{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T15:17:08Z","timestamp":1786720628773,"version":"build-2736575974"},"reference-count":45,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T00:00:00Z","timestamp":1756425600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Beijing Natural Science Foundatio","award":["7202121"],"award-info":[{"award-number":["7202121"]}]},{"name":"Beijing Natural Science Foundatio","award":["81703715"],"award-info":[{"award-number":["81703715"]}]},{"name":"National Natural Science Foundation of Chinan","award":["7202121"],"award-info":[{"award-number":["7202121"]}]},{"name":"National Natural Science Foundation of Chinan","award":["81703715"],"award-info":[{"award-number":["81703715"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background: Cucurbitacin B (CuB) is a relatively unique and valuable component in plants of the Cucurbitaceae family due to its diverse and remarkable physiological activities, but its specific mechanisms in regulating tumor metabolism and immune response remain unclear. The hypoxic tumor microenvironment (TME) of pancreatic cancer induces metabolic reprogramming in cancer cells, causing them to rely on glycolysis for energy. LDHA, a key enzyme in glycolysis, can suppress glycolysis and tumor growth when inhibited. Objective: The objective of this study was to investigate the mechanism of CuB against pancreatic cancer and its effect on the immune system. Methods: In this study, cell migration\/invasion assays, immunofluorescence, ELISA, Western blot, CETSA, flow cytometry, mouse models, and metabolomic and transcriptomic analyses were utilized to systematically elucidate the mechanism by which CuB inhibits pancreatic cancer and activates the immune system. Results: This study confirms that CuB inhibits pancreatic cancer by suppressing the PI3K\/Akt\/mTOR pathway and activating PINK1\/Parkin to induce mitophagy, thereby inhibiting cell migration, invasion, and proliferation. It downregulates the expression of LDHA to block glycolysis, reduce lactate production and efflux, and improve the acidic TME. CuB also induces ICD to activate dendritic cells, promote CD8+ T-cell and M1 macrophage infiltration, and reduce the levels of regulatory T cells. Metabolomic and transcriptomic analyses validate CuB\u2019s dual effects on metabolic reprogramming and immune activation. Conclusions: This study, for the first time, reveals that CuB induces mitophagy via the PI3K\/Akt\/mTOR and PINK1\/Parkin pathways to selectively eliminate damaged mitochondria and suppress tumor energy metabolism. CuB inhibits pancreatic cancer through a triple mechanism\u2014inducing mitophagy, inhibiting glycolysis, and activating immunity\u2014which provides innovative insights for pancreatic cancer therapy.<\/jats:p>","DOI":"10.3390\/nu17172809","type":"journal-article","created":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T12:25:57Z","timestamp":1756470357000},"page":"2809","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Cucurbitacin B from Cucurbitaceae Plants: Treating Pancreatic Cancer via Inducing Mitophagy, Inhibiting Glycolysis, and Enhancing Immune Function"],"prefix":"10.3390","volume":"17","author":[{"given":"Dongge","family":"Yin","sequence":"first","affiliation":[{"name":"School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyue","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohong","family":"Jing","sequence":"additional","affiliation":[{"name":"School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuting","family":"Lin","sequence":"additional","affiliation":[{"name":"School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yufei","family":"Sun","sequence":"additional","affiliation":[{"name":"School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongrong","family":"Chang","sequence":"additional","affiliation":[{"name":"School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Feng","sequence":"additional","affiliation":[{"name":"School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1482-7108","authenticated-orcid":false,"given":"Xiaoxv","family":"Dong","sequence":"additional","affiliation":[{"name":"School of Chinese Materia 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 Materia 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 Materia 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 Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"106587","DOI":"10.1016\/j.phrs.2022.106587","article-title":"Cucurbitacin B: A review of its pharmacology, toxicity, and pharmacokinetics","volume":"187","author":"Dai","year":"2023","journal-title":"Pharmacol. Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"5876","DOI":"10.1158\/0008-5472.CAN-09-0536","article-title":"Cucurbitacin B induces apoptosis by inhibition of the JAK\/STAT pathway and potentiates antiproliferative effects of gemcitabine on pancreatic cancer cells","volume":"69","author":"Thoennissen","year":"2009","journal-title":"Cancer Res."},{"key":"ref_3","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. Clin."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2008","DOI":"10.1016\/S0140-6736(20)30974-0","article-title":"Pancreatic cancer","volume":"395","author":"Mizrahi","year":"2020","journal-title":"Lancet"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/s13045-020-01030-w","article-title":"Targeting hypoxic tumor microenvironment in pancreatic cancer","volume":"14","author":"Tao","year":"2021","journal-title":"J. Hematol. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.tibs.2015.12.001","article-title":"The Warburg effect: How does it benefit cancer cells?","volume":"41","author":"Liberti","year":"2016","journal-title":"Trends. Biochem. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/j.semcancer.2022.11.007","article-title":"Role of LDH in tumor glycolysis: Regulation of LDHA by small molecules for cancer therapeutics","volume":"87","author":"Sharma","year":"2022","journal-title":"Semin. Cancer Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1186\/s13046-024-03042-7","article-title":"Pan-cancer analysis implicates novel insights of lactate metabolism into immunotherapy response prediction and survival prognostication","volume":"43","author":"Chen","year":"2024","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1296","DOI":"10.1038\/s41417-023-00639-6","article-title":"Features of metabolism associated molecular patterns in pancreatic ductal adenocarcinoma","volume":"30","author":"Chen","year":"2023","journal-title":"Cancer Gene Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3919","DOI":"10.1073\/pnas.1219555110","article-title":"Strengthened glycolysis under hypoxia supports tumor symbiosis and hexosamine biosynthesis in pancreatic adenocarcinoma","volume":"110","author":"Guillaumond","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1016\/j.immuni.2021.04.008","article-title":"Glycolytic ATP fuels phosphoinositide 3-kinase signaling to support effector T helper 17 cell responses","volume":"54","author":"Xu","year":"2021","journal-title":"Immunity"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e2303835","DOI":"10.1002\/adma.202303835","article-title":"Extracellular Vesicles-Derived Hybrid Nanoplatforms for Amplified CD47 Blockade-Based Cancer Immunotherapy","volume":"35","author":"Tang","year":"2023","journal-title":"Adv. Mater."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1186\/s13045-023-01430-8","article-title":"Novel strategies for cancer immunotherapy: Counter-immunoediting therapy","volume":"16","author":"Liu","year":"2023","journal-title":"J. Hematol. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"155177","DOI":"10.1016\/j.phymed.2023.155177","article-title":"Cucurbitacin B suppresses hepatocellular carcinoma progression through inducing DNA damage-dependent cell cycle arrest","volume":"126","author":"Li","year":"2024","journal-title":"Phytomedicine"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1177\/1535370220917367","article-title":"Cucurbitacin B and cisplatin induce the cell death pathways in MB49 mouse bladder cancer model","volume":"245","author":"Kurman","year":"2020","journal-title":"Exp. Biol. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"154669","DOI":"10.1016\/j.phymed.2023.154669","article-title":"Label-free-based quantitative proteomic analysis of the inhibition of cisplatin-resistant ovarian cancer cell proliferation by cucurbitacin B","volume":"111","author":"Yin","year":"2023","journal-title":"Phytomedicine"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1371","DOI":"10.1152\/physrev.00026.2020","article-title":"Regulation and metabolic functions of mTORC1 and mTORC2","volume":"101","author":"Szwed","year":"2021","journal-title":"Physiol. Rev."},{"key":"ref_18","first-page":"380","article-title":"Rapamycin induces Smad activity in prostate cancer cell lines","volume":"51","author":"Hanrahan","year":"2023","journal-title":"Urol. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3774","DOI":"10.2174\/0929867329666220107153253","article-title":"Cucurbitacins and the immune system: Update in research on anti-inflammatory, antioxidant, and immunomodulatory mechanisms","volume":"29","author":"Silvestre","year":"2022","journal-title":"Curr. Med. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1002\/anie.201804882","article-title":"Nanoparticle-mediated immunogenic cell death enables and potentiates cancer immunotherapy","volume":"58","author":"Duan","year":"2019","journal-title":"Angew. Chem. Int. Ed. Engl."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Kesar, U., Markelc, B., Jesenko, T., Ursic Valentinuzzi, K., Cemazar, M., Strojan, P., and Sersa, G. (2023). Effects of electrochemotherapy on immunologically important modifications in tumor cells. Vaccines, 11.","DOI":"10.3390\/vaccines11050925"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1038\/s41419-020-03221-2","article-title":"Detection of immunogenic cell death and its relevance for cancer therapy","volume":"11","author":"Fucikova","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1007\/s11418-015-0918-4","article-title":"Cucurbitacin B induces DNA damage and autophagy mediated by reactive oxygen species (ROS) in MCF-7 breast cancer cells","volume":"69","author":"Ren","year":"2015","journal-title":"J. Nat. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1158\/1940-6207.CAPR-14-0286","article-title":"Cucurbitacin B alters the expression of tumor-related genes by epigenetic modifications in NSCLC and inhibits NNK-induced lung tumorigenesis","volume":"8","author":"Shukla","year":"2015","journal-title":"Cancer Prev. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4313204","DOI":"10.1155\/2016\/4313204","article-title":"PTEN activation by DNA damage induces protective autophagy in response to Cucurbitacin B in hepatocellular carcinoma cells","volume":"2016","author":"Niu","year":"2016","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1038\/s41419-024-07122-6","article-title":"Metabolic gatekeepers: Harnessing tumor-derived metabolites to optimize T cell-based immunotherapy efficacy in the tumor microenvironment","volume":"15","author":"Zheng","year":"2024","journal-title":"Cell Death Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"23141","DOI":"10.18632\/oncotarget.8153","article-title":"The altered glucose metabolism in tumor and a tumor acidic microenvironment associated with extracellular matrix metalloproteinase inducer and monocarboxylate transporters","volume":"7","author":"Li","year":"2016","journal-title":"Oncotarget"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1002\/JLB.3A0718-274RR","article-title":"Lactate secreted by cervical cancer cells modulates macrophage phenotype","volume":"10","author":"Stone","year":"2019","journal-title":"J. Leukoc. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2204808","DOI":"10.1002\/advs.202204808","article-title":"Insights into the effect of catalytic intratumoral lactate depletion on metabolic reprogramming and immune activation for antitumoral activity","volume":"10","author":"Zhao","year":"2023","journal-title":"Adv. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.mattod.2023.07.003","article-title":"Biomimetic multifunctional nanodrugs enable regulating abnormal tumor metabolism and amplifying PDT-induced immunotherapy for synergistically enhanced tumor ablation","volume":"68","author":"Liu","year":"2023","journal-title":"Mater. Today"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1016\/j.canlet.2010.01.029","article-title":"Cucurbitacin B induces apoptosis and S phase cell cycle arrest in BEL-7402 human hepatocellular carcinoma cells and is effective via oral administration","volume":"294","author":"Chan","year":"2010","journal-title":"Cancer Lett."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Liu, P., Xiang, Y., Liu, X., Zhang, T., Yang, R., Chen, S., Xu, L., Yu, Q., Zhao, H., and Zhang, L. (2019). Cucurbitacin B induces the lysosomal degradation of EGFR and suppresses the CIP2A\/PP2A\/Akt signaling axis in gefitinib-resistant non-small cell lung cancer. Molecules, 24.","DOI":"10.3390\/molecules24030647"},{"key":"ref_33","first-page":"1018","article-title":"Cucurbitacin B inhibits tumor angiogenesis by triggering the mitochondrial signaling pathway in endothelial cells","volume":"42","author":"Piao","year":"2018","journal-title":"Int. J. Mol. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2215","DOI":"10.1002\/ptr.8146","article-title":"Cucurbitacin B modulates M2 macrophage differentiation and attenuates osteosarcoma progression via PI3K\/AKT pathway","volume":"38","author":"Wu","year":"2024","journal-title":"Phytother. Res."},{"key":"ref_35","first-page":"495","article-title":"Cucurbitacin B regulates immature myeloid cell differentiation and enhances antitumor immunity in patients with lung cancer","volume":"27","author":"Lu","year":"2012","journal-title":"Cancer Biother. Radiopharm."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Zhang, W., Lu, C., Cai, S., Feng, Y., Shan, J., and Di, L. (2022). Aconiti Lateralis Radix Praeparata as potential anticancer herb: Bioactive compounds and molecular mechanisms. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.870282"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Rong, L., Li, Z., Leng, X., Li, H., Ma, Y., Chen, Y., and Song, F. (2020). Salidroside induces apoptosis and protective autophagy in human gastric cancer AGS cells through the PI3K\/Akt\/mTOR pathway. Biomed. Pharmacother., 122.","DOI":"10.1016\/j.biopha.2019.109726"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2348","DOI":"10.1002\/jcp.25737","article-title":"The Role of Exercise and TFAM in Preventing Skeletal Muscle Atrophy","volume":"232","author":"Theilen","year":"2017","journal-title":"J. Cell Physiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e10409","DOI":"10.15252\/emmm.201910409","article-title":"Mitochondrial MsrB2 serves as a switch and transducer for mitophagy","volume":"11","author":"Lee","year":"2019","journal-title":"EMBO Mol. Med."},{"key":"ref_40","first-page":"74","article-title":"Mechanism of cucurbitacin B in inhibiting the proliferation of HuCCT1 cells by regulating glycolysis","volume":"28","author":"Li","year":"2022","journal-title":"Chin. J. Exp. Tradit. Med. Formul."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"215350","DOI":"10.1016\/j.ccr.2023.215350","article-title":"Photodynamic therapy combined with immunotherapy: Recent advances and future research directions","volume":"495","author":"Repetowski","year":"2023","journal-title":"Coord Chem. Rev."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1038\/s41586-019-1678-1","article-title":"Metabolic regulation of gene expression by histone lactylation","volume":"574","author":"Zhang","year":"2019","journal-title":"Nature"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1016\/j.cmet.2016.08.011","article-title":"LDHA-associated lactic acid production blunts tumor immunosurveillance by T and NK cells","volume":"24","author":"Brand","year":"2016","journal-title":"Cell Metab."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"112317","DOI":"10.1016\/j.celrep.2023.112317","article-title":"Murine cytomegalovirus downregulates ERAAP and induces an unconventional T cell response to self","volume":"42","author":"Geiger","year":"2023","journal-title":"Cell Rep."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"9297","DOI":"10.3748\/wjg.v21.i31.9297","article-title":"Perspectives in the treatment of pancreatic adenocarcinoma","volume":"21","author":"Juarez","year":"2015","journal-title":"World J. Gastroenterol."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/17\/17\/2809\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:35:11Z","timestamp":1760034911000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/17\/17\/2809"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,29]]},"references-count":45,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["nu17172809"],"URL":"https:\/\/doi.org\/10.3390\/nu17172809","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,29]]}}}