Evidence map›Paper›PMID 34917911›Full record

ArticleJHEP reports : innovation in hepatology2022

ROCK2 inhibition attenuates profibrogenic immune cell function to reverse thioacetamide-induced liver fibrosis.

Christina Nalkurthi, Wayne A Schroder, Michelle Melino, Katharine M Irvine, Melanie Nyuydzefe, Wei Chen, Jing Liu, Michele W L Teng, Geoffrey R Hill, Patrick Bertolino and 5 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in JHEP reports : innovation in hepatology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
36citing papers in PubMed, 1 pooled it
5.8field-weighted citation impact, top 2% of its field
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

36 citing papers in PubMed, 1 synthesis or guideline pooled it, 70 citations in OpenAlex.

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  9. Identification of Novel Kv1.3 Channel-Interacting Proteins Using Proximity Labelling in T-Cells.Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology · 2025
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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

15 authors at 8 institutions in 2 countries.

Christina NalkurthiQIMR Berghofer Medical Research Institute, Brisbane, Australia.
Wayne A SchroderQIMR Berghofer Medical Research Institute, Brisbane, Australia.
Michelle MelinoQIMR Berghofer Medical Research Institute, Brisbane, Australia.
Katharine M IrvineMater Research, Translational Research Institute, University of Queensland, Brisbane, Australia.
Melanie NyuydzefeKadmon Corporation LLC, New York, NY, USA.
Wei ChenKadmon Corporation LLC, New York, NY, USA.
Jing LiuQIMR Berghofer Medical Research Institute, Brisbane, Australia.
Michele W L TengQIMR Berghofer Medical Research Institute, Brisbane, Australia.
Geoffrey R HillClinical Research Division, Fred Hutchinson Cancer Research Centre, Seattle, WA, USA.
Patrick BertolinoCentenary Institute, Sydney, Australia.
Bruce R BlazarMasonic Cancer Center and Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.
Gregory C MillerEnvoi Specialist Pathologists, Brisbane, Australia.
Andrew D CloustonEnvoi Specialist Pathologists, Brisbane, Australia.
Alexandra Zanin-ZhorovEquilibre BioPharmaceuticals LLC, New York, NY, USA.
Kelli P A MacDonaldQIMR Berghofer Medical Research Institute, Brisbane, Australia.
QIMR Berghofer Medical Research Institute · AUEnvoi Specialist Pathologists · AUEon Corporation (United States) · USCentenary Institute · AUFred Hutch Cancer Center · USThe University of Queensland · AUTranslational Research Institute · AUUniversity of Minnesota · US

Funding

Transgenic/KnockoutP01AI056299 · NIAID · HARVARD UNIVERSITY (MEDICAL SCHOOL) · PI SHARPE, ARLENE H. · 2003 to 2023
$42.5M
NIAID NIH HHS P01 AI056299
6 · The paper itself

Abstract

BACKGROUND &

aimsFibrosis, the primary cause of morbidity in chronic liver disease, is induced by pro-inflammatory cytokines, immune cell infiltrates, and tissue resident cells that drive excessive myofibroblast activation, collagen production, and tissue scarring. Rho-associated kinase 2 (ROCK2) regulates key pro-fibrotic pathways involved in both inflammatory reactions and altered extracellular matrix remodelling, implicating this pathway as a potential therapeutic target.

methodsWe used the thioacetamide-induced liver fibrosis model to examine the efficacy of administration of the selective ROCK2 inhibitor KD025 to prevent or treat liver fibrosis and its impact on immune composition and function.

resultsProphylactic and therapeutic administration of KD025 effectively attenuated thioacetamide-induced liver fibrosis and promoted fibrotic regression. KD025 treatment inhibited liver macrophage tumour necrosis factor production and disrupted the macrophage niche within fibrotic septae. ROCK2 targeting

conclusionsAs IL-17 and IgG-Fc binding promote pathogenic macrophage differentiation, together our data demonstrate that ROCK2 inhibition prevents and reverses liver fibrosis through direct and indirect effects on macrophage function and highlight the therapeutic potential of ROCK2 inhibition in liver fibrosis. LAY SUMMARY: By using a clinic-ready small-molecule inhibitor, we demonstrate that selective ROCK2 inhibition prevents and reverses hepatic fibrosis through its pleiotropic effects on pro-inflammatory immune cell function. We show that ROCK2 mediates increased IL-17 production, antibody production, and macrophage dysregulation, which together drive fibrogenesis in a model of chemical-induced liver fibrosis. Therefore, in this study, we not only highlight the therapeutic potential of ROCK2 targeting in chronic liver disease but also provide previously undocumented insights into our understanding of cellular and molecular pathways driving the liver fibrosis pathology.

Indexed as

ALT, alanine aminotransferaseAST, aspartate aminotransferaseB cellsBcl6, B-cell lymphoma 6BMDM, bone marrow-derived macrophagescGVHD, chronic graft-vs-host diseaseCLD, chronic liver diseaseCol1a2, collagen type α1DR, ductular reactionECM, extracellular matrixGC, germinal centreHCC, hepatocellular carcinomaHSC, hepatic stellate cellIHC, immunohistochemicalIL-17InflammationLiver fibrosisLPS, lipopolysaccharideMacrophagesMMP, matrix metalloproteinaseNASH, non-alcoholic steatohepatitispCofilin, phosphorylated cofilinpMac, peritoneal macrophagespSTAT3, phosphorylated signal transducer and activator of transcriptionqRT-PCR, quantitative real-time PCRRAR, retinoic acid receptorROCK2ROCK2, Rho-associated kinase 2ROCK, Rho-associated coiled-coil forming protein kinasesRORγt, RAR-related orphan receptor gammaSR, Sirius redSTAT3, signal transducer and activator of transcription 3TAA, thioacetamideTfh, T follicular helperTGF-β, transforming growth factor-betaTh17, T helper 17TherapyTNF, tumour necrosis factorα-SMA, alpha smooth muscle actin

Identifiers

PMID34917911
PMCPMC8645924
OpenAlexW3204188118

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC-ND
Read underepoch 390

Registered trials

None linked

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.