phaidra.vetmeduni.ac.at o:5432 DOI 10.3389/fimmu.2026.1674527 IQDMA disrupts STAT5 nuclear transport through CDC42-PAK2 axis collapse in cutaneous T-cell lymphoma Background: ‘Cutaneous 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. Methods: 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. Results: IQDMA reduced tumor volume by 90.7% (P = 0.0001), significantly outperforming PUVA (46.2%, P = 0.0074). Immunohistochemical analysis demonstrated 45.6% and 40.0% reductions in STAT3+ (P = 0.01) and STAT5+ (P = 0.0478) tumor cells, respectively. Strikingly, while phospho-STAT5 (pY-STAT5) and total STAT5 positively correlated in vehicle-treated tumors (r = +0.57), IQDMA treatment inverted this relationship to a significant negative correlation (r = −0.74, P = 0.046), with pY-STAT5 redistributing from nucleus to cytoplasm—indicating 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’ g = −4.49, FDR = 0.032). Downstream, CCND2 (Cyclin D2)—a direct STAT5 transcriptional target—showed 86% reduction, confirming functional STAT5 blockade. Kinase-substrate network analysis revealed PAK1 substrates were 4.9-fold enriched among downregulated proteins (OR = 4.91, P = 0.011), validating the PAK-STAT axis as IQDMA’s primary mechanism. Conclusion: 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—a dual mechanism distinct from selective JAK inhibitors that warrants clinical evaluation. eng CDC42 Cutaneous T-cell Lymphoma Multi-kinase Inhibitor Mycosis Fungoides Nuclear Transporter PAK Kinase Quantitative Proteomics STAT3 And STAT5 2026-08-19T08:01:33.659Z LOMv1.0 Author BEGIN:VCARD VERSION:3.0 N:Dey;Saptaswa; FN:Saptaswa Dey END:VCARD BEGIN:VCARD VERSION:3.0 N:Sorger;Helena; FN:Helena Sorger X-ORCID:https://orcid.org/0000-0002-3380-7770 END:VCARD BEGIN:VCARD VERSION:3.0 N:Schlederer;Michaela; FN:Michaela Schlederer END:VCARD BEGIN:VCARD VERSION:3.0 N:Perchthaler;Isabella; FN:Isabella Perchthaler END:VCARD BEGIN:VCARD VERSION:3.0 N:Metzelder;Martin; FN:Martin Metzelder END:VCARD BEGIN:VCARD VERSION:3.0 N:Kenner;Lukas; FN:Lukas Kenner X-ORCID:https://orcid.org/0000-0003-2184-1338 END:VCARD BEGIN:VCARD VERSION:3.0 N:Moriggl;Richard; FN:Richard Moriggl X-ORCID:https://orcid.org/0000-0003-0918-9463 END:VCARD BEGIN:VCARD VERSION:3.0 N:Wolf;Peter; FN:Peter Wolf END:VCARD https://w3id.org/kim/hcrt/scheme https://w3id.org/kim/hcrt/text Textdokument Text LOMv1.0 yes https://creativecommons.org/licenses/by/4.0 application/pdf 31779327 https://phaidra.vetmeduni.ac.at/o:5432 https://phaidra.vetmeduni.ac.at/api/object/o:5432/thumbnail LOMv1.0 discipline