{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,19]],"date-time":"2026-01-19T06:09:24Z","timestamp":1768802964430,"version":"3.49.0"},"reference-count":45,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2022,10,28]],"date-time":"2022-10-28T00:00:00Z","timestamp":1666915200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012226","name":"Fundamental Research Funds for the Central Universities","doi-asserted-by":"publisher","award":["21620106"],"award-info":[{"award-number":["21620106"]}],"id":[{"id":"10.13039\/501100012226","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012226","name":"Fundamental Research Funds for the Central Universities","doi-asserted-by":"publisher","award":["81871987"],"award-info":[{"award-number":["81871987"]}],"id":[{"id":"10.13039\/501100012226","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["21620106"],"award-info":[{"award-number":["21620106"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81871987"],"award-info":[{"award-number":["81871987"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>AMPK-related protein kinase 5 (ARK5) is involved in a broad spectrum of physiological and cell events, and aberrant expression of ARK5 has been observed in a wide variety of solid tumors, including liver cancer. However, the role of ARK5 in liver fibrosis remains largely unexplored. We found that ARK5 expression was elevated in mouse fibrotic livers, and showed a positive correlation with the progression of liver fibrosis. ARK5 was highly expressed not only in activated hepatic stellate cells (HSCs), but also in hepatocytes. In HSCs, ARK5 prevents the degradation of transforming growth factor \u03b2 type I receptor (T\u03b2RI) and mothers against decapentaplegic homolog 4 (Smad4) proteins by inhibiting the expression of Smad ubiquitin regulatory factor 2 (Smurf2), thus maintaining the continuous transduction of the transforming growth factor \u03b2 (TGF-\u03b2) signaling pathway, which is essential for cell activation, proliferation and survival. In hepatocytes, ARK5 induces the occurrence of epithelial-mesenchymal transition (EMT), and also promotes the secretion of inflammatory factors. Inflammatory factors, in turn, further enhance the activation of HSCs and deepen the degree of liver fibrosis. Notably, we demonstrated in a mouse model that targeting ARK5 with the selective inhibitor HTH-01-015 attenuates CCl4-induced liver fibrosis in mice. Taken together, the results indicate that ARK5 is a critical driver of liver fibrosis, and promotes liver fibrosis by synergy between HSCs and hepatocytes.<\/jats:p>","DOI":"10.3390\/ijms232113084","type":"journal-article","created":{"date-parts":[[2022,10,30]],"date-time":"2022-10-30T04:57:34Z","timestamp":1667105854000},"page":"13084","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Enhanced Expression of ARK5 in Hepatic Stellate Cell and Hepatocyte Synergistically Promote Liver Fibrosis"],"prefix":"10.3390","volume":"23","author":[{"given":"Yang","family":"You","sequence":"first","affiliation":[{"name":"Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou 510630, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9911-2322","authenticated-orcid":false,"given":"Chongqing","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou 510630, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junru","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou 510630, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hengdong","family":"Qu","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou 510630, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou 510630, China"},{"name":"Department of Hepatological Surgery, The First Affiliated Hospital, Jinan University, Guangzhou 510630, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ziwei","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou 510630, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinying","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The First Affiliated Hospital, Jinan University, Guangzhou 510630, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jian","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou 510630, China"},{"name":"Department of Hepatological Surgery, The First Affiliated Hospital, Jinan University, Guangzhou 510630, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1551","DOI":"10.1002\/hep.31457","article-title":"Perturbation of Specific Signaling Pathways Is Involved in Initiation of Mouse Liver Fibrosis","volume":"73","author":"Chen","year":"2021","journal-title":"Hepatology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.gene.2018.06.053","article-title":"Emerging role and therapeutic implication of Wnt signaling pathways in liver fibrosis","volume":"674","author":"Wang","year":"2018","journal-title":"Gene"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1136\/gutjnl-2019-318372","article-title":"Rilpivirine attenuates liver fibrosis through selective STAT1-mediated apoptosis in hepatic stellate cells","volume":"69","author":"Alegre","year":"2020","journal-title":"Gut"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.addr.2017.05.007","article-title":"Hepatic stellate cells as key target in liver fibrosis","volume":"121","author":"Higashi","year":"2017","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1002\/hep.29881","article-title":"Tyrosine kinase SYK is a potential therapeutic target for liver fibrosis","volume":"68","author":"Qu","year":"2018","journal-title":"Hepatology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1002\/hep.30820","article-title":"Sestrin 