Evidence map›Paper›PMID 39522884›Full record

ArticleJournal of hepatology2025

Multi-modal analysis of human hepatic stellate cells identifies novel therapeutic targets for metabolic dysfunction-associated steatotic liver disease.

Hyun Young Kim, Sara Brin Rosenthal, Xiao Liu, Charlene Miciano, Xiaomeng Hou, Michael Miller, Justin Buchanan, Olivier B Poirion, Daisy Chilin-Fuentes, Cuijuan Han and 12 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Journal of hepatology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 54 papers.

0numbers the graph read from it
0cells of the map it votes in
54citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

54 citing papers in PubMed.

  1. Article
  2. Article
  3. Review
  4. Review
  5. Article
  6. Precision pathophysiology in steatotic liver disease.Clinical and molecular hepatology · 2026
    Review
  7. Article
  8. Article
  9. Review
  10. Article
  11. Article
  12. Article
  13. Article
  14. Review
  15. Article
  16. Review
  17. Article
  18. Article
  19. Review
  20. Iturin derived fromiScience · 2026
    Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

22 authors.

Hyun Young KimDepartment of Medicine, University of California San Diego, La Jolla, California, USA; Department of Surgery, University of California San Diego, La Jolla, California, USA.
Sara Brin RosenthalCenter for Computational Biology and Bioinformatics, University of California San Diego, La Jolla, California, USA.
Xiao LiuDepartment of Medicine, University of California San Diego, La Jolla, California, USA; Department of Surgery, University of California San Diego, La Jolla, California, USA.
Charlene MicianoDepartment of Cellular and Molecular Medicine, University of California San Diego, La Jolla, California, USA; Center for Epigenomics, University of California San Diego, La Jolla, California, USA.
Xiaomeng HouDepartment of Cellular and Molecular Medicine, University of California San Diego, La Jolla, California, USA; Center for Epigenomics, University of California San Diego, La Jolla, California, USA.
Michael MillerDepartment of Cellular and Molecular Medicine, University of California San Diego, La Jolla, California, USA; Center for Epigenomics, University of California San Diego, La Jolla, California, USA.
Justin BuchananDepartment of Cellular and Molecular Medicine, University of California San Diego, La Jolla, California, USA; Center for Epigenomics, University of California San Diego, La Jolla, California, USA.
Olivier B PoirionDepartment of Cellular and Molecular Medicine, University of California San Diego, La Jolla, California, USA; Center for Epigenomics, University of California San Diego, La Jolla, California, USA.
Daisy Chilin-FuentesDepartment of Medicine, University of California San Diego, La Jolla, California, USA.
Cuijuan HanDepartment of Medicine, University of California San Diego, La Jolla, California, USA.
Mojgan HousseiniDepartment of Pathology, University of California San Diego, La Jolla, California, USA.
Raquel Carvalho-Gontijo WeberDepartment of Medicine, University of California San Diego, La Jolla, California, USA; Department of Surgery, University of California San Diego, La Jolla, California, USA.
Sadatsugu SakaneDepartment of Medicine, University of California San Diego, La Jolla, California, USA; Department of Surgery, University of California San Diego, La Jolla, California, USA.
Wonseok LeeDepartment of Medicine, University of California San Diego, La Jolla, California, USA; Department of Surgery, University of California San Diego, La Jolla, California, USA.
Huayi ZhaoDepartment of Medicine, University of California San Diego, La Jolla, California, USA; Department of Surgery, University of California San Diego, La Jolla, California, USA.
Karin DiggleDepartment of Medicine, University of California San Diego, La Jolla, California, USA.
Sebastian PreisslDepartment of Cellular and Molecular Medicine, University of California San Diego, La Jolla, California, USA; Center for Epigenomics, University of California San Diego, La Jolla, California, USA; Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Christopher K GlassDepartment of Cellular and Molecular Medicine, University of California San Diego, La Jolla, California, USA.
Bing RenDepartment of Cellular and Molecular Medicine, University of California San Diego, La Jolla, California, USA; Center for Epigenomics, University of California San Diego, La Jolla, California, USA.
Allen WangDepartment of Cellular and Molecular Medicine, University of California San Diego, La Jolla, California, USA; Center for Epigenomics, University of California San Diego, La Jolla, California, USA. Electronic address: a5wang@health.ucsd.edu.
David A BrennerDepartment of Medicine, University of California San Diego, La Jolla, California, USA; Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA. Electronic address: dbrenner@sbpdiscovery.org.
Tatiana KisselevaDepartment of Surgery, University of California San Diego, La Jolla, California, USA. Electronic address: tkisseleva@health.ucsd.edu.

