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Updated: Jun 11, 2025
Human Liver Microphysiological System for Assessing Drug-Induced Liver Toxicity In Vitro
Published on: January 31, 2022
New finding based on Comparative Toxicogenomics Database: Hepatic YY1 mediates drug-induced liver injury
Jin-Quan Zhao1, Yuan Sun1, Lu-Lu Yang1
1State Key Laboratory of Natural Medicines, China Pharmaceutical University, No. 639 Longmian Avenue, Nanjing 211198, China.
Background:
YY1 plays a crucial part in the onset and progression of numerous liver diseases, yet the significant contribution of YY1 to drug-induced liver injury (DILI) appears to have been underestimated by researchers.
Purpose:
To reveal the underlying role of YY1 in DILI.
Method:
The compounds that interact with YY1 were queried in the Comparative Toxicogenomics Database (CTD), with the majority found to be hepatotoxic, which includes certain widely used drugs. Molecular docking and SPR characterized the robust binding of hepatotoxic compounds to YY1. The duty of YY1 in DILI was investigated in Diosbulbin B (DIOB), a recently identified hepatotoxic compound that tightly associates with YY1, and further validated on ANIT, LCA, APAP, and CDDP. Transcriptomic analysis disclosed the underlying mechanisms involved in DIOB-induced liver injury. RT-qPCR, immunohistochemistry, immunofluorescence, western blotting, and cellular transfection techniques were employed to validate the specific mechanism.
Results:
Among the 94 compounds affecting YY1 expression in the CTD, 59 compounds exhibited hepatotoxicity, showing close interactions with YY1 and almost consistent binding sites by molecular docking. The SPR validated the tough binding of several hepatotoxic compounds to YY1, including five FDA-approved hepatotoxic drugs. Mechanistically, the involvement of YY1 in DILI was uncovered through the cholestasis lens, mice hepatic YY1 was up-regulated by hepatotoxic DIOB and transcriptionally inhibited FXR and its downstream BSEP and MRP2 expression, initiating early in cholestatic liver injury and persisting to drive the progression of cholestasis. ANIT and LCA-induced model of cholestasis provided evidence for the hypothesis that YY1 frequently mediates drug induced cholestasis (DIC). APAP and CDDP indicated that YY1 may also be involved in hepatocellular and mixed type DILI.
Conclusion:
YY1 widely mediated the development of DIC and also might be engaged in other types of DILI. YY1 presented a common target for hepatotoxic medications and the targeting of liver YY1 for drug development may offer a novel approach for managing DILI.
Insights
The transcription factor YY1 is a key player in drug-induced liver injury (DILI), particularly in drug-induced cholestasis. Targeting YY1 in the liver may offer new strategies for managing DILI.
Area of Science:
- Hepatology
- Toxicology
- Molecular Biology
Background:
- The transcription factor YY1 is implicated in liver disease pathogenesis.
- Its specific role in drug-induced liver injury (DILI) has been underestimated.
- Understanding YY1's function is crucial for addressing DILI.
Purpose of the Study:
- To elucidate the role of YY1 in the development of DILI.
- To investigate YY1 as a potential therapeutic target for liver injury.
Main Methods:
- Queried the Comparative Toxicogenomics Database (CTD) for compounds interacting with YY1.
- Utilized molecular docking and Surface Plasmon Resonance (SPR) to assess binding affinity.
- Investigated YY1's role in DILI using Diosbulbin B (DIOB) and other models (ANIT, LCA, APAP, CDDP).
- Employed transcriptomic analysis and molecular techniques (RT-qPCR, western blotting) to uncover mechanisms.
Main Results:
- 59 out of 94 compounds affecting YY1 expression in CTD were hepatotoxic, showing strong binding to YY1.
- SPR confirmed robust binding of hepatotoxic compounds, including FDA-approved drugs.
- YY1 up-regulation by DIOB inhibited FXR, BSEP, and MRP2, driving cholestatic liver injury.
- YY1 was identified as a mediator of drug-induced cholestasis (DIC) and potentially other DILI types.
Conclusions:
- YY1 broadly mediates the development of drug-induced cholestasis (DIC).
- YY1 may also be involved in hepatocellular and mixed types of DILI.
- Targeting hepatic YY1 presents a novel therapeutic strategy for managing DILI.
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