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Study · In vitro (cells) · 2026

2 results

Mechanistically resolved prediction of compound hepatotoxicity using primary human liver spheroids-Application to recent real-world cases.

Li Y, Sheng H, Zhou T, Xing C, Kukasch M, Shao S, Youhanna S, Vorrink SU, Liang Y, Nies AT, Dressler J, Kölz C and 10 more

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Ryu J, Taebnia N, Jacob D, Hauser C, Petersson C, Klein K, Burk O, Shi B, He Q, Lauschke VM

Drug metabolism and disposition: the biological fate of chemicals22 Jun 2026Cited by 2 (Europe PMC)

PMID42418948 (opens in a new tab)DOI10.1016/j.dmd.2026.100346 (opens in a new tab)PepBankPUB-42418948
Publisher pagePubMedAsk about this study
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Summary

Drug-induced liver injury remains a major cause of clinical trial attrition and postmarketing drug withdrawals, reflecting persistent translational gaps in predictive preclinical models of compound hepatotoxicity. Here, we applied a well-characterized 3-dimensional primary human liver spheroid platform to interrogate diverse mechanisms of hepatotoxicity and benchmark performance against recent real-world clinical cases. After multicenter technology transfer, spheroids maintained stable hepatic functionality, including expression of metabolic enzymes and transporters, albumin secretion, and long-term CYP activity. Importantly, repeated-dose exposure to established hepatotoxins demonstrated robust, concentration-dependent toxicity with excellent interexperimental (R2 = 0.98) and interdonor (R2 = 0.89) reproducibility. To resolve toxicity mechanisms, we implemented Seahorse extracellular flux analysis in liver spheroids, which enabled sensitive detection of early mitochondrial dysfunction, allowing mechanistic discrimination between mitochondrial and nonmitochondrial toxins. Cholestatic liability was identified using bile acid coexposure with accurate classification of chlorpromazine and bosentan and confirmation of bile salt export pump downregulation. Importantly, the model also recapitulated hepatotoxicity signals observed in recent clinical development, including for Bruton's tyrosine kinase inhibitors (tolebrutinib and evobrutinib), oral glucagon-like peptide-1 receptor agonists (danuglipron vs orforglipron), synergistic toxicity on azelaprag-tirzepatide coexposure and enhanced sensitivity to the IL-17A inhibitor LY3509754 on coculture with nonparenchymal liver cells. Collectively, we present new assays for the mechanistic resolution of hepatotoxicity and provide further evidence that 3-dimensional human liver spheroids enable reproducible, mechanistically informative, and clinically aligned assessment of drug-induced liver injury across multiple modalities, which supports their application for preclinical de-risking of drug candidates. SIGNIFICANCE STATEMENT: This study shows that primary human liver spheroids provide a reproducible and mechanistically informative platform for preclinical assessments of drug metabolism and liver toxicity. The model maintains stable CYP expression and metabolic activity, captures the impact of nonparenchymal cells on hepatic clearance, and detects mitochondrial, cholestatic, and interaction-driven toxicity, including recent real-world clinical cases. These findings support 3-dimensional human liver spheroids as translational new approach methodologies for integrating metabolism and toxicity in drug development.
CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study2

1 result from studies that gave the peptide. No result from this study comes from people.

  1. 01LabIn vitro (cells)Safety outcome

    In human liver spheroids, the model recapitulated hepatotoxicity signals for the danuglipron versus orforglipron comparison, without a stated direction.

    In plain wordsIn lab tests, liver spheroids captured toxicity signals for danuglipron versus orforglipron, but the abstract did not state the difference's direction.

    Peptide
    Orforglipron
    Outcome
    Direction not reportedHepatotoxicity signal
    Study

    humann: not reported in source

    Primary human liver spheroids
    Comparator
    Danuglipron
    Outcome group
    Adverse events · Liver
    Studied dose
    Dose not stated

    Source sentences

    Summary
    oral glucagon-like peptide-1 receptor agonists (danuglipron vs orforglipron)
    1 context sentence
    Summary · context
    Here, we applied a well-characterized 3-dimensional primary human liver spheroid platform to interrogate diverse mechanisms of hepatotoxicity and benchmark performance against recent real-world clinical cases.

Studies that did not test the peptide alone1

In this study, Tirzepatide was a lab tool or a carrier, part of a mix, or the subject of a lab method. These results are not evidence about taking Tirzepatide.

  1. 02LabNot a test of Tirzepatide aloneIn vitro (cells)Safety outcome

    In human liver spheroids, azelaprag-tirzepatide coexposure produced synergistic toxicity.

    In plain wordsIn lab tests, azelaprag and tirzepatide together produced synergistic liver toxicity.

    Peptide
    Tirzepatide
    Outcome
    IncreaseSynergistic hepatotoxicity
    Study

    humann: not reported in source

    Primary human liver spheroids
    Outcome group
    Adverse events · Liver

    Source sentences

    Summary
    synergistic toxicity on azelaprag-tirzepatide coexposure
    1 context sentence
    Summary · context
    Here, we applied a well-characterized 3-dimensional primary human liver spheroid platform to interrogate diverse mechanisms of hepatotoxicity and benchmark performance against recent real-world clinical cases.

    In this study, Tirzepatide was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Tirzepatide.

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

  1. Version 3Current

    14 Oct 2026, 05:02 UTC

    Study results updated

  2. Version 2

    14 Oct 2026, 01:46 UTC

    Study data updated · source update from Europe PMC

  3. Version 1

    9 Oct 2026, 03:07 UTC

    First added · source update from Europe PMC

Subjects

Terms as the source lists them.

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