{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T23:01:32Z","timestamp":1785452492055,"version":"3.56.0"},"reference-count":98,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T00:00:00Z","timestamp":1767830400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002467","name":"Dankook University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100002467","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Sinensetin, a polymethoxylated flavone abundant in citrus fruits, has been recognized for its broad biological activities and wide use in traditional medicine around the world. Emerging clinical evidence from flavonoid-enriched orange juice interventions indicates antioxidant and anti-inflammatory effects, aligning with extensive preclinical data. In this review, we explored in vitro and in vivo findings on the anti-inflammatory and anticancer actions of sinensetin and delineated the underlying cellular pathways, especially in terms of proposed targets for sinensetin. In inflammatory settings, sinensetin attenuates NF-\u03baB activation, lowers pro-inflammatory cytokines (e.g., TNF-\u03b1, IL-6), and enhances antioxidant defenses, supporting its reported antioxidant, anti-bacterial, anti-viral, and anti-obesity properties. Across multiple tumor models, sinensetin suppresses oncogenic signaling\u2014including \u03b2-catenin, PI3K\/AKT, VEGF, NRF2, P53, and MKK6\u2014concomitant with reduced proliferation, migration, and survival signaling. We further discuss emerging immunological effects, including modulation of innate immune cell activation and cytokine production, which may contribute to tumor microenvironment reprogramming and inflammation resolution. Together, these mechanistic insights position sinensetin as a promising lead for chemopreventive and adjunct therapeutic strategies. Our efforts aim to provide insights into the future translational development and clinical evaluation of sinensetin and its derivatives.<\/jats:p>","DOI":"10.3390\/cells15020110","type":"journal-article","created":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T12:56:55Z","timestamp":1767877015000},"page":"110","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["From Orange to Oncology: Anti-Inflammatory and Anti-Cancer Mechanisms of Sinensetin"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6910-9213","authenticated-orcid":false,"given":"Dong Joon","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Microbiology, College of Medicine, Dankook University, Cheonan-si 31116, Chungcheongnam-do, Republic of Korea"},{"name":"Multidrug-Resistant Refractory Cancer Convergence Research Center (MRCRC), Dankook University, Cheonan-si 31116, Chungcheongnam-do, Republic of Korea"},{"name":"Department of Pathophysiology, School of Basic Medical Sciences, Academy of Medical Science, College of Medicine, Zhengzhou University, Zhengzhou 450008, China"},{"name":"China-US (Henan) Hormel Cancer Institute, Zhengzhou 450008, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Songyeon","family":"Ahn","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Medicine, Dankook University, Cheonan-si 31116, Chungcheongnam-do, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaomeng","family":"Xie","sequence":"additional","affiliation":[{"name":"Chest Hospital of Zhengzhou University, Zhengzhou 450008, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4743-8048","authenticated-orcid":false,"given":"Yeon-Sun","family":"Seong","sequence":"additional","affiliation":[{"name":"Multidrug-Resistant Refractory Cancer Convergence Research Center (MRCRC), Dankook University, Cheonan-si 31116, Chungcheongnam-do, Republic of Korea"},{"name":"Department of Biochemistry, College of Medicine, Dankook University, Cheonan-si 31116, Chungcheongnam-do, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6895-0465","authenticated-orcid":false,"given":"Yong Weon","family":"Yi","sequence":"additional","affiliation":[{"name":"Multidrug-Resistant Refractory Cancer Convergence Research Center (MRCRC), Dankook University, Cheonan-si 31116, Chungcheongnam-do, Republic of Korea"},{"name":"Department of Biochemistry, College of Medicine, Dankook University, Cheonan-si 