{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T11:10:16Z","timestamp":1785323416407,"version":"3.55.0"},"reference-count":46,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T00:00:00Z","timestamp":1767657600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82405037"],"award-info":[{"award-number":["82405037"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Pyroptosis is a type of programmed cell death (PCD) with pro-inflammatory properties, which is characterized by the swelling with bubbles and the release of LDH and inflammatory cell cytokines. Polyphyllin II (PPII) is the main active ingredient of the Chinese herb Rhizoma Paridis and has been proven to exert high efficacy against a variety of malignant tumors. At present, the anti-tumor research on PPII mainly focuses on apoptosis that is an anti-inflammatory type of PCD, but other potential modes of death cell death and mechanisms of PPII remain to be discovered. Here, we first found that PPII could effectively inhibit the growth of hepatocellular carcinoma (HCC) cells via pyroptosis. After treatment with PPII, the morphology of swelling with bubbles and the formation of pores in the cell membrane in HCC cells were observed, and LDH and cell cytokines (IL-1\u03b2, IL-18, IL-6, TNF-\u03b1, IFN-\u03b2, and IFN-\u03b3) were released. Furthermore, the flow cytometry results showed that PPII could activate oxidative stress by increasing Ca2+ influx, thereby promoting the production of ROS to exert anti-tumor effects. RNA sequencing revealed that pyroptosis is closely linked to several signaling pathways, including the MAPK, TNF, Rap1, mTOR, and FoxO pathways, as well as the PD-L1 expression and PD-1 checkpoint pathway. An in vivo study demonstrated that PPII treatment suppressed liver tumor growth in mice by pyroptosis in a dose-dependent manner, and it showed no obvious side effects within a certain range. The Western blot results of tumor tissues revealed that the pyroptosis effect of PPII on liver cancer was associated with the activation of the NLRP3\/Caspase1\/GSDMD pathway, which upregulates the expression of NLRP3, Cleaved-Caspase 1, GSDMD-N, IL-1\u03b2, and IL-18 proteins and downregulates the expression of pro-Caspase 1 and GSDMD proteins. In summary, our findings revealed the pyroptosis effect and mechanism of PPII in HCC cells in vitro and in vivo, suggesting that PPII may be used as a potential pyroptosis inducer for HCC treatment in the future.<\/jats:p>","DOI":"10.3390\/antiox15010075","type":"journal-article","created":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T13:49:46Z","timestamp":1767707386000},"page":"75","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Polyphyllin II Triggers Pyroptosis in Hepatocellular Carcinoma via Modulation of the ROS\/NLRP3\/Caspase-1\/GSDMD Axis"],"prefix":"10.3390","volume":"15","author":[{"given":"Huating","family":"Huang","sequence":"first","affiliation":[{"name":"School of Chinese Material Medica, Beijing University of Chinese Medicine, Beijing 102488, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boran","family":"Ni","sequence":"additional","affiliation":[{"name":"The Department of Endocrinology, Guang\u2019anmen Hospital of China Academy of Chinese Medical Sciences, Beijing 100053, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Chinese Material Medica, Beijing University of Chinese Medicine, Beijing 102488, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenqi","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Chinese Material Medica, Beijing University of Chinese Medicine, Beijing 102488, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zishuo","family":"Guo","sequence":"additional","affiliation":[{"name":"School of Chinese Material Medica, Beijing University of Chinese Medicine, Beijing 102488, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nan","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Chinese Material Medica, Beijing University of Chinese Medicine, Beijing 102488, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Chinese Material Medica, Beijing University of Chinese Medicine, Beijing 102488, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3077-1626","authenticated-orcid":false,"given":"Xingbin","family":"Yin","sequence":"additional","affiliation":[{"name":"School of Chinese Material Medica, Beijing University of Chinese Medicine, Beijing 102488, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changhai","family":"Qu","sequence":"additional","affiliation":[{"name":"School of Chinese Material Medica, Beijing University of Chinese Medicine, Beijing 102488, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Ni","sequence":"additional","affiliation":[{"name":"School of Chinese Material Medica, Beijing University of Chinese Medicine, Beijing 102488, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxv","family":"Dong","sequence":"additional","affiliation":[{"name":"School of Chinese Material Medica, Beijing University of Chinese Medicine, Beijing 102488, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"109595","DOI":"10.1016\/j.biopha.2019.109595","article-title":"Pyroptosis: A new frontier in cancer","volume":"121","author":"Fang","year":"2020","journal-title":"Biomed. Pharmacother."