{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T07:42:25Z","timestamp":1770363745422,"version":"3.49.0"},"reference-count":31,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T00:00:00Z","timestamp":1770249600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100015800","name":"Jilin Province innovation capacity construction funds","doi-asserted-by":"publisher","award":["2021FGWCXNLJSSZ01"],"award-info":[{"award-number":["2021FGWCXNLJSSZ01"]}],"id":[{"id":"10.13039\/100015800","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related mortality worldwide, with limited therapeutic options and poor clinical outcomes. Mounting evidence suggests that targeting cancer-specific metabolic and redox adaptations represents a promising therapeutic strategy. Peroxiredoxin 1 (PRDX1), a key antioxidant enzyme that is frequently overexpressed in HCC, enables tumor cells to neutralize excessive reactive oxygen species (ROS), thereby sustaining survival and conferring therapeutic resistance. In this study, using human hepatocellular carcinoma HepG2 cells as an in vitro model, we identify ginsenoside Rg5 (Rg5) as a previously unrecognized small-molecule inhibitor of PRDX1. Structural and functional analyses demonstrate that Rg5 directly binds to the Asn145 residue of PRDX1, effectively suppressing its peroxidase activity. Mechanistically, this inhibition disrupts ROS detoxification in HepG2 cells, leading to mitochondrial ROS accumulation, activation of the intrinsic apoptotic pathway, and consequent HepG2 cell death. Additionally, Rg5 not only suppresses HepG2 cell survival but also acts synergistically with doxorubicin, a first-line chemotherapeutic agent, to markedly enhance antitumor efficacy and potentially mitigate chemoresistance. Collectively, these findings suggest that PRDX1 inhibition may represent a broadly exploitable vulnerability in liver cancer and establish Rg5 as a promising candidate for developing targeted and combinatorial therapies against HCC.<\/jats:p>","DOI":"10.3390\/molecules31030557","type":"journal-article","created":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T16:30:47Z","timestamp":1770309047000},"page":"557","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Ginsenoside Rg5 Targets PRDX1 to Disrupt Redox Homeostasis and Induce Mitochondria-Dependent Apoptosis in Human Hepatocellular Carcinoma HepG2 Cells"],"prefix":"10.3390","volume":"31","author":[{"given":"Hai-Lun","family":"Ye","sequence":"first","affiliation":[{"name":"Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, School of Life Sciences, Jilin University, Changchun 130012, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5956-0799","authenticated-orcid":false,"given":"Ya-Ni","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, School of Life Sciences, Jilin University, Changchun 130012, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gang-Ao","family":"Li","sequence":"additional","affiliation":[{"name":"Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, School of Life Sciences, Jilin University, Changchun 130012, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xing-Hui","family":"Jin","sequence":"additional","affiliation":[{"name":"Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, School of Life Sciences, Jilin University, Changchun 130012, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guan-Ting","family":"Wu","sequence":"additional","affiliation":[{"name":"Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, School of Life Sciences, Jilin University, Changchun 130012, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang","family":"Li","sequence":"additional","affiliation":[{"name":"Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, School of Life Sciences, Jilin University, Changchun 130012, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying-Hua","family":"Jin","sequence":"additional","affiliation":[{"name":"Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, School of Life Sciences, Jilin University, Changchun 130012, China"},{"name":"Ginseng Research Institute, Jilin University, Changchun 130021, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1038\/s41568-021-00435-0","article-title":"The role of ROS in tumour development and progression","volume":"22","author":"Cheung","year":"2022","journal-title":"Nat. Rev. Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"4839","DOI":"10.7150\/thno.56747","article-title":"The double-edged roles of ROS in cancer prevention and therapy","volume":"11","author":"Wang","year":"2021","journal-title":"Theranostics"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/s41573-024-00979-4","article-title":"Targeting ROS in cancer: Rationale and strategies","volume":"23","author":"Glorieux","year":"2024","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Brandl, N., Seitz, R., Sendtner, N., M\u00fcller, M., and G\u00fclow, K. (2025). Living on the Edge: ROS Homeostasis in Cancer Cells and Its Potential as a Therapeutic Target. Antioxidants, 14.","DOI":"10.3390\/antiox14081002"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Aggarwal, V., Tuli, H.S., Varol, A., Thakral, F., Yerer, M.B., Sak, K., Varol, M., Jain, A., Khan, M.A., and Sethi, G. (2019). Role of Reactive Oxygen Species in Cancer Progression: Molecular Mechanisms and Recent Advancements. Biomolecules, 9.","DOI":"10.3390\/biom9110735"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Purohit, V., Simeone, D.M., and Lyssiotis, C. (2019). Metabolic Regulation of Redox Balance in Cancer. Cancers, 11.","DOI":"10.3390\/cancers11070955"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"102355","DOI":"10.1016\/j.cbpa.2023.102355","article-title":"The multifaceted nature of peroxiredoxins in chemical biology","volume":"76","author":"Villar","year":"2023","journal-title":"Curr. Opin. Chem. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"114896","DOI":"10.1016\/j.biopha.2023.114896","article-title":"New insights into the roles of peroxiredoxins in cancer","volume":"164","author":"Liu","year":"2023","journal-title":"Biomed. Pharmacother."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.freeradbiomed.2023.11.009","article-title":"Dual role of PRDX1 in redox-regulation and tumorigenesis: Past and future","volume":"210","author":"Guan","year":"2024","journal-title":"Free Radic. Biol. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"103392","DOI":"10.1016\/j.redox.2024.103392","article-title":"HJURP inhibits sensitivity to ferroptosis inducers in prostate cancer cells by enhancing the peroxidase activity of PRDX1","volume":"77","author":"Lai","year":"2024","journal-title":"Redox Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1707","DOI":"10.7150\/ijbs.84494","article-title":"Hspb1 protects against severe acute pancreatitis by attenuating apoptosis and ferroptosis via interacting with Anxa2 to restore the antioxidative activity of Prdx1","volume":"20","author":"He","year":"2024","journal-title":"Int. J. Biol. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"5070","DOI":"10.7150\/ijbs.99804","article-title":"PRDX1 inhibits ferroptosis by binding to Cullin-3 as a molecular chaperone in colorectal cancer","volume":"20","author":"Song","year":"2024","journal-title":"Int. J. Biol. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1038\/s41392-022-01231-4","article-title":"Celastrol suppresses colorectal cancer via covalent targeting peroxiredoxin 1","volume":"8","author":"Xu","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2895","DOI":"10.7150\/jca.86568","article-title":"Expression And Prognostic Role of PRDX1 In Gastrointestinal Cancers","volume":"14","author":"Zhang","year":"2023","journal-title":"J. Cancer"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Wu, Q., Cao, H., Jin, J., Ma, D., Niu, Y., Yu, Y., Wang, X., and Xia, Y. (2025). Integrated multi-omics analysis reveals the functional and prognostic significance of lactylation-related gene PRDX1 in breast cancer. Front. Mol. Biosci., 12.","DOI":"10.3389\/fmolb.2025.1580622"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1186\/s12967-021-02792-8","article-title":"Expression and prognostic roles of PRDXs gene family in hepatocellular carcinoma","volume":"19","author":"Xu","year":"2021","journal-title":"J. Transl. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"10705","DOI":"10.1007\/s12035-024-04247-9","article-title":"PRDX1 Interfering Peptide Disrupts Amino Acids 70-90 of PRDX1 to Inhibit the TLR4\/NF-\u03baB Signaling Pathway and Attenuate Neuroinflammation and Ischemic Brain Injury","volume":"61","author":"Ma","year":"2024","journal-title":"Mol. Neurobiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1016\/j.jgr.2016.08.004","article-title":"Role of ginsenosides, the main active components of Panax ginseng, in inflammatory responses and diseases","volume":"41","author":"Kim","year":"2017","journal-title":"J. Ginseng Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/j.jgr.2025.03.008","article-title":"Ginsenoside Rh2 alleviates inflammatory response and enhances motor function recovery in spinal cord injury mice via the ROS\/MAPK14 signaling pathway","volume":"49","author":"Wu","year":"2025","journal-title":"J. Ginseng Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.jgr.2021.05.005","article-title":"Rg3-enriched red ginseng extract promotes lung cancer cell apoptosis and mitophagy by ROS production","volume":"46","author":"Hwang","year":"2022","journal-title":"J. Ginseng Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.bcp.2017.12.004","article-title":"Ginsenoside Rh4 induces apoptosis and autophagic cell death through activation of the ROS\/JNK\/p53 pathway in colorectal cancer cells","volume":"148","author":"Wu","year":"2018","journal-title":"Biochem. Pharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"156941","DOI":"10.1016\/j.phymed.2025.156941","article-title":"Ginsenoside Rg5 ameliorates lipopolysaccharide (LPS)-induced acute liver injury via interfering Autophagy\/Nrf2\/Ferroptosis signal axis","volume":"144","author":"Shan","year":"2025","journal-title":"Phytomedicine"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Kciuk, M., Gieleci\u0144ska, A., Mujwar, S., Ko\u0142at, D., Ka\u0142uzi\u0144ska-Ko\u0142at, \u017b., Celik, I., and Kontek, R. (2023). Doxorubicin-An Agent with Multiple Mechanisms of Anticancer Activity. Cells, 12.","DOI":"10.3390\/cells12040659"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Lee, J., Choi, M.-K., and Song, I.-S. (2023). Recent Advances in Doxorubicin Formulation to Enhance Pharmacokinetics and Tumor Targeting. Pharmaceuticals, 16.","DOI":"10.3390\/ph16060802"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1016\/j.drudis.2021.09.020","article-title":"Advances in understanding the role of P-gp in doxorubicin resistance: Molecular pathways, therapeutic strategies, and prospects","volume":"27","author":"Mirzaei","year":"2022","journal-title":"Drug Discov. Today"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1016\/j.freeradbiomed.2022.06.232","article-title":"The beginning of GPX2 and 30 years later","volume":"188","author":"Esworthy","year":"2022","journal-title":"Free Radic. Biol. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1080\/15548627.2018.1474995","article-title":"Inhibition of TRAF6 ubiquitin-ligase activity by PRDX1 leads to inhibition of NFKB activation and autophagy activation","volume":"14","author":"Min","year":"2018","journal-title":"Autophagy"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1111\/jcmm.12955","article-title":"Peroxiredoxin 1-an antioxidant enzyme in cancer","volume":"21","author":"Ding","year":"2017","journal-title":"J. Cell. Mol. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"362","DOI":"10.18632\/oncotarget.28720","article-title":"PRDX1 protects ATM from arsenite-induced proteotoxicity and maintains its stability during DNA damage signaling","volume":"16","author":"Ali","year":"2025","journal-title":"Oncotarget"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"29389","DOI":"10.1038\/srep29389","article-title":"Peroxiredoxin 1 interacts with and blocks the redox factor APE1 from activating interleukin-8 expression","volume":"6","author":"Nassour","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_31","first-page":"101639","article-title":"Peroxiredoxin-1 as a molecular chaperone that regulates glutathione S-transferase P1 activity and drives mutidrug resistance in ovarian cancer cells","volume":"37","author":"Fan","year":"2024","journal-title":"Biochem. Biophys. Rep."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/3\/557\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T16:30:51Z","timestamp":1770309051000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/3\/557"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,5]]},"references-count":31,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["molecules31030557"],"URL":"https:\/\/doi.org\/10.3390\/molecules31030557","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,5]]}}}