{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T16:48:51Z","timestamp":1786121331867,"version":"build-2736575974"},"reference-count":56,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T00:00:00Z","timestamp":1786060800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>This study aimed to investigate the regulatory effect and molecular mechanism of Berberine (BBR) on programmed death-ligand 1 (PD-L1) expression in Triple-Negative Breast Cancer (TNBC) cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      <jats:italic>In vitro<\/jats:italic>\n                      cellular experiments (using MDA-MB-231 and BT-549 cell lines) and mouse models (Balb\/c-nu and Balb\/c mice) were performed. Combined with techniques including Western blot and immunofluorescence assay, the effect of BBR on PD-L1 expression was evaluated.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      BBR reduced PD-L1 protein expression in TNBC cells in a time- and dose-dependent manner, decreased the membrane localization of PD-L1, and inhibited interferon-\u03b3 (IFN-\u03b3)-induced PD-L1 upregulation. Mechanistically, BBR activated autophagy by inhibiting the PI3K-Akt pathway, leading to PD-L1 degradation primarily mediated by the autophagy-lysosome pathway, with minimal contribution from the proteasome under the conditions tested. Cycloheximide (CHX) pulse-chase assay confirmed the degradation kinetics of PD-L1. Experiments evaluating lysosomal function excluded the influence of abnormal lysosomal function, demonstrating that this degradation was independent of the ubiquitin-proteasome system and did not affect lysosomal function. Furthermore, BBR increased the expression and release of immunogenic cell death (ICD)-associated markers in TNBC cells, including calreticulin (CRT) exposure and high-mobility group box 1 (HMGB1) release.\n                      <jats:italic>In vivo<\/jats:italic>\n                      experiments showed that BBR treatment did not significantly reduce tumor volume or weight in Balb\/c-nu mice, but effectively decreased tumor volume and weight in the 4T1 Balb\/c mouse model without obvious systemic toxicity. In the tumor tissues of 4T1 Balb\/c mice, the proportion of CD8\n                      <jats:sup>+<\/jats:sup>\n                      CD3\n                      <jats:sup>+<\/jats:sup>\n                      and CD69\n                      <jats:sup>+<\/jats:sup>\n                      CD8\n                      <jats:sup>+<\/jats:sup>\n                      activated T cells was significantly increased, the expression level of granzyme B in CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells was notably elevated, and the number of regulatory T cells (Tregs, CD4\n                      <jats:sup>+<\/jats:sup>\n                      CD25\n                      <jats:sup>+<\/jats:sup>\n                      Foxp3\n                      <jats:sup>+<\/jats:sup>\n                      ) was significantly reduced.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>BBR can regulate PD-L1 degradation and induce ICD through the PI3K-Akt-autophagy pathway. Its mode of immune checkpoint degradation and immunogenic activation provides experimental evidence for the immunotherapy of TNBC.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1797840","type":"journal-article","created":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T04:22:26Z","timestamp":1786076546000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Berberine induces PD-L1 degradation via the autophagy-lysosome pathway through the PI3K-Akt pathway and enhances immunogenic cell death in triple-negative breast cancer"],"prefix":"10.3389","volume":"17","author":[{"given":"Yuqin","family":"Wei","sequence":"first","affiliation":[{"name":"Department of Comprehensive Cancer Center (Ward 2), The Second Affiliated Hospital of Guangxi Medical University","place":["Nanning, 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