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e2400254","DOI":"10.1002\/smll.202400254","article-title":"\u201cMulti-in-One\u201d Yolk-Shell Structured Nanoplatform Inducing Pyroptosis and Antitumor Immune Response Through Cascade Reactions","volume":"20","author":"Wang","year":"2024","journal-title":"Small"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2768","DOI":"10.1016\/j.apsb.2021.02.006","article-title":"Gasdermin D in pyroptosis","volume":"11","author":"Burdette","year":"2021","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1038\/s41586-020-2079-1","article-title":"A bioorthogonal system reveals antitumour immune function of pyroptosis","volume":"579","author":"Wang","year":"2020","journal-title":"Nature"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e2209379","DOI":"10.1002\/adma.202209379","article-title":"A Dual-Responsive STAT3 Inhibitor Nanoprodrug Combined with Oncolytic Virus Elicits Synergistic Antitumor Immune Responses by Igniting Pyroptosis","volume":"35","author":"Su","year":"2023","journal-title":"Adv. Mater."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"20167","DOI":"10.1021\/acsnano.4c03034","article-title":"Dual-Responsive Epigenetic Inhibitor Nanoprodrug Combined with Oncolytic Virus Synergistically Boost Cancer Immunotherapy by Igniting Gasdermin E-Mediated Pyroptosis","volume":"18","author":"Wang","year":"2024","journal-title":"ACS Nano"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e202215307","DOI":"10.1002\/anie.202215307","article-title":"ZIF-8 Nanoparticles Evoke Pyroptosis for High-Efficiency Cancer Immunotherapy","volume":"62","author":"Ding","year":"2023","journal-title":"Angew. Chem. Int. Ed. Engl."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1021\/acsnano.2c09242","article-title":"Radiofrequency-Activated Pyroptosis of Bi-Valent Gold Nanocluster for Cancer Immunotherapy","volume":"17","author":"Zhang","year":"2023","journal-title":"ACS Nano"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4310","DOI":"10.7150\/thno.71086","article-title":"Pyroptosis in inflammatory diseases and cancer","volume":"12","author":"Rao","year":"2022","journal-title":"Theranostics"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"111022","DOI":"10.1016\/j.intimp.2023.111022","article-title":"Caspase-3\/GSDME mediated pyroptosis: A potential pathway for sepsis","volume":"124","author":"Jiao","year":"2023","journal-title":"Int. Immunopharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1038\/s41420-022-00906-9","article-title":"HDAC11 promotes both NLRP3\/caspase-1\/GSDMD and caspase-3\/GSDME pathways causing pyroptosis via ERG in vascular endothelial cells","volume":"8","author":"Yao","year":"2022","journal-title":"Cell Death Discov."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"5473","DOI":"10.1002\/ptr.7989","article-title":"Recent advances in pyroptosis, liver disease, and traditional Chinese medicine: A review","volume":"37","author":"He","year":"2023","journal-title":"Phytother. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"105748","DOI":"10.1016\/j.phrs.2021.105748","article-title":"Cucurbitacin B inhibits non-small cell lung cancer in vivo and in vitro by triggering TLR4\/NLRP3\/GSDMD-dependent pyroptosis","volume":"170","author":"Yuan","year":"2021","journal-title":"Pharmacol. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"122369","DOI":"10.1016\/j.biomaterials.2023.122369","article-title":"Biomimetic Prussian blue nanocomplexes for chemo-photothermal treatment of triple-negative breast cancer by enhancing ICD","volume":"303","author":"Long","year":"2023","journal-title":"Biomaterials"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"122333","DOI":"10.1016\/j.biomaterials.2023.122333","article-title":"An acid-responsive MOF nanomedicine for augmented anti-tumor immunotherapy via a metal ion interference-mediated pyroptotic pathway","volume":"302","author":"Feng","year":"2023","journal-title":"Biomaterials"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1186\/s12951-025-03608-3","article-title":"Multifunctional nanoagent for enhanced cancer radioimmunotherapy via pyroptosis and cGAS-STING activation","volume":"23","author":"Xu","year":"2025","journal-title":"J. Nanobiotechnol."