31116, Chungcheongnam-do, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1038\/s41573-020-00114-z","article-title":"Natural Products in Drug Discovery: Advances and Opportunities","volume":"20","author":"Atanasov","year":"2021","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/S0960-894X(02)00854-5","article-title":"Siphonols A\u2013E: Novel Nitric Oxide Inhibitors from Orthosiphon stamineus of Indonesia","volume":"13","author":"Awale","year":"2003","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1002\/(SICI)1099-1573(199905)13:3<222::AID-PTR447>3.0.CO;2-P","article-title":"Effect of Extracts of Orthosiphon stamineus Benth, Hieracium pilosella L., Sambucus nigra L. and Arctostaphylos uva-ursi (L.) Spreng. in Rats","volume":"13","author":"Beaux","year":"1999","journal-title":"Phytother. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/j.jep.2009.04.014","article-title":"Diuretic Properties of Orthosiphon stamineus Benth","volume":"124","author":"Adam","year":"2009","journal-title":"J. Ethnopharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Mohamed, E.A.H., Siddiqui, M.J.A., Ang, L.F., Sadikun, A., Chan, S.H., Tan, S.C., Asmawi, M.Z., and Yam, M.F. (2012). Potent \u03b1-Glucosidase and \u03b1-Amylase Inhibitory Activities of Standardized 50% Ethanolic Extracts and Sinensetin from Orthosiphon stamineus Benth as Anti-Diabetic Mechanism. BMC Complement. Altern. Med., 12.","DOI":"10.1186\/1472-6882-12-176"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.jams.2013.01.005","article-title":"Antidiabetic Properties and Mechanism of Action of Orthosiphon stamineus Benth Bioactive Sub-Fraction in Streptozotocin-Induced Diabetic Rats","volume":"6","author":"Mohamed","year":"2013","journal-title":"J. Acupunct. Meridian Stud."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Jie, L.H., Jantan, I., Yusoff, S.D., Jalil, J., and Husain, K. (2021). Sinensetin: An Insight on Its Pharmacological Activities, Mechanisms of Action and Toxicity. Front. Pharmacol., 11.","DOI":"10.3389\/fphar.2020.553404"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2563","DOI":"10.1021\/jf063138v","article-title":"Polymethoxylated Flavones and Other Phenolic Derivates from Citrus in Their Inhibitory Effects on P-Glycoprotein-Mediated Transport of Talinolol in Caco-2 Cells","volume":"55","author":"Castro","year":"2007","journal-title":"J. Agric. Food Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.lfs.2006.09.006","article-title":"Polymethoxylated Flavones Induce Ca2+-Mediated Apoptosis in Breast Cancer Cells","volume":"80","author":"Sergeev","year":"2006","journal-title":"Life Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1711","DOI":"10.1248\/cpb.48.1711","article-title":"Constituents of the Vietnamese Medicinal Plant Orthosiphon stamineus","volume":"48","author":"Tezuka","year":"2008","journal-title":"Chem. Pharm. Bull."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"27","DOI":"10.26599\/FSHW.2022.9250003","article-title":"Natural Sources, Refined Extraction, Biosynthesis, Metabolism, and Bioactivities of Dietary Polymethoxyflavones (PMFs)","volume":"13","author":"Gan","year":"2024","journal-title":"Food Sci. Hum. Wellness"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1002\/mnfr.201100680","article-title":"In Vitro and in Vivo Structure and Activity Relationship Analysis of Polymethoxylated Flavonoids: Identifying Sinensetin as a Novel Antiangiogenesis Agent","volume":"56","author":"Lam","year":"2012","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"106393","DOI":"10.1016\/j.fitote.2025.106393","article-title":"Antimicrobial Potential of the Leaves of Citrus grandis (L.) Osbeck Collected from Iraq: Bioassay-Guided Isolation of Sinensetin as the Anti-MRSA Compound","volume":"181","author":"Nahar","year":"2025","journal-title":"Fitoterapia"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"116649","DOI":"10.1016\/j.jpba.2024.116649","article-title":"Identification of Anti-SARS-CoV-2 Compounds from Qingwen Zhike Prescription and Exploration of Their Underlying Mechanism by UPLC-Q-Exactive Orbitrap MS, High-Throughput Screening Assays and Transmission Electron