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In addition to its beta cell proliferative and regenerative effects, which result from inhibition of DYRK1A (\u2018Target 1\u2019), harmine also induces expression of essential transcription factors and other genes involved in beta cell identity and function, exemplified by\n                      <jats:italic>PDX1<\/jats:italic>\n                      ,\n                      <jats:italic>MAFA<\/jats:italic>\n                      ,\n                      <jats:italic>NKX6.1<\/jats:italic>\n                      ,\n                      <jats:italic>MAFB<\/jats:italic>\n                      ,\n                      <jats:italic>SIX3<\/jats:italic>\n                      ,\n                      <jats:italic>SLC2A2<\/jats:italic>\n                      ,\n                      <jats:italic>ENTPD3<\/jats:italic>\n                      and others. Harmine also rapidly enhances glucose-stimulated insulin secretion in vitro and in vivo. These beta cell identity-enhancing effects are not due to DYRK1A inhibition. We hypothesise that they reflect interactions of harmine with a second target (\u2018Target 2\u2019). We aimed to identify Target 2.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We performed an in-depth analysis of multiple different small-molecule inhibitors of DYRK1A in human pancreatic islets using gene expression, single-cell RNA-seq, proliferation, immunocytochemistry of beta cell transcription factors and identity markers, and solid-phase precipitation combined with proteomics.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>All small-molecule DYRK1A inhibitors studied (harmine, 2-2c, 5-IT, INDY, leucettine, CC-401, GNF4877) induced human beta cell proliferation via inhibition of DYRK1A. In contrast, silencing DYRK1A had no effect on beta cell transcription factors and identity markers. Further, harmine, 2-2c and 5-IT but not INDY, leucettine, CC-401 or GNF4877 enhanced expression of beta cell phenotypic markers. The enhanced expression of beta cell identity markers resulted from an unexpected activation by harmine of an as-yet unidentified Target 2 that activates the protein kinase A (PKA) pathway.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\/interpretation<\/jats:title>\n                    <jats:p>These findings make it clear that all DYRK1A inhibitors are not interchangeable. Those that drive both beta cell proliferation and identity\/function will likely be preferable for diabetes therapy. Unravelling the mechanisms controlling the complex harmine\u2013PKA\u2013DYRK1A interactome will provide fruitful ground for future studies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00125-026-06857-5","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T11:20:26Z","timestamp":1789989626000},"page":"3592-3608","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Harmine selectively enhances human beta cell identity markers and function via protein kinase A pathways"],"prefix":"10.1007","volume":"69","author":[{"given":"Peng","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kunal","family":"Kumar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Lambertini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongtao","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivia","family":"Wood","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuxuan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aidan","family":"Pillard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donald K.","family":"Scott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joao A.","family":"Paulo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven P.","family":"Gygi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susmita","family":"Khamrui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Mueller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adolfo","family":"Garcia-Ocana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esra","family":"Karakose","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael B.","family":"Lazarus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert J.","family":"DeVita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew F.","family":"Stewart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,21]]},"reference":[{"key":"6857_CR1","unstructured":"World Health Organization. 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Bergstein, L. and T. Schwartz, and M. and F. Farkouh families for their constant support of this research. We thank S. Mueller at Evotec in Munich, Germany, for help with proteomics. We also thank the NIDDK-supported Human Islet and Adenovirus Core (HIAC) of the Einstein-Sinai Diabetes Research Center (ES-DRC), the NIDDK Integrated Islet Distribution Program (IIDP), Prodo Laboratories, P. MacDonald at the Alberta Diabetes Institute Islet Core at the University of Alberta in Edmonton (\n                      \n                      ) with the assistance of the Human Organ Procurement and Exchange (HOPE) program, Trillium Gift of Life Network (TGLN), and other Canadian organ procurement organisations. We also thank T. Kin (University of Alberta, Edmonton, AB, Canada), P. Witkowski (University of Chicago, Chicago, IL, USA) and. F. Kandeel (City of Hope Medical Center, Duarte, CA, USA) for providing human organ donor islets.","order":1,"name":"Ethics","label":"Acknowledgements","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"The datasets generated and\/or analysed during the current study are available from the corresponding author upon reasonable request. Data will be made available upon publication of this article and will remain available for at least 5 years following publication. Data will be shared with qualified researchers for academic, non-commercial research purposes, subject to institutional approvals, material transfer agreements where applicable, and compliance with relevant ethical and data-sharing regulations.","order":2,"name":"Ethics","label":"Data availability","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"This work was supported by NIH grants P30DK020541, R01DK116873, R01DK116904, R01DK125285, R01DK105015, R01DK129196, R01 GM132129, R01DK139631, R35GM124838, R35CA232128 and P01CA203655.","order":3,"name":"Ethics","label":"Funding","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"PW, AFS, KK, RJD and AGO are inventors on patents filed by The Icahn School of Medicine at Mount Sinai. PaulexBio has licensed this patent portfolio from The Icahn School of Medicine at Mount Sinai. AFS, RJD and AGO are consultants for PaulexBio. AGO consults for Sun Pharmaceuticals. The other authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.","order":4,"name":"Ethics","label":"Authors\u2019 relationships and activities","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"PW, KK, RJD and AFS conceived and designed the study. PW, OW, HL, AP, SC, MBL, SK, EK and SM acquired data and performed experiments. PW, LL and AFS analysed and interpreted data. KK, RJD, DKS, AGO and EK contributed critical reagents, technical expertise and interpretation of data. JAP and SPG contributed to proteomic analyses, technical expertise and interpretation of data. PW and AFS drafted the manuscript. All authors critically reviewed and revised the manuscript for important intellectual content and approved the final version for publication. PW and AFS guarantee the data in this manuscript.","order":5,"name":"Ethics","label":"Contribution statement","group":{"name":"EthicsHeading","label":"Ethics"}}]}}