fibrosis in liver diseases. This review explores the unique functions of LSECs in liver pathology, particularly their roles in immune tolerance, antigen presentation, and the modulation [...] Read more.
Liver Sinusoidal Endothelial Cells (LSECs) play a crucial role in maintaining liver homeostasis, regulating immune responses, and fibrosis in liver diseases. This review explores the unique functions of LSECs in liver pathology, particularly their roles in immune tolerance, antigen presentation, and the modulation of hepatic stellate cells (HSCs) during fibrosis. LSECs act as key regulators of immune balance in the liver by preventing excessive immune activation while also filtering antigens and interacting with immune cells, including Kupffer cells and T cells. Metabolic Dysfunction-Associated Fatty Liver Disease(MAFLD) is significant because it can lead to advanced liver dysfunction, such as cirrhosis and liver cancer. The prevalence of Metabolic Associated Steatohepatitis (MASH) is increasing globally, particularly in the United States, and is closely linked to rising rates of obesity and type 2 diabetes. Early diagnosis and intervention are vital to prevent severe outcomes, highlighting the importance of studying LSECs in liver disease. However, during chronic liver diseases, LSECs undergo dysfunction, leading to their capillarization, loss of fenestrations, and promotion of pro-fibrotic signaling pathways such as Transforming growth factor-beta (TGF-β), which subsequently activates HSCs and contributes to the progression of liver fibrosis. The review also discusses the dynamic interaction between LSECs, HSCs, and other hepatic cells during the progression of liver diseases, emphasizing how changes in LSEC phenotype contribute to liver scarring and fibrosis. Furthermore, it highlights the potential of LSECs as therapeutic targets for modulating immune responses and preventing fibrosis in liver diseases. By restoring LSECs’ function and targeting pathways associated with their dysfunction, novel therapies could be developed to halt or reverse liver disease progression. The findings of this review reinforce the importance of LSECs in liver pathology and suggest that they hold significant promises as targets for future treatment strategies aimed at addressing chronic liver diseases. Full article
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