Microscopy","volume":"255","author":"Zhao","year":"2025","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1016\/S0006-291X(02)00755-6","article-title":"Reversal of P-Glycoprotein-Mediated Multidrug Resistance by 5,6,7,3\u2032,4\u2032-Pentamethoxyflavone (Sinensetin)","volume":"295","author":"Choi","year":"2002","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1016\/j.bbrc.2004.06.020","article-title":"Reversal of P-Glycoprotein-Mediated MDR by 5,7,3\u2032,4\u2032,5\u2032-Pentamethoxyflavone and SAR","volume":"320","author":"Choi","year":"2004","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1936","DOI":"10.1007\/s11095-007-9320-6","article-title":"Effects of Various Methoxyflavones on Vincristine Uptake and Multidrug Resistance to Vincristine in P-Gp-Overexpressing K562\/ADM Cells","volume":"24","author":"Ohtani","year":"2007","journal-title":"Pharm. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.taap.2019.02.010","article-title":"Inhibitory Effects of Flavonoids on P-Glycoprotein in Vitro and in Vivo: Food\/Herb-Drug Interactions and Structure\u2013Activity Relationships","volume":"369","author":"Bai","year":"2019","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"113","DOI":"10.62347\/RGZG2120","article-title":"Identification of Sinensetin as a Selective Inhibitor for Mitogen-Activated Protein Kinase Kinase 6 and an Anticancer Agent for Non-Small Cell Lung Cancer","volume":"15","author":"Xie","year":"2025","journal-title":"Am. J. Cancer Res."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Li, Y., Li, W., Ye, Z., Ji, C., and Zhou, Z. (2024). Antioxidant, Anti-Inflammatory, and Anticancer Activities of Five Citrus Peel Essential Oils. Antioxidants, 13.","DOI":"10.3390\/antiox13121562"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"020008","DOI":"10.1063\/5.0204840","article-title":"Sinensetin Content in Java Tea (Orthosiphon aristatus (Blume) Miq.) Based on Age Level of Leaf","volume":"3095","author":"Mujahid","year":"2024","journal-title":"AIP Conf. Proc."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1002\/bmc.718","article-title":"Determination of Polymethoxylated Flavones in Peels of Selected Jamaican and Mexican Citrus (Citrus spp.) Cultivars by High-performance Liquid Chromatography","volume":"21","author":"Green","year":"2007","journal-title":"Biomed. Chromatogr."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"136","DOI":"10.31665\/JFB.2022.18319","article-title":"Synthetic Pathways of Sinensetin and Derivatives as an Alternate Source in Biological Activity Study","volume":"19","author":"Wang","year":"2022","journal-title":"J. Food Bioact."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.exppara.2019.03.008","article-title":"Identification of Sinensetin and Nobiletin as Major Antitrypanosomal Factors in a Citrus Cultivar","volume":"200","author":"Nakanishi","year":"2019","journal-title":"Exp. Parasitol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1186\/s40104-024-01012-9","article-title":"Hesperidin Ameliorates H2O2-Induced Bovine Mammary Epithelial Cell Oxidative Stress via the Nrf2 Signaling Pathway","volume":"15","author":"Huang","year":"2024","journal-title":"J. Anim. Sci. Biotechnol."},{"key":"ref_26","first-page":"2341470","article-title":"Hesperidin Activates Nrf2 to Protect Cochlear Hair Cells from Cisplatin-Induced Damage","volume":"29","author":"Lou","year":"2024","journal-title":"Redox Rep. Commun. Free Radic. Res."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Gao, J., Yuan, L., Jiang, H., Li, G., Zhang, Y., Zhou, R., Xian, W., Zou, Y., Du, Q., and Zhou, X. (2024). Naringenin Modulates Oxidative Stress and Lipid Metabolism: Insights from Network Pharmacology, Mendelian Randomization, and Molecular Docking. Front. Pharmacol., 15.","DOI":"10.3389\/fphar.2024.1448308"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Flores-Pe\u00f1a, R., Monroy-Ramirez, H.C., Caloca-Camarena, F., Arceo-Orozco, S., Salto-Sevilla, J.A., Galicia-Moreno, M., and Armendariz-Borunda, J. (2025). Naringin and Naringenin in Liver Health: A Review of Molecular and Epigenetic Mechanisms and Emerging Therapeutic Strategies. Antioxidants, 14.","DOI":"10.3390\/antiox14080979"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"921","DOI":"10.2174\/0118715206360266250115065234","article-title":"Effects of Citrus-Derived Diosmetin on Melanoma: Induction of Apoptosis and Autophagy Mediated by PI3K\/Akt\/mTOR Pathway Inhibition","volume":"25","author":"Li","year":"2025","journal-title":"Anti-Cancer Agents Med. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Jeong, S.H., Kim, H.H., Ha, S.E., Park, M.Y., Bhosale, P.B., Abusaliya, A., Park, K.I., Heo, J.D., Kim, H.W., and Kim, G.S. (2022). Flavones: Six Selected Flavones and Their Related Signaling Pathways That Induce Apoptosis in Cancer. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms231810965"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Zhao, C., Lai, W., Li, Y., Hong, K., and Xu, Y. (2025). Potential and Mechanism of Nobiletin in Diabetes Mellitus and Associated Complications. Pharmaceuticals, 18.","DOI":"10.3390\/ph18101528"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Kim, E., Mawatari, K., Yoo, S.-H., and Chen, Z. (2023). The Circadian Nobiletin-ROR Axis Suppresses Adipogenic Differentiation and I\u03baB\u03b1\/NF-\u03baB Signaling in Adipocytes. Nutrients, 15.","DOI":"10.3390\/nu15183919"},{"key":"ref_33","first-page":"4709818","article-title":"Therapeutic Implications of a Polymethoxylated Flavone, Tangeretin, in the Management of Cancer via Modulation of Different Molecular Pathways","volume":"2021","author":"Arafa","year":"2021","journal-title":"Adv. Pharmacol. Pharm. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1080\/15384047.2015.1108491","article-title":"Tangeretin Derivative, 5-Acetyloxy-6,7,8,4\u2032-Tetramethoxyflavone Induces G2\/M Arrest, Apoptosis and Autophagy in Human Non-Small Cell Lung Cancer Cells In Vitro and In Vivo","volume":"17","author":"Li","year":"2015","journal-title":"Cancer Biol. Ther."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"116759","DOI":"10.1016\/j.foodres.2025.116759","article-title":"Effects of a Flavonoid-Enriched Orange Juice on Antioxidant Capacity, Lipid Profile, and Inflammation in Obese Patients: A Randomized Placebo-Controlled Trial","volume":"217","author":"Valle","year":"2025","journal-title":"Food Res. Int."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Zhou, W., Shi, Y., Wang, H., Yu, C., Zhu, H., and Wu, A. (2021). Sinensetin Reduces Osteoarthritis Pathology in the Tert-Butyl Hydroperoxide-Treated Chondrocytes and the Destabilization of the Medial Meniscus Model Mice via the AMPK\/mTOR Signaling Pathway. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.713491"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"104461","DOI":"10.1016\/j.phrs.2019.104461","article-title":"Enhancement of Epithelial Cell Autophagy Induced by Sinensetin Alleviates Epithelial Barrier Dysfunction in Colitis","volume":"148","author":"Xiong","year":"2019","journal-title":"Pharmacol. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3012","DOI":"10.1007\/s11064-021-03406-x","article-title":"Sinensetin Attenuates Amyloid Beta25-35-Induced Oxidative Stress, Inflammation, and Apoptosis in SH-SY5Y Cells Through the TLR4\/NF-\u03baB Signaling Pathway","volume":"46","author":"Zhi","year":"2021","journal-title":"Neurochem. Res."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Youn, K., Yu, Y., Lee, J., Jeong, W.-S., Ho, C.-T., and Jun, M. (2017). Polymethoxyflavones: Novel \u03b2-Secretase (BACE1) Inhibitors from Citrus Peels. Nutrients, 9.","DOI":"10.3390\/nu9090973"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"114101","DOI":"10.1016\/j.intimp.2025.114101","article-title":"Sinensetin Attenuates LPS-Induced Acute Pulmonary Inflammation in Mice and RAW264.7 Cells by Modulating NF-\u03baB P65-Mediated Immune Resistance and STAT3-Mediated Tissue Resilience","volume":"148","author":"Xu","year":"2025","journal-title":"Int. Immunopharmacol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"9973","DOI":"10.1039\/D2FO01304E","article-title":"Sinensetin Attenuates IL-1\u03b2-Induced Cartilage Damage and Ameliorates Osteoarthritis by Regulating SERPINA3","volume":"13","author":"Liu","year":"2022","journal-title":"Food Funct."