{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T19:05:49Z","timestamp":1789585549597,"version":"build-2803163510"},"reference-count":40,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2024,4,30]],"date-time":"2024-04-30T00:00:00Z","timestamp":1714435200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"ANID\/FONDECYT","award":["#1200255"],"award-info":[{"award-number":["#1200255"]}]},{"name":"ANID\/FONDECYT","award":["#15150012"],"award-info":[{"award-number":["#15150012"]}]},{"name":"ANID\/FONDECYT","award":["R01-077379"],"award-info":[{"award-number":["R01-077379"]}]},{"name":"ANID\/FONDAP","award":["#1200255"],"award-info":[{"award-number":["#1200255"]}]},{"name":"ANID\/FONDAP","award":["#15150012"],"award-info":[{"award-number":["#15150012"]}]},{"name":"ANID\/FONDAP","award":["R01-077379"],"award-info":[{"award-number":["R01-077379"]}]},{"name":"NIH\/NIGMS","award":["#1200255"],"award-info":[{"award-number":["#1200255"]}]},{"name":"NIH\/NIGMS","award":["#15150012"],"award-info":[{"award-number":["#15150012"]}]},{"name":"NIH\/NIGMS","award":["R01-077379"],"award-info":[{"award-number":["R01-077379"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Liver fibrosis, characterized by excessive extracellular matrix (ECM) deposition, can progress to cirrhosis and increases the risk of liver cancer. Hepatic stellate cells (HSCs) play a pivotal role in fibrosis progression, transitioning from a quiescent to activated state upon liver injury, wherein they proliferate, migrate, and produce ECM. Calcium signaling, involving the inositol 1,4,5-trisphosphate receptor (IP3R), regulates HSC activation. This study investigated the efficacy of a novel IP3R inhibitor, desmethylxestospongin B (dmXeB), in preventing HSC activation. Freshly isolated rat HSCs were activated in vitro in the presence of varying dmXeB concentrations. The dmXeB effectively inhibited HSC proliferation, migration, and expression of fibrosis markers without toxicity to the primary rat hepatocytes or human liver organoids. Furthermore, dmXeB preserved the quiescent phenotype of HSCs marked by retained vitamin A storage. Mechanistically, dmXeB suppressed mitochondrial respiration in activated HSCs while enhancing glycolytic activity. Notably, methyl pyruvate, dimethyl \u03b1-ketoglutarate, and nucleoside supplementation all individually restored HSC proliferation despite dmXeB treatment. Overall, dmXeB demonstrates promising anti-fibrotic effects by inhibiting HSC activation via IP3R antagonism without adverse effects on other liver cells. These findings highlight dmXeB as a potential therapeutic agent for liver fibrosis treatment, offering a targeted approach to mitigate liver fibrosis progression and its associated complications.<\/jats:p>","DOI":"10.3390\/cells13090765","type":"journal-article","created":{"date-parts":[[2024,5,2]],"date-time":"2024-05-02T08:42:57Z","timestamp":1714639377000},"page":"765","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Novel Inositol 1,4,5-Trisphosphate Receptor Inhibitor Antagonizes Hepatic Stellate Cell Activation: A Potential Drug to Treat Liver Fibrosis"],"prefix":"10.3390","volume":"13","author":[{"given":"Natalia","family":"Smith-Cortinez","sequence":"first","affiliation":[{"name":"Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen (UMCG), 9713 GZ Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janette","family":"Heegsma","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen (UMCG), 9713 GZ Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masa","family":"Podunavac","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of California, Oakland, CA 94607, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Armen","family":"Zakarian","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of California, Oakland, CA 94607, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1115-2790","authenticated-orcid":false,"given":"J. 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Investig."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1159\/000456581","article-title":"Liver Fibrosis: Understanding the Dynamics of Bidirectional Wound Repair to Inform the Design of Markers and Therapies","volume":"35","author":"Iredale","year":"2017","journal-title":"Dig. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1007\/s00535-017-1404-4","article-title":"Human hepatic stellate cell isolation and characterization","volume":"53","author":"Shang","year":"2018","journal-title":"J. Gastroenterol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Saeed, A., Dullaart, R.P.F., Schreuder, T.C.M.A., Blokzijl, H., and Faber, K.N. (2017). Disturbed Vitamin A Metabolism in Non-Alcoholic Fatty Liver Disease (NAFLD). Nutrients, 10.","DOI":"10.3390\/nu10010029"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Dewidar, B., Meyer, C., Dooley, S., and Meindl-Beinker, N. (2019). TGF-\u03b2 in Hepatic Stellate Cell Activation and Liver Fibrogenesis-Updated 2019. Cells, 8.","DOI":"10.3390\/cells8111419"},{"key":"ref_6","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_7","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1146\/annurev-pathol-011110-130246","article-title":"Pathogenesis of liver fibrosis","volume":"6","author":"Friedman","year":"2011","journal-title":"Annu. Rev. Pathol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.1053\/j.gastro.2012.07.115","article-title":"Hedgehog controls hepatic stellate cell fate by regulating metabolism","volume":"143","author":"Chen","year":"2012","journal-title":"Gastroenterology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1465","DOI":"10.1053\/j.gastro.2017.12.022","article-title":"Hedgehog-YAP Signaling Pathway Regulates Glutaminolysis to Control Activation of Hepatic Stellate Cells","volume":"154","author":"Du","year":"2018","journal-title":"Gastroenterology"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Smith-Cortinez, N., van Eunen, K., Heegsma, J., Serna-Salas, S.A., Sydor, S., Bechmann, L.P., Moshage, H., Bakker, B.M., and Faber, K.N. (2020). Simultaneous Induction of Glycolysis and Oxidative Phosphorylation during Activation of Hepatic Stellate Cells Reveals Novel Mitochondrial Targets to Treat Liver Fibrosis. Cells, 9.","DOI":"10.3390\/cells9112456"},{"key":"ref_11","unstructured":"Smith Cortinez, N. (2020). Novel Molecular Targets in Hepatic Stellate Cells for the Treatment of Liver Fibrosis. [Ph.D. Thesis, University of Groningen]."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"G975","DOI":"10.1152\/ajpgi.00401.2006","article-title":"Molecular basis for calcium signaling in hepatic stellate cells","volume":"292","author":"Kruglov","year":"2007","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1111\/j.1476-5381.2011.01599.x","article-title":"Azelnidipine is a calcium blocker that attenuates liver fibrosis and may increase antioxidant defence","volume":"165","author":"Ohyama","year":"2012","journal-title":"Br. J. Pharmacol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1016\/j.ceca.2008.11.006","article-title":"Intracellular calcium signals regulate growth of hepatic stellate cells via specific effects on cell cycle progression","volume":"45","author":"Soliman","year":"2009","journal-title":"Cell Calcium."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1515","DOI":"10.3748\/wjg.v11.i10.1515","article-title":"Effects of drug serum of anti-fibrosis I herbal compound on calcium in hepatic stellate cell and its molecular mechanism","volume":"11","author":"Xiao","year":"2005","journal-title":"World J. Gastroenterol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3780","DOI":"10.1016\/j.bbadis.2018.09.011","article-title":"Deficiency in augmenter of liver regeneration accelerates liver fibrosis by promoting migration of hepatic stellate cell","volume":"1864","author":"Ai","year":"2018","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1016\/j.cell.2010.06.007","article-title":"Essential regulation of cell bioenergetics by constitutive InsP3 receptor Ca2+ transfer to mitochondria","volume":"142","author":"Miller","year":"2010","journal-title":"Cell"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Lovy, A., Ahumada-Castro, U., Bustos, G., Farias, P., Gonzalez-Billault, C., Molg\u00f3, J., and Cardenas, C. (2020). Concerted Action of AMPK and Sirtuin-1 Induces Mitochondrial Fragmentation Upon Inhibition of Ca2+ Transfer to Mitochondria. Front. Cell Dev. Biol., 8.","DOI":"10.3389\/fcell.2020.00378"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.celrep.2016.03.045","article-title":"Selective Vulnerability of Cancer Cells by Inhibition of Ca2+ Transfer from Endoplasmic Reticulum to Mitochondria","volume":"15","author":"McNeal","year":"2016","journal-title":"Cell Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2051","DOI":"10.1016\/j.febslet.2005.02.053","article-title":"A competitive inhibitor of IP3-mediated Ca2+ signalling in cultured rat myotubes, isolated myonuclei, and neuroblastoma (NG108-15) cells","volume":"579","author":"Jaimovich","year":"2005","journal-title":"FEBS Lett."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"11278","DOI":"10.1002\/anie.202102259","article-title":"Scalable Total Synthesis, IP3R Inhibitory Activity of Desmethylxestospongin B, and Effect on Mitochondrial Function and Cancer Cell Survival","volume":"60","author":"Podunavac","year":"2021","journal-title":"Angew. Chem. Int. Ed. Engl."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1002\/hep.1840120311","article-title":"Acetaldehyde selectively stimulates collagen production in cultured rat liver fat-storing cells but not in hepatocytes","volume":"12","author":"Moshage","year":"1990","journal-title":"Hepatology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/j.cell.2014.11.050","article-title":"Long-term culture of genome-stable bipotent stem cells from adult human liver","volume":"160","author":"Huch","year":"2015","journal-title":"Cell"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Woudenberg-Vrenken, T.E., de la Rosa, L.C., Buist-Homan, M., Faber, K.N., and Moshage, H. (2013). Metformin protects rat hepatocytes against bile acid-induced apoptosis. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0071773"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2959","DOI":"10.1021\/bi2018909","article-title":"Role of mitochondrial Ca2+ in the regulation of cellular energetics","volume":"51","author":"Glancy","year":"2012","journal-title":"Biochemistry"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"eaay1212","DOI":"10.1126\/scisignal.aay1212","article-title":"Cancer cells with defective oxidative phosphorylation require endoplasmic reticulum-to-mitochondria Ca2+ transfer for survival","volume":"13","author":"Cardenas","year":"2020","journal-title":"Sci. Signal."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"701518","DOI":"10.4061\/2010\/701518","article-title":"The effect of mitochondrial dysfunction on cytosolic nucleotide metabolism","volume":"2010","author":"Desler","year":"2010","journal-title":"J. Nucleic Acids."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"6483","DOI":"10.3748\/wjg.v25.i44.6483","article-title":"Inositol 1,4,5-trisphosphate receptor in the liver: Expression and function","volume":"25","author":"Lemos","year":"2019","journal-title":"World J. Gastroenterol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1427","DOI":"10.1038\/nm.3735","article-title":"Chronic enrichment of hepatic endoplasmic reticulum-mitochondria contact leads to mitochondrial dysfunction in obesity","volume":"20","author":"Arruda","year":"2014","journal-title":"Nat. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1002\/hep4.1012","article-title":"Hepatic Inositol 1,4,5 Trisphosphate Receptor Type 1 Mediates Fatty Liver","volume":"1","author":"Feriod","year":"2017","journal-title":"Hepatol. Commun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.1016\/j.celrep.2018.01.010","article-title":"IP3 Receptor-Dependent Cytoplasmic Ca2+ Signals Are Tightly Controlled by Cav\u03b23","volume":"22","author":"Belkacemi","year":"2018","journal-title":"Cell Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1016\/j.tem.2019.02.005","article-title":"Calcium Signaling as a Therapeutic Target for Liver Steatosis","volume":"30","author":"Ali","year":"2019","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2008","DOI":"10.1002\/hep.27199","article-title":"Continuation of metformin use after a diagnosis of cirrhosis significantly improves survival of patients with diabetes","volume":"60","author":"Zhang","year":"2014","journal-title":"Hepatology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1038\/s41591-018-0087-6","article-title":"Metformin reverses established lung fibrosis in a bleomycin","volume":"24","author":"Rangarajan","year":"2018","journal-title":"Nat. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/j.aohep.2020.05.006","article-title":"Curcumin downregulates Smad pathways and reduces hepatic stellate cells activation in experimental fibrosis","volume":"19","author":"Segovia","year":"2020","journal-title":"Ann. Hepatol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1186\/s12964-021-00762-7","article-title":"Calcium signaling in hepatitis B virus infection and its potential as a therapeutic target","volume":"19","author":"Kong","year":"2021","journal-title":"Cell Commun. Signal."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1384","DOI":"10.1002\/hep.28988","article-title":"Hepatostat: Liver regeneration and normal liver tissue maintenance","volume":"65","author":"Michalopoulos","year":"2017","journal-title":"Hepatology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1038\/nature11826","article-title":"In vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regeneration","volume":"494","author":"Huch","year":"2013","journal-title":"Nature"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.biomaterials.2015.11.026","article-title":"Novel human hepatic organoid model enables testing of drug-induced liver fibrosis in vitro","volume":"78","author":"Leite","year":"2016","journal-title":"Biomaterials"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1162","DOI":"10.1111\/liv.12587","article-title":"Calcium signalling from the type I inositol 1,4,5-trisphosphate receptor is required at early phase of liver regeneration","volume":"35","author":"Oliveira","year":"2015","journal-title":"Liver Int."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/9\/765\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:36:36Z","timestamp":1760106996000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/9\/765"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,30]]},"references-count":40,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2024,5]]}},"alternative-id":["cells13090765"],"URL":"https:\/\/doi.org\/10.3390\/cells13090765","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4,30]]}}}