},{"key":"ref_17","first-page":"100755","article-title":"Preparation and anti-tumor effect in hepatocellular carcinoma treatment of AS1411 aptamer-targeted polyphyllin II-loaded PLGA nanoparticles","volume":"9","author":"Huang","year":"2024","journal-title":"J. Sci.-Adv. Mater. Dev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1781","DOI":"10.1080\/13880209.2022.2120021","article-title":"Polyphyllin II induced apoptosis of NSCLC cells by inhibiting autophagy through the mTOR pathway","volume":"60","author":"Jiao","year":"2022","journal-title":"Pharm. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"224","DOI":"10.3892\/mmr.2024.13348","article-title":"Polyphyllin II inhibits breast cancer cell proliferation via the PI3K\/Akt signaling pathway","volume":"30","author":"Miao","year":"2024","journal-title":"Mol. Med. Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"201","DOI":"10.5582\/bst.2012.v6.4.201","article-title":"Paris saponin II of Rhizoma Paridis--a novel inducer of apoptosis in human ovarian cancer cells","volume":"6","author":"Xiao","year":"2012","journal-title":"Biosci. Trends"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Li, J.K., Sun, H.T., Jiang, X.L., Chen, Y.F., Zhang, Z., Wang, Y., Chen, W.Q., Zhang, Z., Sze, S.C.W., and Zhu, P.L. (2022). Polyphyllin II Induces Protective Autophagy and Apoptosis via Inhibiting PI3K\/AKT\/mTOR and STAT3 Signaling in Colorectal Cancer Cells. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms231911890"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1038\/s41418-018-0214-4","article-title":"Comparing the effects of different cell death programs in tumor progression and immunotherapy","volume":"26","author":"Messmer","year":"2019","journal-title":"Cell Death Differ."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1186\/s13045-020-00946-7","article-title":"Ferroptosis, necroptosis, and pyroptosis in anticancer immunity","volume":"13","author":"Tang","year":"2020","journal-title":"J. Hematol. Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/j.mib.2013.04.004","article-title":"Inflammasome-mediated pyroptotic and apoptotic cell death, and defense against infection","volume":"16","author":"Aachoui","year":"2013","journal-title":"Curr. Opin. Microbiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1038\/s41586-024-07345-9","article-title":"Complete biosynthesis of QS-21 in engineered yeast","volume":"629","author":"Liu","year":"2024","journal-title":"Nature"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2212","DOI":"10.1038\/s41467-020-16043-9","article-title":"N-GSDMD trafficking to neutrophil organelles facilitates IL-1beta release independently of plasma membrane pores and pyroptosis","volume":"11","author":"Karmakar","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1186\/s12964-023-01359-y","article-title":"Simvastatin induces pyroptosis via ROS\/caspase-1\/GSDMD pathway in colon cancer","volume":"21","author":"Xie","year":"2023","journal-title":"Cell Commun. Signal."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"122948","DOI":"10.1016\/j.jenvman.2024.122948","article-title":"Quercetin attenuates SiO(2)-induced ZBP-1-mediated PANoptosis in mouse neuronal cells via the ROS\/TLR4\/NF-kappab pathway","volume":"370","author":"Liu","year":"2024","journal-title":"J. Environ. Manag."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2401","DOI":"10.1016\/j.cell.2022.06.003","article-title":"Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications","volume":"185","author":"Stockwell","year":"2022","journal-title":"Cell"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2088","DOI":"10.1021\/acs.nanolett.0c04778","article-title":"Ultrasound-Augmented Mitochondrial Calcium Ion Overload by Calcium Nanomodulator to Induce Immunogenic Cell Death","volume":"21","author":"Zheng","year":"2021","journal-title":"Nano Lett."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1267","DOI":"10.1038\/sj.cdd.4402147","article-title":"Mitochondrial Ca2+ as a key regulator of cell life and death","volume":"14","author":"Giacomello","year":"2007","journal-title":"Cell Death Differ."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2402022","DOI":"10.1002\/adfm.202402022","article-title":"A Copper\/Ferrous-Engineering Redox Homeostasis Disruptor for Cuproptosis\/Ferroptosis Co-Activated Nanocatalytic Therapy in Liver Cancer","volume":"34","author":"Zhang","year":"2024","journal-title":"Adv. Funct. Mater."