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1002\/jat.4250","article-title":"Sinensetin Attenuates Oxygen\u2013Glucose Deprivation\/Reperfusion-induced Neurotoxicity by MAPK Pathway in Human Cerebral Microvascular Endothelial Cells","volume":"42","author":"Yang","year":"2022","journal-title":"J. Appl. Toxicol."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Li, J., Jie, X., Liang, X., Chen, Z., Xie, P., Pan, X., Zhou, B., and Li, J. (2020). Sinensetin Suppresses Influenza a Virus-Triggered Inflammation through Inhibition of NF-\u03baB and MAPKs Signalings. BMC Complement. Med. Ther., 20.","DOI":"10.1186\/s12906-020-02918-3"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1002\/ptr.4683","article-title":"Effects of Sinensetin on Lipid Metabolism in Mature 3T3-L1 Adipocytes","volume":"27","author":"Kang","year":"2012","journal-title":"Phytother. Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1038\/s41392-023-01484-7","article-title":"Amyloid \u03b2-Based Therapy for Alzheimer\u2019s Disease: Challenges, Successes and Future","volume":"8","author":"Zhang","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1017\/S1461145711000149","article-title":"Increased NF-\u03baB Signalling up-Regulates BACE1 Expression and Its Therapeutic Potential in Alzheimer\u2019s Disease","volume":"15","author":"Chen","year":"2012","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"105428","DOI":"10.1016\/j.arabjc.2023.105428","article-title":"Systems Pharmacology-Based Dissection of Potential Mechanisms of Exocarpium Citri Grandis for the Treatment of Chronic Bronchitis","volume":"17","author":"Huang","year":"2024","journal-title":"Arab. J. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1330","DOI":"10.1016\/j.bbrc.2005.10.001","article-title":"Nobiletin and Its Related Flavonoids with CRE-Dependent Transcription-Stimulating and Neuritegenic Activities","volume":"337","author":"Nagase","year":"2005","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1397","DOI":"10.1007\/s00702-013-1025-x","article-title":"Potent Activity of Nobiletin-Rich Citrus Reticulata Peel Extract to Facilitate cAMP\/PKA\/ERK\/CREB Signaling Associated with Learning and Memory in Cultured Hippocampal Neurons: Identification of the Substances Responsible for the Pharmacological Action","volume":"120","author":"Kawahata","year":"2013","journal-title":"J. Neural Transm."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"348","DOI":"10.21037\/tcr-23-1317","article-title":"Sinensetin Suppresses Breast Cancer Cell Progression via Wnt\/\u03b2-Catenin Pathway Inhibition","volume":"13","author":"Zhu","year":"2024","journal-title":"Transl. Cancer Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"e70024","DOI":"10.1002\/jbt.70024","article-title":"Sinensetin Inhibits the Movement Ability and Tumor Immune Microenvironment of Non-small Cell Lung Cancer Through the Inactivation of AKT\/\u0392-Catenin Axis","volume":"38","author":"Shi","year":"2024","journal-title":"J. Biochem. Mol. Toxicol."},{"key":"ref_52","first-page":"1251","article-title":"Sinensetin Flavone Exhibits Potent Anticancer Activity against Drug-Resistant Human Gallbladder Adenocarcinoma Cells by Targeting PTEN\/PI3K\/AKT Signalling Pathway, Induces Cellular Apoptosis and Inhibits Cell Migration and Invasion","volume":"25","author":"Huang","year":"2020","journal-title":"J. BU Off. J. Balk. Union Oncol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"360","DOI":"10.3892\/etm.2022.11287","article-title":"Sinensetin Suppresses Angiogenesis in Liver Cancer by Targeting the VEGF\/VEGFR2\/AKT Signaling Pathway","volume":"23","author":"Li","year":"2022","journal-title":"Exp. Ther. Med."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2413","DOI":"10.1007\/s12013-024-01352-3","article-title":"Sinensetin Inhibits Angiogenesis in Lung Adenocarcinoma via the miR-374c-5p\/VEGF-A\/VEGFR-2\/AKT Axis","volume":"82","author":"Ji","year":"2024","journal-title":"Cell Biochem. Biophys."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"8038","DOI":"10.1021\/acs.jafc.3c00867","article-title":"Virtual Screening of Nrf2 Dietary-Derived Agonists and Safety by a New Deep-Learning Model and Verified In Vitro and In Vivo","volume":"71","author":"Liu","year":"2023","journal-title":"J. Agric. Food Chem."