{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T01:13:55Z","timestamp":1792113235977,"version":"4.4.0"},"reference-count":90,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T00:00:00Z","timestamp":1773705600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002428","name":"Austrian Science Fund","doi-asserted-by":"publisher","award":["W1241"],"award-info":[{"award-number":["W1241"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\u2018Cutaneous T-cell lymphoma (CTCL), particularly tumor stage mycosis fungoides (MF), presents significant therapeutic challenges due to limited treatment efficacy. This study addresses the unmet need for novel targeted therapies targeting the constitutively hyperactive STAT3\/5 pathway.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Kinome-wide profiling revealed that IQDMA selectively inhibits PAK2 (69%) and JAK3 (61%), kinases critical for STAT5 nuclear transport and activation. Using a C57BL\/6 intradermal T-cell lymphoma model, we evaluated IQDMA efficacy against conventional psoralen + UV-A (PUVA) phototherapy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      IQDMA reduced tumor volume by 90.7% (\n                      <jats:italic>P<\/jats:italic>\n                      = 0.0001), significantly outperforming PUVA (46.2%,\n                      <jats:italic>P<\/jats:italic>\n                      = 0.0074). Immunohistochemical analysis demonstrated 45.6% and 40.0% reductions in STAT3\n                      <jats:sup>+<\/jats:sup>\n                      (\n                      <jats:italic>P<\/jats:italic>\n                      = 0.01) and STAT5\n                      <jats:sup>+<\/jats:sup>\n                      (\n                      <jats:italic>P<\/jats:italic>\n                      = 0.0478) tumor cells, respectively. Strikingly, while phospho-STAT5 (pY-STAT5) and total STAT5 positively correlated in vehicle-treated tumors (\n                      <jats:italic>r<\/jats:italic>\n                      = +0.57), IQDMA treatment inverted this relationship to a significant negative correlation (\n                      <jats:italic>r<\/jats:italic>\n                      = \u22120.74,\n                      <jats:italic>P<\/jats:italic>\n                      = 0.046), with pY-STAT5 redistributing from nucleus to cytoplasm\u2014indicating disruption of STAT5 nuclear transport. Quantitative proteomics identified CDC42, the obligate scaffold for PAK2 activation, as the only mechanistically critical protein achieving statistical significance (Hedges\u2019\n                      <jats:italic>g<\/jats:italic>\n                      = \u22124.49, FDR = 0.032). Downstream, CCND2 (Cyclin D2)\u2014a direct STAT5 transcriptional target\u2014showed 86% reduction, confirming functional STAT5 blockade. Kinase-substrate network analysis revealed PAK1 substrates were 4.9-fold enriched among downregulated proteins (OR = 4.91,\n                      <jats:italic>P<\/jats:italic>\n                      = 0.011), validating the PAK-STAT axis as IQDMA\u2019s primary mechanism.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings establish a CDC42-PAK-STAT nuclear transport axis wherein IQDMA simultaneously inhibits PAK2 kinase activity and depletes its CDC42 scaffold, creating cytoplasmic pY-STAT5 retention that uncouples phosphorylation from transcriptional execution\u2014a dual mechanism distinct from selective JAK inhibitors that warrants clinical evaluation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1674527","type":"journal-article","created":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T14:36:27Z","timestamp":1773758187000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["IQDMA disrupts STAT5 nuclear transport through CDC42-PAK2 axis collapse in cutaneous T-cell lymphoma"],"prefix":"10.3389","volume":"17","author":[{"given":"Saptaswa","family":"Dey","sequence":"first","affiliation":[{"name":"Department of Dermatology and Venereology, Medical University of Graz","place":["Graz, Austria"]},{"name":"Department of Pathology, Medical University of Vienna","place":["Vienna, Austria"]},{"name":"BioTechMed-Graz","place":["Graz, Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helena","family":"Sorger","sequence":"additional","affiliation":[{"name":"Unit of Functional Cancer Genomics, Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna","place":["Vienna, Austria"]},{"name":"Department of Pediatric and Adolescent Surgery, Medical University of Vienna","place":["Vienna, Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michaela","family":"Schlederer","sequence":"additional","affiliation":[{"name":"Department of Pathology, Medical University of Vienna","place":["Vienna, Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabella","family":"Perchthaler","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Venereology, Medical University of Graz","place":["Graz, Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Metzelder","sequence":"additional","affiliation":[{"name":"Department of Pediatric and Adolescent Surgery, Medical University of Vienna","place":["Vienna, Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lukas","family":"Kenner","sequence":"additional","affiliation":[{"name":"Department of Pathology, Medical University of Vienna","place":["Vienna, Austria"]},{"name":"Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna","place":["Vienna, Austria"]},{"name":"Comprehensive Cancer Center, Medical University of Vienna","place":["Vienna, Austria"]},{"name":"Christian Doppler Laboratory for Applied Metabolomics (CDL-AM), Division of Nuclear Medicine, Medical University of Vienna","place":["Vienna, Austria"]},{"name":"CBmed GmbH Center for Biomarker Research in Medicine","place":["Graz, Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Moriggl","sequence":"additional","affiliation":[{"name":"Unit of Functional Cancer Genomics, Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna","place":["Vienna, Austria"]},{"name":"'Department of Biosciences & Medical Biology, Biochemistry and Metabolism Research, Paris Lodron University of Salzburg","place":["Salzburg, Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Wolf","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Venereology, Medical University of Graz","place":["Graz, Austria"]},{"name":"BioTechMed-Graz","place":["Graz, Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2004-09-3502","article-title":"WHO-EORTC classification for cutaneous lymphomas","volume":"105","author":"Willemze","year":"2005","journal-title":"Blood"},{"key":"B2","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/j.ejca.2017.02.027","article-title":"European Organisation for Research and Treatment of Cancer consensus 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