Funding

UC San Diego Clinical and Translational Research InstituteUL1TR001442 · NCATS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI FIRESTEIN, GARY S, HOGARTH, MICHAEL · 2015 to 2024
$88.3M
Yeast Genetics and Stress Response Genes-BiomedicalP42ES010337 · NIEHS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI TUKEY, ROBERT H · 2000 to 2022
$69.8M
The Southernearch Center for ALPD and CirrhosisP50AA011999 · NIAAA · UNIVERSITY OF SOUTHERN CALIFORNIA · PI ANNA S. GUKOVSKAYA · 1999 to 2026
$45.8M
San Diego Digestive Diseases Research CenterP30DK120515 · NIDDK · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI LARS ECKMANN, Bernd G. Schnabl · 2019 to 2026
$10.8M
Transcriptional co-regulators and macrophage gene expressionR01DK091183 · NIDDK · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI GLASS, CHRISTOPHER K · 2011 to 2025
$9.9M
Inactivation of Hepatic Stellate Cells During Reversal of Liver FibrosisR01DK099205 · NIDDK · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI BRENNER, DAVID A., KISSELEVA, TATIANA · 2014 to 2025
$4.8M
The Role of Portal Fibroblasts in Cholestatic Liver FibrosisR01DK101737 · NIDDK · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI KISSELEVA, TATIANA · 2014 to 2025
$3.8M
Novel IL-23 inhibitor for the treatment of alcohol associated liver diseaseU01AA029019 · NIAAA · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI KISSELEVA, TATIANA, LOOMBA, ROHIT · 2020 to 2024
$3.7M
The role of IL-17 signaling in alcohol-induced HCCR01AA028550 · NIAAA · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI BRENNER, DAVID A., KISSELEVA, TATIANA · 2021 to 2025
$2.3M
Collagen fibers and fragments regulate pancreatic cancer metabolism and growth.R01CA285997 · NCI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI DAVID A. BRENNER, Michael Karin · 2024 to 2026
$2.2M
The Role of IL-17 in Alcoholic Liver Disease and CancerU01AA022614 · NIAAA · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI KARIN, MICHAEL, KISSELEVA, TATIANA · 2014 to 2018
$1.8M
Development and validation of a novel 3D human in vitro model of nonalcoholic steatohepatitis to be used for novel therapeutic screening and research on disease mechanism.R44DK115242 · NIDDK · ORGANOVO, INC. · PI MINER, JEFFREY N. · 2017 to 2019
$1.7M
NCATS NIH HHS UL1 TR001442NCI NIH HHS R01 CA285997NIAAA NIH HHS P50 AA011999NIAAA NIH HHS R01 AA028550NIAAA NIH HHS U01 AA022614NIAAA NIH HHS U01 AA029019NIDDK NIH HHS P30 DK120515NIDDK NIH HHS R01 DK091183NIDDK NIH HHS R01 DK099205NIDDK NIH HHS R01 DK101737NIDDK NIH HHS R01 DK111866NIDDK NIH HHS R44 DK115242NIDDK NIH HHS R56 DK088837NIEHS NIH HHS P42 ES010337
6 · The paper itself

Abstract

BACKGROUND &

aimsMetabolic dysfunction-associated steatotic liver disease ranges from metabolic dysfunction-associated steatotic liver (MASL) to metabolic dysfunction-associated steatohepatitis (MASH) with fibrosis. Transdifferentiation of hepatic stellate cells (HSCs) into fibrogenic myofibroblasts plays a critical role in the pathogenesis of MASH liver fibrosis. We compared transcriptome and chromatin accessibility of human HSCs from NORMAL, MASL, and MASH livers at single-cell resolution. We aimed to identify genes that are upregulated in activated HSCs and to determine which of these genes are key in the pathogenesis of MASH fibrosis.

methodsEighteen human livers were profiled using single-nucleus (sn)RNA-seq and snATAC-seq. High priority targets were identified, then tested in 2D human HSC cultures, 3D human liver spheroids, and HSC-specific gene knockout mice.

resultsMASH-enriched activated HSC subclusters are the major source of extracellular matrix proteins. We identified a set of concurrently upregulated and more accessible core genes (GAS7, SPON1, SERPINE1, LTBP2, KLF9, EFEMP1) that drive activation of HSCs. Expression of these genes was regulated via crosstalk between lineage-specific (JUNB/AP1), cluster-specific (RUNX1/2) and signal-specific (FOXA1/2) transcription factors. The pathological relevance of the selected targets, such as SERPINE1 (PAI-1), was demonstrated using dsiRNA-based HSC-specific gene knockdown or pharmacological inhibition of PAI-1 in 3D human MASH liver spheroids, and HSC-specific Serpine1 knockout mice.

conclusionThis study identified novel gene targets and regulatory mechanisms underlying activation of fibrogenic HSCs in MASH, and demonstrated that genetic or pharmacological inhibition of select genes suppressed liver fibrosis. IMPACT AND IMPLICATIONS: Herein, we present the results of a multi-modal sequencing analysis of human hepatic stellate cells (HSCs) from NORMAL, MASL (metabolic dysfunction-associated steatotic liver), and metabolic dysfunction-associated steatohepatitis (MASH) livers. We identified additional subclusters that were not detected by previous studies and characterized the mechanism by which HSCs are activated in MASH livers, including the transcriptional machinery that induces the transdifferentiation of HSCs into myofibroblasts. For the first time, we described the pathogenic role of activated HSC-derived PAI-1 (a product of the SERPINE1 gene) in the development of MASH liver fibrosis. Targeting the RUNX1/2-SERPINE1 axis could be a novel strategy for the treatment of liver fibrosis in patients.

Indexed as

Fatty LiverHepatic Stellate CellsLiver CirrhosisAnimalsCell TransdifferentiationHumansLiverMaleMiceMice, KnockoutNon-alcoholic Fatty Liver DiseaseTranscriptomeactivation of human HSCsliver fibrosisMASHMASLDsnRNA-seq and snATAC-seq

Identifiers

PMID39522884
PMCPMC12306656

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.