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Kim, S.M., Ha, S.E., Lee, H.J., Rampogu, S., Vetrivel, P., Kim, H.H., Saralamma, V.V.G., Lee, K.W., and Kim, G.S. (2020). Sinensetin Induces Autophagic Cell Death through P53-Related AMPK\/mTOR Signaling in Hepatocellular Carcinoma HepG2 Cells. Nutrients, 12.","DOI":"10.3390\/nu12082462"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1007\/s11010-019-03592-x","article-title":"SC79, a Novel Akt Activator, Protects Dopaminergic Neuronal Cells from MPP+ and Rotenone","volume":"461","author":"Zhu","year":"2019","journal-title":"Mol. Cell. Biochem."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Xu, Y., Hang, W.-L., Zhou, X.-M., and Wu, Q. (2021). Exploring the Mechanism Whereby Sinensetin Delays the Progression of Pulmonary Fibrosis Based on Network Pharmacology and Pulmonary Fibrosis Models. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.693061"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"123015","DOI":"10.1016\/j.lfs.2024.123015","article-title":"Cancer Stem Cell Markers: Symphonic Masters of Chemoresistance and Immune Evasion","volume":"355","year":"2024","journal-title":"Life Sci."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1186\/s12964-022-00906-3","article-title":"An Update of Nrf2 Activators and Inhibitors in Cancer Prevention\/Promotion","volume":"20","author":"Pouremamali","year":"2022","journal-title":"Cell Commun. Signal."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1097\/CAD.0000000000000756","article-title":"Sinensetin Induces Apoptosis and Autophagy in the Treatment of Human T-Cell Lymphoma","volume":"30","author":"Tan","year":"2019","journal-title":"Anti-Cancer Drugs"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.1126\/science.add7859","article-title":"Architecture of the MKK6-P38\u03b1 Complex Defines the Basis of MAPK Specificity and Activation","volume":"381","author":"Juyoux","year":"2023","journal-title":"Science"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1186\/s13578-022-00823-5","article-title":"Targeting Tumor-Associated Macrophages for Cancer Treatment","volume":"12","author":"Li","year":"2022","journal-title":"Cell Biosci."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Pan, Y., Yu, Y., Wang, X., and Zhang, T. (2020). Tumor-Associated Macrophages in Tumor Immunity. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.583084"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1533","DOI":"10.7150\/ijbs.15943","article-title":"Cyclooxygenase-2 in Tumor-Associated Macrophages Promotes Metastatic Potential of Breast Cancer Cells through Akt Pathway","volume":"12","author":"Gan","year":"2016","journal-title":"Int. J. Biol. Sci."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Na, Y.-R., Yoon, Y.-N., Son, D.-I., and Seok, S.-H. (2013). Cyclooxygenase-2 Inhibition Blocks M2 Macrophage Differentiation and Suppresses Metastasis in Murine Breast Cancer Model. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0063451"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1038\/s41698-024-00522-z","article-title":"Targeting M2-Like Tumor-Associated Macrophages Is a Potential Therapeutic Approach to Overcome Antitumor Drug Resistance","volume":"8","author":"Wang","year":"2024","journal-title":"npj Precis. Oncol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1271\/bbb.110908","article-title":"Sinensetin Attenuates LPS-Induced Inflammation by Regulating the Protein Level of I\u03baB-\u03b1","volume":"76","author":"Shin","year":"2012","journal-title":"Biosci. Biotechnol. Biochem."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"33514","DOI":"10.1021\/acsomega.3c03319","article-title":"Sinensetin Attenuated Macrophagic NLRP3 Inflammasomes Formation via SIRT1-NRF2 Signaling","volume":"8","author":"Lin","year":"2023","journal-title":"ACS Omega"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1055\/s-0031-1298458","article-title":"Flavonoids Eupatorin and Sinensetin Present in Orthosiphon stamineus Leaves Inhibit Inflammatory Gene Expression and STAT1 Activation","volume":"78","author":"Laavola","year":"2012","journal-title":"Planta Med."