{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T03:36:56Z","timestamp":1783654616709,"version":"3.55.0"},"reference-count":56,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T00:00:00Z","timestamp":1763424000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T00:00:00Z","timestamp":1763424000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82203533"],"award-info":[{"award-number":["82203533"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82173087"],"award-info":[{"award-number":["82173087"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Phytotherapy Research"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Pancreatic cancer is a common malignant tumor of the digestive tract, with insidious onset and rapid metastasis. Most patients have already developed to an advanced stage at the time of diagnosis, and the fatality rate is very high. In recent years, immunotherapy has emerged as a promising potential treatment for pancreatic cancer. Some studies have shown that piperine has the potential to inhibit pancreatic cancer, but the role of piperine in tumor progression and tumor immunity in\u00a0vivo remains unclear. The effects and mechanisms of piperine on the immunity of pancreatic cancer were studied. The effects of piperine on the proliferation, migration and apoptosis of pancreatic cancer Panc02 and PANC\u20101 cells were detected by CCK\u20108, plate colony formation, CFSE staining, wound healing, transwell and flow cytometry. The effects of piperine on the growth, metastasis and immune microenvironment of pancreatic cancer were studied by constructing subcutaneous and orthotopic pancreatic cancer models in mice and using live animal imaging and flow cytometry. The intersection targets of piperine and pancreatic cancer were analyzed by network pharmacology and RNA\u2010seq, and the key genes of immune cell changes were identified. The specific effects of piperine on CD47 in pancreatic cancer tissues and cells were studied by immunohistochemistry, flow cytometry, qRT\u2010PCR, and Western blot. Tumor cells were cocultured with peritoneal\/bone marrow\u2010derived macrophages or CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells to explore the cellular mechanism, and the phagocytosis of macrophages and the activation of CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells were detected by immunofluorescence, magnetic bead sorting and flow cytometry. In the in\u00a0vitro experiments, piperine inhibited the proliferation and migration of the pancreatic cancer cell lines\u00a0Panc02 and PANC\u20101, and induced its apoptosis. In the in\u00a0vivo experiments, piperine inhibited the growth and metastasis of subcutaneous and orthotopic pancreatic tumors in mice. In the immune microenvironment, piperine significantly increased the proportion of macrophages, especially M1\u2010type macrophages, as well as the proportion of CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells in the tumor and spleen. Moreover, piperine reduced the expression of CD47 at the mRNA and protein levels of pancreatic cancer cells, thus enhancing the phagocytosis of macrophages toward tumor cells, and increasing the activation level of CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells. Our results suggest that piperine enhances its antitumor immunity in pancreatic cancer by blocking the immune checkpoint CD47. Therefore, piperine is expected to provide a new approach for the immunotherapy of pancreatic cancer.\n                  <\/jats:p>","DOI":"10.1002\/ptr.70110","type":"journal-article","created":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T03:35:51Z","timestamp":1763523351000},"page":"194-212","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Piperine Inhibits the Immune Checkpoint\n                    <scp>CD47<\/scp>\n                    to Enhance Immunity Against Pancreatic Cancer"],"prefix":"10.1002","volume":"40","author":[{"given":"Xue","family":"He","sequence":"first","affiliation":[{"name":"The Second Clinical Medical School of Guangdong Pharmaceutical University (Guangdong Second Provincial General Hospital), The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangdong Provincial Key Laboratory of Pharmaceutical Preparations Research and Evaluation, School of Life Sciences and Biopharmaceutics Guangdong Pharmaceutical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinting","family":"Lu","sequence":"additional","affiliation":[{"name":"The Second Clinical Medical School of Guangdong Pharmaceutical University (Guangdong Second Provincial General Hospital), The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangdong Provincial Key Laboratory of Pharmaceutical Preparations Research and Evaluation, School of Life Sciences and Biopharmaceutics Guangdong Pharmaceutical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Zhang","sequence":"additional","affiliation":[{"name":"The Second Clinical Medical School of Guangdong Pharmaceutical University (Guangdong Second Provincial General Hospital), The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangdong Provincial Key Laboratory of Pharmaceutical Preparations Research and Evaluation, School of Life Sciences and Biopharmaceutics Guangdong Pharmaceutical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing","family":"Lin","sequence":"additional","affiliation":[{"name":"The Second Clinical Medical School of Guangdong Pharmaceutical University (Guangdong Second Provincial General Hospital), The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangdong Provincial Key Laboratory of Pharmaceutical Preparations Research and Evaluation, School of Life Sciences and Biopharmaceutics Guangdong Pharmaceutical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huijiao","family":"Lu","sequence":"additional","affiliation":[{"name":"The Second Clinical Medical School of Guangdong Pharmaceutical University (Guangdong Second Provincial General Hospital), The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangdong Provincial Key Laboratory of Pharmaceutical Preparations Research and Evaluation, School of Life Sciences and Biopharmaceutics Guangdong Pharmaceutical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaoan","family":"Yu","sequence":"additional","affiliation":[{"name":"The Second Clinical Medical School of Guangdong Pharmaceutical University (Guangdong Second Provincial General Hospital), The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangdong Provincial Key Laboratory of Pharmaceutical Preparations Research and Evaluation, School of Life Sciences and Biopharmaceutics Guangdong Pharmaceutical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Li","sequence":"additional","affiliation":[{"name":"The Second Clinical Medical School of Guangdong Pharmaceutical University (Guangdong Second Provincial General Hospital), The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangdong Provincial Key Laboratory of Pharmaceutical Preparations Research and Evaluation, School of Life Sciences and Biopharmaceutics Guangdong Pharmaceutical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Xi","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology The First Affiliated Hospital of Guangdong Pharmaceutical University  Guangzhou China"},{"name":"School of Biomedical Sciences and Engineering South China University of Technology  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4083-374X","authenticated-orcid":false,"given":"Rongxin","family":"Zhang","sequence":"additional","affiliation":[{"name":"The Second Clinical Medical School of Guangdong Pharmaceutical University (Guangdong Second Provincial General Hospital), The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangdong Provincial Key Laboratory of 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