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Cellular senescence is now recognized as a significant contributor to organ fibrosis, largely driven by transforming growth factor beta (TGF-\u03b2) signaling, such as in metabolic dysfunction-associated steatohepatitis (MASH), idiopathic pulmonary fibrosis (IPF), chronic kidney disease (CKD), and myocardial fibrosis, which can lead to heart failure, cystic fibrosis, and fibrosis in pancreatic tumors, to name a few. MASH is a progressive inflammatory and fibrotic liver condition that has reached pandemic proportions, now considered the largest non-viral contributor to the need for liver transplantation. Methods: We previously studied Oxy210, an anti-fibrotic and anti-inflammatory, orally bioavailable, oxysterol-based drug candidate for MASH, using APOE*3-Leiden.CETP mice, a humanized hyperlipidemic mouse model that closely recapitulates the hallmarks of human MASH. In this model, treatment of mice with Oxy210 for 16 weeks caused significant amelioration of the disease, evidenced by reduced hepatic inflammation, lipid deposition, and fibrosis, atherosclerosis and adipose tissue inflammation. Results: Here we demonstrate increased hepatic expression of senescence-associated genes and senescence-associated secretory phenotype (SASP), correlated with the expression of pro-fibrotic and pro-inflammatorygenes in these mice during the development of MASH that are significantly inhibited by Oxy210. Using the HepG2 human hepatocyte cell line, we demonstrate the induced expression of senescent-associated genes and SASP by TGF-\u03b2 and inhibition by Oxy210. Conclusions: These findings further support the potential therapeutic effects of Oxy210 mediated in part through inhibition of senescence-driven hepatic fibrosis and inflammation in MASH and perhaps in other senescence-associated fibrotic diseases.<\/jats:p>","DOI":"10.3390\/cells14151191","type":"journal-article","created":{"date-parts":[[2025,8,4]],"date-time":"2025-08-04T09:41:17Z","timestamp":1754300477000},"page":"1191","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Oxy210 Inhibits Hepatic Expression of Senescence-Associated, Pro-Fibrotic, and Pro-Inflammatory Genes in Mice During Development of MASH and in Hepatocytes In Vitro"],"prefix":"10.3390","volume":"14","author":[{"given":"Feng","family":"Wang","sequence":"first","affiliation":[{"name":"MAX BioPharma Inc., Santa Monica, CA 90404, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3540-3013","authenticated-orcid":false,"given":"Simon T.","family":"Hui","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Stappenbeck","sequence":"additional","affiliation":[{"name":"MAX BioPharma Inc., Santa Monica, CA 90404, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1829-576X","authenticated-orcid":false,"given":"Dorota","family":"Kaminska","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9013-0228","authenticated-orcid":false,"given":"Aldons J.","family":"Lusis","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3312-294X","authenticated-orcid":false,"given":"Farhad","family":"Parhami","sequence":"additional","affiliation":[{"name":"MAX BioPharma Inc., Santa Monica, CA 90404, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1633","DOI":"10.14336\/AD.2023.0222","article-title":"TGF-\u03b2 as A Master Regulator of Aging-Associated Tissue Fibrosis","volume":"14","author":"Ren","year":"2023","journal-title":"Aging Dis."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Yanai, H., Adachi, H., Hakoshima, M., Iida, S., and Katsuyama, H. (2023). Metabolic-Dysfunction-Associated Steatotic Liver Disease-Its Pathophysiology, Association with Atherosclerosis and Cardiovascular Disease, and Treatments. Int. J. Mol. Sci., 24.","DOI":"10.20944\/preprints202309.1062.v1"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e158450","DOI":"10.1172\/JCI158450","article-title":"Cellular senescence: A key therapeutic target in aging and diseases","volume":"132","author":"Zhang","year":"2022","journal-title":"J. Clin. Investig."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1407","DOI":"10.1007\/s12325-020-01287-0","article-title":"Cellular Senescence as a Therapeutic Target for Age-Related Diseases: A Review","volume":"37","author":"Mendivil","year":"2020","journal-title":"Adv. Ther."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Lushchak, O., Schosserer, M., and Grillari, J. (2023). Senopathies\u2014Diseases Associated with Cellular Senescence. Biomolecules, 13.","DOI":"10.3390\/biom13060966"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Bonnet, L., Alexandersson, I., Baboota, R.K., Kroon, T., Oscarsson, J., Smith, U., and Boucher, J. (2022). Cellular Senescence in Hepatocytes Contributes to Metabolic Disturbances in NASH. Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.957616"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Stahl, E.C., Haschak, M.J., Popovic, B., and Brown, B.N. (2018). Macrophages in the Aging Liver and Age-Related Liver Disease. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.02795"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/j.jhep.2024.03.014","article-title":"Phenotypes and Ontogeny of Senescent Hepatic Stellate Cells in Metabolic Dysfunction-Associated Steatohepatitis","volume":"81","author":"Yashaswini","year":"2024","journal-title":"J. Hepatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"15691","DOI":"10.1038\/ncomms15691","article-title":"Cellular Senescence Drives Age-Dependent Hepatic Steatosis","volume":"8","author":"Ogrodnik","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.jcmgh.2023.09.008","article-title":"The Origin and Fate of Liver Myofibroblasts","volume":"17","author":"Kim","year":"2024","journal-title":"Cell. Mol. Gastroenterol. Hepatol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Yanagisawa, H., Maeda, H., Noguchi, I., Tanaka, M., Wada, N., Nagasaki, T., Kobayashi, K., Kanazawa, G., Taguchi, K., and Chuang, V.T.G. (2024). Carbon Monoxide-Loaded Red Blood Cells Ameliorate Metabolic Dysfunction-Associated Steatohepatitis Progression via Enhancing AMP-Activated Protein Kinase Activity and Inhibiting Kupffer Cell Activation. Redox Biol., 76.","DOI":"10.1016\/j.redox.2024.103314"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1324","DOI":"10.1038\/nm1663","article-title":"TLR4 Enhances TGF-\u03b2 Signaling and Hepatic Fibrosis","volume":"13","author":"Seki","year":"2007","journal-title":"Nat. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1002\/jhbp.245","article-title":"Recent Advancement of Molecular Mechanisms of Liver Fibrosis","volume":"22","author":"Seki","year":"2015","journal-title":"J. Hepatobiliary Pancreat. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2182","DOI":"10.1002\/hep.30113","article-title":"The Genetic Architecture of Diet-Induced Hepatic Fibrosis in Mice","volume":"68","author":"Hui","year":"2018","journal-title":"Hepatology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e00296","DOI":"10.1002\/edm2.296","article-title":"Oxy210, a Novel Inhibitor of Hedgehog and TGF-\u03b2 Signalling, Ameliorates Hepatic Fibrosis and Hypercholesterolemia in Mice","volume":"4","author":"Hui","year":"2021","journal-title":"Endocrinol. Diabetes Metab."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Stappenbeck, F., Wang, F., Sinha, S.K., Hui, S.T., Farahi, L., Mukhamedova, N., Fleetwood, A., Murphy, A.J., Sviridov, D., and Lusis, A.J. (2024). Anti-Inflammatory Oxysterol, Oxy210, Inhibits Atherosclerosis in Hyperlipidemic Mice and Inflammatory Responses of Vascular Cells. Cells, 13.","DOI":"10.3390\/cells13191632"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Wang, F., Stappenbeck, F., Tang, L.Y., Zhang, Y.E., Hui, S.T., Lusis, A.J., and Parhami, F. (2022). Oxy210, a Semi-Synthetic Oxysterol, Exerts Anti-Inflammatory Effects in Macrophages via Inhibition of Toll-like Receptor (TLR) 4 and TLR2 Signaling and Modulation of Macrophage Polarization. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23105478"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"104064","DOI":"10.1016\/j.drudis.2024.104064","article-title":"Unveiling the Role of the Hedgehog Signaling Pathway in Chronic Liver Disease: Therapeutic Insights and Strategies","volume":"29","author":"Nair","year":"2024","journal-title":"Drug Discov. Today"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.3892\/ijo.2014.2552","article-title":"TGF-\u03b2\/Smad Signaling during Hepatic Fibro-carcinogenesis (Review)","volume":"45","author":"Yoshida","year":"2014","journal-title":"Int. J. Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Wang, F., Stappenbeck, F., and Parhami, F. (2023). Oxy210, a Semi-Synthetic Oxysterol, Inhibits Profibrotic Signaling in Cellular Models of Lung and Kidney Fibrosis. Pharmaceuticals, 16.","DOI":"10.3390\/ph16010114"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Tominaga, K., and Suzuki, H.I. (2019). TGF-\u03b2 Signaling in Cellular Senescence and Aging-Related Pathology. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20205002"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"eaaw0254","DOI":"10.1126\/sciadv.aaw0254","article-title":"The Innate Immune Sensor Toll-Like Receptor 2 Controls the Senescence-Associated Secretory Phenotype","volume":"5","author":"Hari","year":"2019","journal-title":"Sci. Adv."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"100113","DOI":"10.1016\/j.mocell.2024.100113","article-title":"The Role of p21 in Cellular Senescence and Aging-Related Diseases","volume":"47","author":"Yan","year":"2024","journal-title":"Mol. Cells"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1016\/j.tcb.2018.02.001","article-title":"Hallmarks of Cellular Senescence","volume":"28","author":"Nehme","year":"2018","journal-title":"Trends Cell Biol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Safwan-Zaiter, H., Wagner, N., and Wagner, K.D. (2022). P16INK4A\u2014More Than a Senescence Marker. Life, 12.","DOI":"10.3390\/life12091332"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Mijit, M., Caracciolo, V., Melillo, A., Amicarelli, F., and Giordano, A. (2020). Role of p53 in the Regulation of Cellular Senescence. Biomolecules, 10.","DOI":"10.3390\/biom10030420"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Kumari, R., and Jat, P. (2021). Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.645593"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1101\/gad.235184.113","article-title":"Cellular Senescence and Its Effector Programs","volume":"28","author":"Salama","year":"2014","journal-title":"Genes Dev."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1007\/s00109-010-0609-2","article-title":"Regulation of Tumor Suppressor p53 at the RNA Level","volume":"88","author":"Vilborg","year":"2010","journal-title":"J. Mol. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1007\/978-1-62703-239-1_3","article-title":"Senescence Regulation by the p53 Protein Family","volume":"Volume 965","author":"Qian","year":"2013","journal-title":"Methods in Molecular Biology"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Wagner, K.D., and Wagner, N. (2022). The Senescence Markers p16INK4A, p14ARF\/p19ARF, and p21 in Organ Development and Homeostasis. Cells, 11.","DOI":"10.3390\/cells11121966"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1446","DOI":"10.1161\/ATVBAHA.117.309451","article-title":"Plasminogen Activator Inhibitor-1 Is a Marker and a Mediator of Senescence","volume":"37","author":"Vaughan","year":"2017","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Yang, Y., Liu, L., Naik, I., Braunstein, Z., Zhong, J., and Ren, B. (2017). Transcription Factor C\/EBP Homologous Protein in Health and Diseases. Front. Immunol., 8.","DOI":"10.3389\/fimmu.2017.01612"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Salazar, G. (2018). NADPH Oxidases and Mitochondria in Vascular Senescence. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19051327"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1042\/BJ20090666","article-title":"The NADPH Oxidase Nox4 Restricts the Replicative Lifespan of Human Endothelial Cells","volume":"423","author":"Lener","year":"2009","journal-title":"Biochem. J."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"101421","DOI":"10.1016\/j.jhepr.2025.101421","article-title":"Antifibrotic Therapies for Metabolic Dysfunction-associated Steatotic Liver Disease","volume":"7","author":"Schwabe","year":"2025","journal-title":"JHEP Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e2149641","DOI":"10.1002\/eji.202149641","article-title":"The \u201cDomino effect\u201d in MASLD: The inflammatory cascade of steatohepatitis","volume":"54","author":"Wensveen","year":"2024","journal-title":"Eur. J. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e20190103","DOI":"10.1084\/jem.20190103","article-title":"Transforming Growth Factor-\u03b2 in Tissue Fibrosis","volume":"217","author":"Frangogiannis","year":"2020","journal-title":"J. Exp. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1007\/s00441-011-1246-y","article-title":"TGF-\u03b2 in Progression of Liver Disease","volume":"347","author":"Dooley","year":"2012","journal-title":"Cell Tissue Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3061","DOI":"10.1097\/CM9.0000000000003439","article-title":"Navigating the Complex Role of Senescence in Liver Disease","volume":"137","author":"Li","year":"2024","journal-title":"Chin. Med. J."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Philips, G.M., Chan, I.S., Swiderska, M., Schroder, V.T., Guy, C., Karaca, G.F., Moylan, C., Venkatraman, T., Feuerlein, S., and Syn, W.-K. (2011). Hedgehog Signaling Antagonist Promotes Regression of Both Liver Fibrosis and Hepatocellular Carcinoma in a Murine Model of Primary Liver Cancer. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0023943"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1002\/hep.26698","article-title":"Transforming Growth Factor beta Signaling in Hepatocytes Participates in Steatohepatitis Through Regulation of Cell Death and Lipid Metabolism in Mice","volume":"59","author":"Yang","year":"2014","journal-title":"Hepatology"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"100301","DOI":"10.1016\/j.jhepr.2021.100301","article-title":"Evaluating Causality of Cellular Senescence in Non-alcoholic Fatty Liver Disease","volume":"3","author":"Meijnikman","year":"2021","journal-title":"JHEP Rep."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1016\/j.cell.2017.05.015","article-title":"Senescence in Health and Disease","volume":"169","author":"He","year":"2017","journal-title":"Cell"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Copp\u00e9, J.P., Patil, C.K., Rodier, F., Sun, Y., Mu\u00f1oz, D.P., Goldstein, J., Nelson, P.S., Desprez, P.Y., and Campisi, J. (2008). Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor Suppressor. PLoS Biol., 6.","DOI":"10.1371\/journal.pbio.0060301"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1556","DOI":"10.1038\/s41591-022-01923-y","article-title":"Cellular Senescence and Senolytics: The Path to the Clinic","volume":"28","author":"Chaib","year":"2022","journal-title":"Nat. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1016\/j.cell.2008.06.049","article-title":"Senescence of Activated Stellate Cells Limits Liver Fibrosis","volume":"134","author":"Krizhanovsky","year":"2008","journal-title":"Cell"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1055\/s-0040-1722262","article-title":"Cellular Senescence in Liver Disease and Regeneration","volume":"41","author":"Gadd","year":"2021","journal-title":"Semin. Liver Dis."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Chaudhary, R., Weiskirchen, R., Ehrlich, M., and Henis, Y.I. (2025). Dual Signaling Pathways of TGF-\u03b2 Superfamily Cytokines in Hepatocytes: Balancing Liver Homeostasis and Disease Progression. Front. Pharmacol., 16.","DOI":"10.3389\/fphar.2025.1580500"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/j.jhep.2018.03.011","article-title":"A Simple Diet- and Chemical-Induced Murine NASH Model with Rapid Progression of Steatohepatitis, Fibrosis and Liver Cancer","volume":"69","author":"Tsuchida","year":"2018","journal-title":"J. Hepatol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1038\/s41392-024-02075-w","article-title":"Hepatocellular Carcinoma: Signaling Pathways and Therapeutic Advances","volume":"10","author":"Zheng","year":"2025","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1890","DOI":"10.1158\/0008-5472.CAN-14-0243","article-title":"Transforming Growth Factor-\u03b2 as a Therapeutic Target in Hepatocellular Carcinoma","volume":"74","author":"Giannelli","year":"2014","journal-title":"Cancer Res."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Gonzalez-Sanchez, E., Vaquero, J., F\u00e9rnandez-Barrena, M.G., Lasarte, J.J., Avila, M.A., Sarobe, P., Reig, M., Calvo, M., and Fabregat, I. (2021). The TGF-\u03b2 Pathway: A Pharmacological Target in Hepatocellular Carcinoma?. Cancers, 13.","DOI":"10.3390\/cancers13133248"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1481","DOI":"10.1007\/s11427-019-9560-7","article-title":"Identification of Hedgehog Signaling as a Potential Oncogenic Driver in an Aggressive Subclass of Human Hepatocellular Carcinoma: A Reanalysis of the TCGA Cohort","volume":"62","author":"Zhao","year":"2019","journal-title":"Sci. China Life Sci."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Ding, J., Li, H.Y., Zhang, L., Zhou, Y., and Wu, J. (2021). Hedgehog Signaling, a Critical Pathway Governing the Development and Progression of Hepatocellular Carcinoma. Cells, 10.","DOI":"10.3390\/cells10010123"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"4330","DOI":"10.3748\/wjg.v23.i24.4330","article-title":"Implication of the Hedgehog Pathway in Hepatocellular Carcinoma","volume":"23","author":"Viscardi","year":"2017","journal-title":"World J. Gastroenterol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"e180310","DOI":"10.1172\/JCI180310","article-title":"The senescence-associated secretome of Hedgehog-deficient hepatocytes drives MASLD progression","volume":"134","author":"Jun","year":"2024","journal-title":"J. Clin. Investig."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"eadi0759","DOI":"10.1126\/scitranslmed.adi0759","article-title":"Found in Translation\u2014Fibrosis in Metabolic Dysfunction-Associated Steatohepatitis (MASH)","volume":"15","author":"Wang","year":"2023","journal-title":"Sci. Transl. Med."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"102294","DOI":"10.1016\/j.arr.2024.102294","article-title":"Lipids and Lipid Metabolism in Cellular Senescence: Emerging Targets for Age-Related Diseases","volume":"97","author":"Zeng","year":"2024","journal-title":"Ageing Res. Rev."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Stappenbeck, F., Wang, F., Tang, L.Y., Zhang, Y.E., and Parhami, F. (2019). Inhibition of Non-Small Cell Lung Cancer Cells by Oxy210, an Oxysterol-Derivative that Antagonizes TGF\u03b2 and Hedgehog Signaling. Cells, 8.","DOI":"10.3390\/cells8101297"},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Tang, L.Y., Spezia, M., Chen, T., Stappenbeck, F., Wang, F., and Parhami, F. (2022). Oxysterol Derivatives Oxy186 and Oxy210 Inhibit WNT Signaling in Non-Small Cell Lung Cancer. Cell Biosci., 12.","DOI":"10.1186\/s13578-022-00857-9"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/15\/1191\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:21:43Z","timestamp":1760034103000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/15\/1191"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,2]]},"references-count":61,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["cells14151191"],"URL":"https:\/\/doi.org\/10.3390\/cells14151191","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,2]]}}}