},{"key":"ref_71","first-page":"147","article-title":"Immunomodulatory Effects of Sinensetin on Macrophage and Cyclophosphamide-Induced Immunosuppression in Mice","volume":"77","author":"Wang","year":"2022","journal-title":"Die Pharm."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"7592","DOI":"10.1039\/D4FO01704H","article-title":"Sinensetin, a Polymethoxyflavone from Citrus Fruits, Ameliorates LPS-Induced Acute Lung Injury by Suppressing Txnip\/NLRP3\/Caspase-1\/GSDMD Signaling-Mediated Inflammatory Responses and Pyroptosis","volume":"15","author":"Xu","year":"2024","journal-title":"Food Funct."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"e33917","DOI":"10.1016\/j.heliyon.2024.e33917","article-title":"Recent Advances in Identifying Protein Targets of Bioactive Natural Products","volume":"10","author":"Jiang","year":"2024","journal-title":"Heliyon"},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Tabana, Y., Babu, D., Fahlman, R., Siraki, A.G., and Barakat, K. (2023). Target Identification of Small Molecules: An Overview of the Current Applications in Drug Discovery. BMC Biotechnol., 23.","DOI":"10.1186\/s12896-023-00815-4"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1016\/j.chembiol.2020.12.001","article-title":"Recent Advances in Identifying Protein Targets in Drug Discovery","volume":"28","author":"Ha","year":"2021","journal-title":"Cell Chem. Biol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/09168451.2018.1533804","article-title":"Recent Advances in Target Identification of Bioactive Natural Products","volume":"83","author":"Yoshida","year":"2018","journal-title":"Biosci. Biotechnol. Biochem."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Li, G., Peng, X., Guo, Y., Gong, S., Cao, S., and Qiu, F. (2021). Currently Available Strategies for Target Identification of Bioactive Natural Products. Front. Chem., 9.","DOI":"10.3389\/fchem.2021.761609"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/S0169-409X(96)00423-1","article-title":"Experimental and Computational Approaches to Estimate Solubility and Permeability in Drug Discovery and Development Settings","volume":"23","author":"Lipinski","year":"1997","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_79","first-page":"268","article-title":"Synthesis of Sinensetin, A Naturally Occurring Polymethoxyflavone","volume":"47","author":"Hossainab","year":"2004","journal-title":"Pak. J. Sci. Ind. Res."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1146\/annurev-biochem-030222-120000","article-title":"The Art and Science of Molecular Docking","volume":"93","author":"Paggi","year":"2024","journal-title":"Annu. Rev. Biochem."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"He, C., Hao, E., Du, C., Wei, W., Wang, X., Liu, T., and Deng, J. (2023). Investigating the Underlying Mechanisms of Ardisia Japonica Extract\u2019s Anti-Blood-Stasis Effect via Metabolomics and Network Pharmacology. Molecules, 28.","DOI":"10.3390\/molecules28217301"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"115887","DOI":"10.1016\/j.jpba.2023.115887","article-title":"Integrated Metabolomics and Network Pharmacology Revealed the Key Active Ingredients for the Treatment of Ulcerative Colitis in the Citrus Reticulata \u2018Dahongpao\u2019 Peel","volume":"239","author":"Li","year":"2024","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"4171","DOI":"10.1111\/jcmm.18002","article-title":"Network Medicine Approaches for Identification of Novel Prognostic Systems Biomarkers and Drug Candidates for Papillary Thyroid Carcinoma","volume":"27","author":"Kori","year":"2023","journal-title":"J. Cell. Mol. Med."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1038\/s41368-024-00305-z","article-title":"Sinensetin Protects against Periodontitis Through Binding to Bach1 Enhancing Its Ubiquitination Degradation and Improving Oxidative Stress","volume":"16","author":"Yuan","year":"2024","journal-title":"Int. J. Oral Sci."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/j.ijbiomac.2020.10.174","article-title":"Inhibitory Mechanism of Sinensetin on \u03b1-Glucosidase and Non-Enzymatic Glycation: Insights from Spectroscopy and Molecular Docking Analyses","volume":"166","author":"Liu","year":"2021","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"e4","DOI":"10.4142\/jvs.21256","article-title":"Anti-Adipogenic Effect of the Flavonoids through the Activation of AMPK in Palmitate (PA)-Treated HepG2 Cells","volume":"23","author":"Rajan","year":"2021","journal-title":"J. Vet. Sci."