3 Protects Against Diet-Induced Nonalcoholic Steatohepatitis in Mice Through Suppression of Transforming Growth Factor \u03b2 Signal Transduction","volume":"71","author":"Huang","year":"2020","journal-title":"Hepatology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1016\/j.jhep.2020.11.016","article-title":"Targeting Nestin(+) hepatic stellate cells ameliorates liver fibrosis by facilitating T\u03b2RI degradation","volume":"74","author":"Chen","year":"2021","journal-title":"J. Hepatol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/j.jhep.2020.07.041","article-title":"Hepatocyte pyroptosis and release of inflammasome particles induce stellate cell activation and liver fibrosis","volume":"74","author":"Gaul","year":"2021","journal-title":"J. Hepatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1053\/j.gastro.2014.07.018","article-title":"Cell death and cell death responses in liver disease: Mechanisms and clinical relevance","volume":"147","author":"Luedde","year":"2014","journal-title":"Gastroenterology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1038\/s41419-020-2429-9","article-title":"Imbalance in mitochondrial dynamics induced by low PGC-1\u03b1 expression contributes to hepatocyte EMT and liver fibrosis","volume":"11","author":"Zhang","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1016\/j.jhep.2018.12.016","article-title":"Hepatocyte-specific suppression of microRNA-221-3p mitigates liver fibrosis","volume":"70","author":"Tsay","year":"2019","journal-title":"J. Hepatol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"269","DOI":"10.3892\/br.2016.578","article-title":"Epithelial-mesenchymal transition in liver fibrosis","volume":"4","author":"Zhao","year":"2016","journal-title":"Biomed. Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"23337","DOI":"10.1074\/jbc.M700194200","article-title":"Fibroblasts derive from hepatocytes in liver fibrosis via epithelial to mesenchymal transition","volume":"282","author":"Zeisberg","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"697","DOI":"10.3892\/etm.2021.10129","article-title":"Role of ARK5 in cancer and other diseases (Review)","volume":"22","author":"Mo","year":"2021","journal-title":"Exp. Ther. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1021\/acs.jmedchem.0c00533","article-title":"Development and Therapeutic Potential of NUAKs Inhibitors","volume":"64","author":"Faisal","year":"2021","journal-title":"J. Med. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"113080","DOI":"10.1016\/j.ejmech.2020.113080","article-title":"Optimization of WZ4003 as NUAK inhibitors against human colorectal cancer","volume":"210","author":"Yang","year":"2021","journal-title":"Eur. J. Med. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1591","DOI":"10.7150\/ijbs.34113","article-title":"miR-424-5p represses the metastasis and invasion of intrahepatic cholangiocarcinoma by targeting ARK5","volume":"15","author":"Wu","year":"2019","journal-title":"Int. J. Biol. Sci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.canlet.2016.04.026","article-title":"ARK5 promotes doxorubicin resistance in hepatocellular carcinoma via epithelial-mesenchymal transition","volume":"377","author":"Xu","year":"2016","journal-title":"Cancer Lett."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"van de Vis, R.A.J., Moustakas, A., and van der Heide, L.P. (2021). NUAK1 and NUAK2 Fine-Tune TGF-\u03b2 Signaling. Cancers, 13.","DOI":"10.3390\/cancers13133377"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"111","DOI":"10.7150\/ijbs.23230","article-title":"The role of TGF-\u03b2\/SMAD4 signaling in cancer","volume":"14","author":"Zhao","year":"2018","journal-title":"Int. J. Biol. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1007\/s00018-022-04279-1","article-title":"Platelets fine-tune effector responses of na\u00efve CD4(+) T cells via platelet factor 4-regulated transforming growth factor \u03b2 signaling","volume":"79","author":"Min","year":"2022","journal-title":"Cell. Mol. Life Sci. CMLS"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2809","DOI":"10.1038\/s41467-021-23048-5","article-title":"Interplay between transforming growth factor-\u03b2 and Nur77 in dual regulations of inhibitor of differentiation 1 for colonic tumorigenesis","volume":"12","author":"Niu","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Sinha, A., Iyengar, P.V., and Ten Dijke, P. (2021). E3 Ubiquitin Ligases: Key Regulators of TGF\u03b2 Signaling in Cancer Progression. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22020476"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1351","DOI":"10.1016\/j.ajpath.2019.03.005","article-title":"Ubiquitin-Specific Protease 15 Maintains Transforming Growth Factor-\u03b2 Pathway Activity by Deubiquitinating Transforming Growth Factor-\u03b2 Receptor I during Wound Healing","volume":"189","author":"Zhao","year":"2019","journal-title":"Am. J. Pathol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1007\/s13238-014-0058-8","article-title":"The regulation of TGF-\u03b2\/SMAD signaling by protein deubiquitination","volume":"5","author":"Zhang","year":"2014","journal-title":"Protein Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"610663","DOI":"10.3389\/fonc.2020.610663","article-title":"Posttranslational Modifications of Smurfs: Emerging Regulation in Cancer","volume":"10","author":"Yang","year":"2020","journal-title":"Front. Oncol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1038\/s41586-019-1897-5","article-title":"TGF-\u03b2 orchestrates fibrogenic and developmental EMTs via the RAS effector RREB1","volume":"577","author":"Su","year":"2020","journal-title":"Nature"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Tadokoro, T., Morishita, A., and Masaki, T. (2021). Diagnosis and Therapeutic Management of Liver Fibrosis by MicroRNA. