{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T14:23:48Z","timestamp":1787927028469,"version":"build-2784847793"},"reference-count":70,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T00:00:00Z","timestamp":1787875200000},"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. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      <jats:italic>Berberine<\/jats:italic>\n                      has shown antitumor activity across multiple malignancies, yet its molecular targets and mechanisms of action in diffuse large B-cell lymphoma (DLBCL) remain incompletely defined. We integrated genetic causality, multi-omics data, and functional validation to identify berberine-related molecular pathways relevant to DLBCL.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We identify bioinformatic screening and Mendelian randomization (MR) on 760 candidate berberine-related genes; 315 with adequate instruments underwent MR for causal links to DLBCL. Follow-up analyses included pathway enrichment, Protein-Protein Interaction (PPI) networks, machine-learning prognostic modeling, molecular docking and dynamics, single-cell RNA sequencing, cell\u2013cell communication inference, bulk transcriptomic validation, and\n                      <jats:italic>in vitro<\/jats:italic>\n                      assays.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      MR identified several berberine-related genes with putative causal associations with DLBCL.\n                      <jats:italic>ABCA1<\/jats:italic>\n                      ,\n                      <jats:italic>ITK, MAPK3, TGM2, and DAPK1<\/jats:italic>\n                      were associated with decreased DLBCL risk, whereas\n                      <jats:italic>CYBB, RAC1, JUN, and CPT1A<\/jats:italic>\n                      were associated with increased risk. Enriched pathways encompassed B-cell receptor signaling, immune checkpoints, apoptosis, and MAPK signaling. Apoptosis pathway activity correlated with favorable prognosis across cohorts. Integrative analyses prioritized\n                      <jats:italic>CYBB<\/jats:italic>\n                      as a central hub. Molecular docking and dynamics indicated stable berberine\u2013\n                      <jats:italic>CYBB<\/jats:italic>\n                      binding. Single-cell analyses showed\n                      <jats:italic>CYBB<\/jats:italic>\n                      + B cells had distinct apoptotic, immunoregulatory, and communication features, including BTLA\u2013TNFRSF14 signaling. Bulk deconvolution linked high\n                      <jats:italic>CYBB<\/jats:italic>\n                      to worse prognosis, proliferation, and an immunosuppressive microenvironment. Functionally,\n                      <jats:italic>CYBB<\/jats:italic>\n                      knockdown reduced DLBCL cell viability and increased apoptosis; berberine inhibited growth dose-dependently, and cellular thermal shift assays supported berberine\u2013\n                      <jats:italic>CYBB<\/jats:italic>\n                      target engagement in cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      This integrative study identifies berberine-related genes with potential causal relevance to DLBCL and prioritizes CYBB as a functionally relevant target linked to apoptosis, immune regulation, and prognosis, highlighting the potential involvement of berberine\u2013\n                      <jats:italic>CYBB<\/jats:italic>\n                      axis underlying berberine activity in DLBCL, although rescue experiments are needed to confirm its specificity and relative contribution.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1870435","type":"journal-article","created":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T13:32:11Z","timestamp":1787923931000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["A multi-omics integrative analyses reveals CYBB-mediated apoptotic and immune dysregulation as a key target of berberine in diffuse large B-cell lymphoma"],"prefix":"10.3389","volume":"17","author":[{"given":"Jiewen","family":"Tan","sequence":"first","affiliation":[{"name":"Department of Hematology, The Eighth Affiliated Hospital, Southern Medical University (The First People\u2019s Hospital of Shunde, Foshan)","place":["Foshan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunman","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Hematology, The Eighth Affiliated Hospital, Southern Medical University (The First People\u2019s Hospital of Shunde, Foshan)","place":["Foshan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yueping","family":"He","sequence":"additional","affiliation":[{"name":"Department of Hematology, The Eighth Affiliated Hospital, Southern Medical University (The First People\u2019s Hospital of Shunde, Foshan)","place":["Foshan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Hematology, The Eighth Affiliated Hospital, Southern Medical University (The First People\u2019s Hospital of Shunde, Foshan)","place":["Foshan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingwen","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Hematology, The Eighth Affiliated Hospital, Southern Medical University (The First People\u2019s Hospital of Shunde, Foshan)","place":["Foshan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changxiu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Hematology, The Eighth Affiliated Hospital, Southern Medical University (The First People\u2019s Hospital of Shunde, Foshan)","place":["Foshan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinman","family":"Zhong","sequence":"additional","affiliation":[{"name":"Department of Hematology, The Eighth Affiliated Hospital, Southern Medical University (The First People\u2019s Hospital of Shunde, Foshan)","place":["Foshan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Xiong","sequence":"additional","affiliation":[{"name":"Department of Hematology, The Eighth Affiliated Hospital, Southern Medical University (The First People\u2019s Hospital of Shunde, Foshan)","place":["Foshan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.softx.2015.06.001","article-title":"GROMACS: high performance molecular simulations through multi-level parallelism from laptops to supercomputers","author":"Abraham","year":"2015","journal-title":"SoftwareX"},{"key":"B2","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1038\/35000501","article-title":"Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling","volume":"403","author":"Alizadeh","year":"2000","journal-title":"Nature"},{"key":"B3","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1152\/physrev.00044.2005","article-title":"The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology","volume":"87","author":"Bedard","year":"2007","journal-title":"Physiol. 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