{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:19:00Z","timestamp":1785403140950,"version":"3.56.0"},"reference-count":40,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T00:00:00Z","timestamp":1785283200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100018542","name":"Sichuan Provincial Natural Science Foundation","doi-asserted-by":"publisher","award":["2026NSFSC1810"],"award-info":[{"award-number":["2026NSFSC1810"]}],"id":[{"id":"10.13039\/501100018542","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82470926"],"award-info":[{"award-number":["82470926"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["82470926"],"award-info":[{"award-number":["82470926"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Osteosarcoma is a common malignant bone tissue tumour that frequently occurs in the adolescent population, with recurrence and metastasis rates that remain high under current treatment strategies, necessitating the development of cost-effective and efficient anti-osteosarcoma drugs. Sanguinarine, a benzophenanthridine alkaloid derived from plants in the Papaveraceae family, possesses anti-tumour capabilities; however, its clinical application is limited due to poor water solubility and potential organ toxicity. Through screening 30 sanguinarine analogues, in this study we found that analogue 25 exhibited significant activity and could suppress cell proliferation and arrest the cell cycle at the G0\/G1 phase in U2OS and MG63 cells, with IC50 values of 1.484 and 1.954 \u03bcM, respectively. Analogue 25 could also induce cell apoptosis by increasing the levels of cleaved caspase-9 and BAX. Subsequently, we demonstrated that analogue 25 increased the ROS level, decreased the mitochondrial membrane potential, and increased lipid peroxidation in osteosarcoma cells. After reducing ROS levels through NAC, analogue 25 was able to regulate mitochondrial-mediated osteosarcoma cell apoptosis by modulating the ROS level. Furthermore, analogue 25 could also regulate the expression of ferroptosis-related proteins (including GPX4, SLC7A11 and PTGS2) through the NRF2\/GPX4 pathway, ultimately leading to the accumulation of lipid peroxidation and ferroptosis. In a xenograft mouse tumour model derived from osteosarcoma cell lines, analogue 25 exhibited stronger anti-tumour activity than sanguinarine by regulating apoptosis and ferroptosis without causing liver or kidney toxicity. These findings highlight that sanguinarine analogue 25 has beneficial effects in treating osteosarcoma.<\/jats:p>","DOI":"10.3390\/antiox15080941","type":"journal-article","created":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T10:13:47Z","timestamp":1785320027000},"page":"941","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Sanguinarine Analogue Targeting ROS Signaling Exhibits Anti-Tumour Effects by Inducing Apoptosis and Ferroptosis in Osteosarcoma"],"prefix":"10.3390","volume":"15","author":[{"given":"Hui","family":"Zhang","sequence":"first","affiliation":[{"name":"Key Lab for Space Biosciences and Biotechnology, School of Life Science and Technology, Northwestern Polytechnical University, Xi\u2019an 710072, China"},{"name":"Advanced Power Research Institute of Northwestern Polytechnical University in Sichuan Tianfu New Area, Chengdu 610213, China"},{"name":"Lab for Bone Metabolism, Xi\u2019an Key Laboratory of Special Medicine and Health Engineering, School of Life Sciences and Technology, Northwestern Polytechnical University, Xi\u2019an 710072, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-5615-9487","authenticated-orcid":false,"given":"Fangjun","family":"Cao","sequence":"additional","affiliation":[{"name":"Shaanxi Institute of Zoology, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaxin","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Lab for Space Biosciences and Biotechnology, School of Life Science and Technology, Northwestern Polytechnical University, Xi\u2019an 710072, China"},{"name":"Advanced Power Research Institute of Northwestern Polytechnical University in Sichuan Tianfu New Area, Chengdu 610213, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenxi","family":"Yun","sequence":"additional","affiliation":[{"name":"Key Lab for Space Biosciences and Biotechnology, School of Life Science and