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22158139"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1717","DOI":"10.1002\/hep.31176","article-title":"Deletion of Protein Kinase D3 Promotes Liver Fibrosis in Mice","volume":"72","author":"Zhang","year":"2020","journal-title":"Hepatology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1913","DOI":"10.1007\/s13277-013-0735-x","article-title":"Overexpression of ARK5 is associated with poor prognosis in hepatocellular carcinoma","volume":"34","author":"Cui","year":"2013","journal-title":"Tumour Biol. J. Int. Soc. Oncodev. Biol. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3757","DOI":"10.1007\/s11010-021-04196-0","article-title":"LINC00922 promotes the proliferation, migration, invasion and EMT process of liver cancer cells by regulating miR-424-5p\/ARK5","volume":"476","author":"Ye","year":"2021","journal-title":"Mol. Cell. Biochem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1002\/hep.28948","article-title":"The origin of fibrogenic myofibroblasts in fibrotic liver","volume":"65","author":"Kisseleva","year":"2017","journal-title":"Hepatology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1038\/nrgastro.2017.38","article-title":"Mechanisms of hepatic stellate cell activation","volume":"14","author":"Tsuchida","year":"2017","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"111572","DOI":"10.1016\/j.mad.2021.111572","article-title":"Hepatic stellate cell senescence in liver fibrosis: Characteristics, mechanisms and perspectives","volume":"199","author":"Zhang","year":"2021","journal-title":"Mech. Ageing Dev."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Zisser, A., Ipsen, D.H., and Tveden-Nyborg, P. (2021). Hepatic Stellate Cell Activation and Inactivation in NASH-Fibrosis-Roles as Putative Treatment Targets?. Biomedicines, 9.","DOI":"10.3390\/biomedicines9040365"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Dewidar, B., Meyer, C., Dooley, S., and Meindl-Beinker, A.N. (2019). TGF-\u03b2 in Hepatic Stellate Cell Activation and Liver Fibrogenesis-Updated 2019. Cells, 8.","DOI":"10.3390\/cells8111419"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1903","DOI":"10.1002\/jcp.29108","article-title":"Transforming growth factor \u03b2 signaling pathway: A promising therapeutic target for cancer","volume":"235","author":"Chen","year":"2020","journal-title":"J. Cell. Physiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1420","DOI":"10.1016\/j.jhep.2021.08.011","article-title":"Therapeutic HNF4A mRNA attenuates liver fibrosis in a preclinical model","volume":"75","author":"Yang","year":"2021","journal-title":"J. Hepatol."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Ramundo, V., Zanirato, G., and Aldieri, E. (2021). The Epithelial-to-Mesenchymal Transition (EMT) in the Development and Metastasis of Malignant Pleural Mesothelioma. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222212216"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"12173","DOI":"10.1002\/jcp.27955","article-title":"Transforming growth factor-\u03b2 signaling: Tumorigenesis and targeting for cancer therapy","volume":"234","author":"Ahmadi","year":"2019","journal-title":"J. Cell. Physiol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"108051","DOI":"10.1016\/j.intimp.2021.108051","article-title":"Crosstalk between hepatic stellate cells and surrounding cells in hepatic fibrosis","volume":"99","author":"Yang","year":"2021","journal-title":"Int. Immunopharmacol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1704","DOI":"10.1136\/gutjnl-2016-313392","article-title":"The HLF\/IL-6\/STAT3 feedforward circuit drives hepatic stellate cell activation to promote liver fibrosis","volume":"67","author":"Xiang","year":"2018","journal-title":"Gut"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Knorr, J., Kaufmann, B., Inzaugarat, M.E., Holtmann, T.M., Geisler, L., Hundertmark, J., Kohlhepp, M.S., Boosheri, L.M., Chilin-Fuentes, D.R., and Birmingham, A. (2022). Interleukin-18 signaling promotes activation of hepatic stellate cells in murine liver fibrosis. Hepatology.","DOI":"10.1002\/hep.32776"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1042\/BJ20131152","article-title":"Characterization of WZ4003 and HTH-01-015 as selective inhibitors of the LKB1-tumour-suppressor-activated NUAK kinases","volume":"457","author":"Banerjee","year":"2014","journal-title":"Biochem. J."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1038\/nprot.2015.017","article-title":"High-yield and high-purity isolation of hepatic stellate cells from normal and fibrotic mouse livers","volume":"10","author":"Mederacke","year":"2015","journal-title":"Nat. Protoc."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/21\/13084\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:04:46Z","timestamp":1760144686000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/21\/13084"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,28]]},"references-count":45,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2022,11]]}},"alternative-id":["ijms232113084"],"URL":"https:\/\/doi.org\/10.3390\/ijms232113084","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,28]]}}}