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.redox.2015.06.019","article-title":"Redox regulation of FoxO transcription factors","volume":"6","author":"Klotz","year":"2015","journal-title":"Redox. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"100907","DOI":"10.1016\/j.drup.2022.100907","article-title":"Research progress of therapeutic effects and drug resistance of immunotherapy based on PD-1\/PD-L1 blockade","volume":"66","author":"Pang","year":"2023","journal-title":"Drug Resist. Updates"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1038\/s41569-023-00946-3","article-title":"The role of the NLRP3 inflammasome and pyroptosis in cardiovascular diseases","volume":"21","author":"Toldo","year":"2024","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.bbrc.2023.06.062","article-title":"Steroidal saponins PPI\/CCRIS\/PSV induce cell death in pancreatic cancer cell through GSDME-dependent pyroptosis","volume":"673","author":"Liu","year":"2023","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"31401","DOI":"10.1021\/acsnano.4c11278","article-title":"Targeted Positron Emission Tomography-Tracked Biomimetic Codelivery Synergistically Amplifies Ferroptosis and Pyroptosis for Inducing Lung Cancer Regression and Anti-PD-L1 Immunotherapy Efficacy","volume":"18","author":"Zhu","year":"2024","journal-title":"ACS Nano"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"8725","DOI":"10.1021\/acs.nanolett.3c02728","article-title":"Targeting Pyroptosis through Lipopolysaccharide-Triggered Noncanonical Pathway for Safe and Efficient Cancer Immunotherapy","volume":"23","author":"Chen","year":"2023","journal-title":"Nano Lett."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e010252","DOI":"10.1136\/jitc-2024-010252","article-title":"Clofarabine induces tumor cell apoptosis, GSDME-related pyroptosis, and CD8(+) T-cell antitumor activity via the non-canonical P53\/STING pathway","volume":"13","author":"Wu","year":"2025","journal-title":"J. Immunother. Cancer"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e2102315","DOI":"10.1002\/adhm.202102315","article-title":"Anti-PD-L1 DNAzyme Loaded Photothermal Mn(2+)\/Fe(3+) Hybrid Metal-Phenolic Networks for Cyclically Amplified Tumor Ferroptosis-Immunotherapy","volume":"11","author":"Liu","year":"2022","journal-title":"Adv. Healthc. Mater."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1186\/s13045-020-00916-z","article-title":"cGAS-STING, an important pathway in cancer immunotherapy","volume":"13","author":"Jiang","year":"2020","journal-title":"J. Hematol. Oncol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"9413","DOI":"10.1021\/acsnano.3c11023","article-title":"Bioorthogonal\/Ultrasound Activated Oncolytic Pyroptosis Amplifies In Situ Tumor Vaccination for Boosting Antitumor Immunity","volume":"18","author":"Xu","year":"2024","journal-title":"ACS Nano"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e011717","DOI":"10.1136\/jitc-2025-011717","article-title":"Enhancing antitumor immunity via ROS-ERS and pyroptosis-induced immunogenic cell death in multiple myeloma","volume":"13","author":"Zhaoyun","year":"2025","journal-title":"J. Immunother. Cancer"},{"key":"ref_44","first-page":"100548","article-title":"Functional metal-organic framework nanoparticles loaded with polyphyllin I for targeted tumor therapy","volume":"8","author":"Wang","year":"2023","journal-title":"J. Sci.-Adv. Mater. Dev."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"109558","DOI":"10.1016\/j.biopha.2019.109558","article-title":"Hepatotoxicity assessment of Rhizoma Paridis in adult zebrafish through proteomes and metabolome","volume":"121","author":"Jia","year":"2020","journal-title":"Biomed. Pharmacother."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1186\/s12951-024-02887-6","article-title":"Co-delivery of polyphyllin II and IR780 PLGA nanoparticles induced pyroptosis combined with photothermal to enhance hepatocellular carcinoma immunotherapy","volume":"22","author":"Huang","year":"2024","journal-title":"J. Nanobiotechnol."}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/15\/1\/75\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T05:13:18Z","timestamp":1767849198000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/15\/1\/75"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,6]]},"references-count":46,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["antiox15010075"],"URL":"https:\/\/doi.org\/10.3390\/antiox15010075","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,6]]}}}