Technology, Northwestern Polytechnical University, Xi\u2019an 710072, China"},{"name":"Advanced Power Research Institute of Northwestern Polytechnical University in Sichuan Tianfu New Area, Chengdu 610213, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0740-9218","authenticated-orcid":false,"given":"Airong","family":"Qian","sequence":"additional","affiliation":[{"name":"Lab for Bone Metabolism, Xi\u2019an Key Laboratory of Special Medicine and Health Engineering, School of Life Sciences and Technology, Northwestern Polytechnical University, Xi\u2019an 710072, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2055-6984","authenticated-orcid":false,"given":"Xiao","family":"Lin","sequence":"additional","affiliation":[{"name":"Key Lab for Space Biosciences and Biotechnology, School of Life Science and Technology, Northwestern Polytechnical University, Xi\u2019an 710072, China"},{"name":"Advanced Power Research Institute of Northwestern Polytechnical University in Sichuan Tianfu New Area, Chengdu 610213, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.canlet.2020.12.024","article-title":"Immunotherapy for osteosarcoma: Fundamental mechanism, rationale, and recent breakthroughs","volume":"500","author":"Chen","year":"2021","journal-title":"Cancer Lett."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"101728","DOI":"10.1016\/j.xcrm.2024.101728","article-title":"Targeting NAT10 inhibits osteosarcoma progression via ATF4\/ASNS-mediated asparagine biosynthesis","volume":"5","author":"Zou","year":"2024","journal-title":"Cell Rep. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1016\/j.canlet.2020.01.020","article-title":"Emerging next-generation sequencing-based discoveries for targeted osteosarcoma therapy","volume":"474","author":"Zhao","year":"2020","journal-title":"Cancer Lett."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1016\/j.gendis.2018.07.002","article-title":"Natural products targeting the p53-MDM2 pathway and mutant p53: Recent advances and implications in cancer medicine","volume":"5","author":"Qin","year":"2018","journal-title":"Genes Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1022","DOI":"10.1038\/s41419-022-05477-2","article-title":"Natural product preferentially targets redox and metabolic adaptations and aberrantly active STAT3 to inhibit breast tumor growth in vivo","volume":"13","author":"Zhu","year":"2022","journal-title":"Cell Death Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"216079","DOI":"10.1016\/j.canlet.2023.216079","article-title":"Prognostic significance of natural products against multidrug tumor resistance","volume":"557","author":"Garg","year":"2023","journal-title":"Cancer Lett."},{"key":"ref_7","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_8","doi-asserted-by":"crossref","first-page":"3029","DOI":"10.7150\/ijbs.82401","article-title":"Natural Nrf2 Inhibitors: A Review of Their Potential for Cancer Treatment","volume":"19","author":"Zhang","year":"2023","journal-title":"Int. J. Biol. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"156337","DOI":"10.1016\/j.phymed.2024.156337","article-title":"Sanguinarine suppresses oral squamous cell carcinoma progression by targeting the PKM2\/TFEB axis to inhibit autophagic flux","volume":"136","author":"Peng","year":"2025","journal-title":"Phytomedicine"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Ullah, A., Zhou, C., Xiao, W., Iqbal, H., Zhang, F., Nan, P., Khan, N.U., Feng, D., Liu, Y., and Tao, R. (2026). Identification of a novel EphB4 inhibitor, Sanguinarine, which attenuates beta-catenin signaling to inhibit tumor proliferation and migration in lung cancer. J. Adv. Res., in press.","DOI":"10.1016\/j.jare.2026.02.044"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1038\/s41419-019-2173-1","article-title":"Sanguinarine inhibits epithelial-mesenchymal transition via targeting HIF-1\u03b1\/TGF-\u03b2 feed-forward loop in hepatocellular carcinoma","volume":"10","author":"Su","year":"2019","journal-title":"Cell Death Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"153503","DOI":"10.1016\/j.phymed.2021.153503","article-title":"Sanguinarine combats hypoxia-induced activation of EphB4 and HIF-1\u03b1 pathways in breast cancer","volume":"84","author":"Su","year":"2021","journal-title":"Phytomedicine"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s13020-024-00881-6","article-title":"Sanguinarine chloride induces ferroptosis by regulating ROS\/BACH1\/HMOX1 signaling pathway in prostate cancer","volume":"19","author":"Liu","year":"2024","journal-title":"Chin. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1111\/jcmm.13043","article-title":"Sanguinarine inhibits growth and invasion of gastric cancer cells via regulation of the DUSP4\/ERK pathway","volume":"21","author":"Zhang","year":"2017","journal-title":"J. Cell. Mol. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"15418","DOI":"10.1021\/acs.jafc.0c06507","article-title":"Simple Analogues of Quaternary Benzo [c] phenanthridine Alkaloids: Discovery of a Novel Antifungal 2-Phenylphthalazin-2-ium Scaffold with Excellent Potency against Phytopathogenic Fungi","volume":"68","author":"Cui","year":"2020","journal-title":"J. Agric. Food Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e70036","DOI":"10.1111\/cpr.70036","article-title":"Glutaminase-1 Mediated Glutaminolysis to Glutathione Synthesis Maintains Redox Homeostasis and Modulates Ferroptosis Sensitivity in Cancer Cells","volume":"58","author":"Bai","year":"2025","journal-title":"Cell Prolif."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e20250005","DOI":"10.1002\/INMD.20250005","article-title":"Mitochondrial dysfunction: Related diseases, influencing factors, and detection","volume":"3","author":"Li","year":"2025","journal-title":"Interdiscip. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1439","DOI":"10.1007\/s00204-023-03476-6","article-title":"ROS-induced lipid peroxidation modulates cell death outcome: Mechanisms behind apoptosis, autophagy, and ferroptosis","volume":"97","author":"Wang","year":"2023","journal-title":"Arch. Toxicol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/j.cell.2017.09.021","article-title":"Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease","volume":"171","author":"Stockwell","year":"2017","journal-title":"Cell"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3150145","DOI":"10.1155\/2019\/3150145","article-title":"Unraveling the Potential Role of Glutathione in Multiple Forms of Cell Death in Cancer Therapy","volume":"2019","author":"Lv","year":"2019","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Zhang, L., Luo, Y.L., Xiang, Y., Bai, X.Y., Qiang, R.R., Zhang, X., Yang, Y.L., and Liu, X.L. (2024). Ferroptosis inhibitors: Past, present and future. Front. Pharmacol., 15.","DOI":"10.3389\/fphar.2024.1407335"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"101107","DOI":"10.1016\/j.redox.2019.101107","article-title":"NRF2 plays a critical role in mitigating lipid peroxidation and ferroptosis","volume":"23","author":"Dodson","year":"2019","journal-title":"Redox Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1016\/j.freeradbiomed.2026.03.068","article-title":"CDDO-Me alleviates doxorubicin\/lapatinib-induced cardiotoxicity by activating the NRF2\/GPX4 axis to inhibit oxidative stress and ferroptosis","volume":"250","author":"Chen","year":"2026","journal-title":"Free Radic. Biol. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e70041","DOI":"10.1111\/cpr.70041","article-title":"Synergistical Induction of Apoptosis via Cold Atmospheric Plasma and Nanohydroxyapatite for Selective Inhibition of Oral Squamous Cell Carcinoma in Tumour Microenvironment","volume":"58","author":"Qi","year":"2025","journal-title":"Cell Prolif."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/j.freeradbiomed.2020.02.027","article-title":"Lipid peroxidation and ferroptosis: The role of GSH and GPx4","volume":"152","author":"Ursini","year":"2020","journal-title":"Free Radic. Biol. Med."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Duda-Madej, A., Viscardi, S., Szewczyk, W., and Topola, E. (2024). Natural Alkaloids in Cancer Therapy: Berberine, Sanguinarine and Chelerythrine against Colorectal and Gastric Cancer. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25158375"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Lin, X.-L., Shi, Y.-N., Cao, Y.-L., Tan, X., Zeng, Y.-L., Luo, S.-T., Li, Y.-M., Qin, L., Xia, B.-H., and Fu, R.-G. (2022). Sanguinarine protects against indomethacin-induced small intestine injury in rats by regulating the Nrf2\/NF-\u03baB pathways. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.960140"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3175","DOI":"10.1111\/bph.16202","article-title":"Sanguinarine induces apoptosis in osteosarcoma by attenuating the binding of STAT3 to the single-stranded DNA-binding protein 1 (SSBP1) promoter region","volume":"180","author":"Wang","year":"2023","journal-title":"Br. J. Pharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"115565","DOI":"10.1016\/j.bcp.2023.115565","article-title":"Insights into the potential of Sanguinarine as a promising therapeutic option for breast cancer","volume":"212","author":"Malla","year":"2023","journal-title":"Biochem. Pharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"153500","DOI":"10.1016\/j.phymed.2021.153500","article-title":"Sanguinarine impedes metastasis and causes inversion of epithelial to mesenchymal transition in breast cancer","volume":"84","author":"Ghauri","year":"2021","journal-title":"Phytomedicine"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e70070","DOI":"10.1002\/ctm2.1","article-title":"Sanguinarine suppresses migration and metastasis in colorectal carcinoma associated with the inversion of EMT through the Wnt\/\u03b2-catenin signaling","volume":"10","author":"Zhu","year":"2020","journal-title":"Clin. Transl. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"56518","DOI":"10.1039\/C4RA06456A","article-title":"Sanguinarine, a promising anticancer therapeutic: Photochemical and nucleic acid binding properties","volume":"4","author":"Kumar","year":"2014","journal-title":"Rsc Adv."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"216622","DOI":"10.1016\/j.canlet.2024.216622","article-title":"Triptolide induces apoptosis and cytoprotective autophagy by ROS accumulation via directly targeting peroxiredoxin 2 in gastric cancer cells","volume":"587","author":"Chen","year":"2024","journal-title":"Cancer Lett."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"103859","DOI":"10.1016\/j.redox.2025.103859","article-title":"Mitochondrial membrane potential and compartmentalized signaling: Calcium, ROS, and beyond","volume":"86","author":"Selim","year":"2025","journal-title":"Redox Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2756","DOI":"10.7150\/ijbs.83348","article-title":"The crosstalk between ferroptosis and mitochondrial dynamic regulatory networks","volume":"19","author":"Li","year":"2023","journal-title":"Int. J. Biol. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1513","DOI":"10.1016\/j.apsb.2021.05.006","article-title":"Identification of ferroptosis as a novel mechanism for antitumor activity of natural product derivative a2 in gastric cancer","volume":"11","author":"Liu","year":"2021","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1016\/j.gendis.2020.09.005","article-title":"Ferroptosis: An emerging therapeutic opportunity for cancer","volume":"9","author":"Wang","year":"2022","journal-title":"Genes Dis."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1038\/s41419-023-06045-y","article-title":"The diversified role of mitochondria in ferroptosis in cancer","volume":"14","author":"Liu","year":"2023","journal-title":"Cell Death Dis."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"103816","DOI":"10.1016\/j.redox.2025.103816","article-title":"Injectable ROS homeostasis protective hydrogel inhibiting microglial ferroptosis through the Nrf2\/Slc7a11\/Gpx4 to alleviate neuropathic pain and promote spinal cord injury repair","volume":"86","author":"Li","year":"2025","journal-title":"Redox Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.phymed.2017.08.006","article-title":"Molecular targets and anticancer potential of sanguinarine-a benzophenanthridine alkaloid","volume":"34","author":"Galadari","year":"2017","journal-title":"Phytomedicine"}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/15\/8\/941\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T10:33:10Z","timestamp":1785321190000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/15\/8\/941"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,29]]},"references-count":40,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["antiox15080941"],"URL":"https:\/\/doi.org\/10.3390\/antiox15080941","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,29]]}}}