{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T14:10:18Z","timestamp":1771510218682,"version":"3.50.1"},"reference-count":23,"publisher":"Brieflands","issue":"1","license":[{"start":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T00:00:00Z","timestamp":1762819200000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["brieflands.com"],"crossmark-restriction":false},"short-container-title":["Iran J Pharm Res"],"abstract":"<jats:p>Background: Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by synovial hyperplasia, persistent inflammation, and joint destruction. Targeted inhibition of intracellular signaling pathways, such as JAK-STAT, has improved RA treatment outcomes, though safety and selectivity remain as concerns. Brepocitinib, a dual TYK2\/JAK1 inhibitor, has shown clinical efficacy in the management of autoimmune diseases, yet its mechanistic impact on synoviocytes remains underexplored. Objectives: To investigate the molecular and functional effects of brepocitinib on MH7A and RA-FLS synoviocytes, a key effector cell type in RA pathogenesis. Methods: MH7A and RA-FLS cells were treated with brepocitinib (0.5 \u00b5M, 1 \u00b5M, and 5 \u00b5M) for 24 hours. Cell viability was assessed. Western blotting was used to examine phosphorylation of TYK2, JAK1, STAT1\/3, and apoptotic markers (BAX, BCL-2, caspase-3). Quantitative PCR and ELISA were performed to evaluate mRNA and protein levels, respectively, of IL-6, TNF-\u03b1, and IFN-\u03b3. Wound healing assays measured synoviocyte migration. Results: Brepocitinib maintained \u2265 85% cell viability across all doses, compared with ~20% viability in doxorubicin-treated controls. At 5 \u00b5M, phosphorylation of JAK1 and STAT3 was suppressed by &gt; 80%, while TYK2 and STAT1 inhibition reached ~70%. IL-6 and TNF-\u03b1 transcripts were reduced by &gt; 80% and IFN-\u03b3 by ~70%, with corresponding decreases in secreted cytokines (IL-6: 100 pg\/mL to 20 pg\/mL; TNF-\u03b1: 150 pg\/mL to 15 pg\/mL; IFN-\u03b3: 41 pg\/mL to 11 pg\/mL). Brepocitinib shifted the BAX\/BCL-2 ratio fourfold in favor of apoptosis and increased cleaved caspase-3 levels to ~80% of maximal response. Functionally, it reduced wound closure from ~75% in controls to ~20% at 5 \u00b5M, confirming potent inhibition of synoviocyte migration. Conclusions: Brepocitinib exerts multi-faceted effects on RA synoviocytes by simultaneously inhibiting inflammatory signaling, suppressing cytokine expression, restoring apoptotic sensitivity, and reducing migratory potential. These findings provide mechanistic support for brepocitinib as a targeted therapeutic agent in RA.<\/jats:p>","DOI":"10.5812\/ijpr-166019","type":"journal-article","created":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T13:11:12Z","timestamp":1771506672000},"update-policy":"https:\/\/doi.org\/10.5812\/crossmark_update_policy","source":"Crossref","is-referenced-by-count":0,"title":["Dual TYK2\/JAK1 Inhibition by Brepocitinib Reprograms Synoviocyte Pathobiology: Mechanistic Insights Into Targeted Therapy for Rheumatoid Arthritis"],"prefix":"10.5812","volume":"25","author":[{"given":"Umar","family":"Saeed","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zahra","family":"Zahid Piracha","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andromeda","family":"M. Nauli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Surya","family":"M. 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