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/j.tox.2009.07.023","article-title":"CYP1-Mediated Antiproliferative Activity of Dietary Flavonoids in MDA-MB-468 Breast Cancer Cells","volume":"264","author":"Androutsopoulos","year":"2009","journal-title":"Toxicology"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1645","DOI":"10.1016\/j.phymed.2014.08.003","article-title":"In Vitro Effect of Important Herbal Active Constituents on Human Cytochrome P450 1A2 (CYP1A2) Activity","volume":"21","author":"Pan","year":"2014","journal-title":"Phytomedicine"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/j.toxlet.2019.11.016","article-title":"Heterotropic Activation of Flavonoids on Cytochrome P450 3A4: A Case Example of Alleviating Dronedarone-Induced Cytotoxicity","volume":"319","author":"Bai","year":"2020","journal-title":"Toxicol. Lett."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"126392","DOI":"10.1016\/j.ijbiomac.2023.126392","article-title":"Structural Changes and Anti-Hepatocellular Carcinoma Activity of Interferon-\u03b3 after Interaction with Sinensetin","volume":"253","author":"Feng","year":"2023","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"4644","DOI":"10.1039\/D0FO03366A","article-title":"Drug-Guided Screening for Pancreatic Lipase Inhibitors in Functional Foods","volume":"12","author":"Zhang","year":"2021","journal-title":"Food Funct."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"5576","DOI":"10.1021\/jf000613v","article-title":"Inhibitors of 15-Lipoxygenase from Orange Peel","volume":"48","author":"Malterud","year":"2000","journal-title":"J. Agric. Food Chem."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1388","DOI":"10.1002\/jat.4628","article-title":"Inhibitory Effect of Flavonoids on Multidrug and Toxin Extrusion Protein 1 Function: Implications for Food\/Herb\u2013Drug Interaction and Drug-induced Kidney Injury","volume":"44","author":"Duan","year":"2024","journal-title":"J. Appl. Toxicol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"152445","DOI":"10.1016\/j.tox.2020.152445","article-title":"Drug Interaction Study of Flavonoids toward OATP1B1 and Their 3D Structure Activity Relationship Analysis for Predicting Hepatoprotective Effects","volume":"437","author":"Fan","year":"2020","journal-title":"Toxicology"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1007\/s13318-020-00634-4","article-title":"Potential Risk of Food-Drug Interactions: Citrus Polymethoxyflavones and Flavanones as Inhibitors of the Organic Anion Transporting Polypeptides (OATP) 1B1, 1B3, and 2B1","volume":"45","author":"Weiss","year":"2020","journal-title":"Eur. J. Drug Metab. Pharmacokinet."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1216","DOI":"10.1126\/science.1231097","article-title":"Evidence for a Common Mechanism of SIRT1 Regulation by Allosteric Activators","volume":"339","author":"Hubbard","year":"2013","journal-title":"Science"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"151","DOI":"10.18632\/aging.100542","article-title":"Sirt1 Activation by Resveratrol Is Substrate Sequence-Selective","volume":"5","author":"Lakshminarasimhan","year":"2013","journal-title":"Aging"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"2031","DOI":"10.1021\/acs.jcim.9b01188","article-title":"Structural Analysis and Identification of False Positive Hits in Luciferase-Based Assays","volume":"60","author":"Yang","year":"2020","journal-title":"J. Chem. Inf. Model."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/2\/110\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,10]],"date-time":"2026-01-10T05:29:15Z","timestamp":1768022955000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/2\/110"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,8]]},"references-count":98,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["cells15020110"],"URL":"https:\/\/doi.org\/10.3390\/cells15020110","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,8]]}}}