PROTAC-Mediated SHP2 and STAT3 Degradation as a Therapeutic Strategy for Rheumatoid Arthritis 2309941

Abstract

Abstract Introduction Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation, fibroblast-like synoviocyte (FLS) hyperplasia, and progressive cartilage and bone destruction. RA FLS acquire an aggressive phenotype that promotes inflammatory cytokine production and drives tissue damage. Despite advances in RA therapies, many patients fail to achieve durable remission, highlighting the need for strategies that target the molecular drivers of joint pathology. The protein tyrosine phosphatase SHP2 (PTPN11) integrates cytokine and growth factor signaling through MAPK, PI3K/Akt, and STAT3 pathways. However, the specific contributions of SHP2—STAT3 signaling to synovial inflammation and RA progression remain poorly defined. Methods Primary FLS isolated from RA patients and healthy donors were treated with selective PROTAC degraders targeting SHP2 (SHP2D26) or STAT3 (SD36). Cell viability, target protein degradation, and downstream signaling were evaluated by MTT and immunoblotting assays. Complementary in vivo studies employed the K/BxN serum transfer arthritis mouse model with conditional deletion of SHP2 in either Prg4+ synovial lining cells or LysM+ myeloid cells. Disease severity was evaluated by ankle measurements, DigiGait analysis, flow cytometry, micro-CT, and IF staining to evaluate synovial inflammation and immune cell infiltration. Results Targeted degradation of SHP2 or STAT3 in RA FLS significantly reduced inflammatory cytokine production and attenuated pro-inflammatory signaling. In vivo, SHP2 deletion in either Prg4+ or LysM+ cells reduced joint swelling, immune cell infiltrates, and synovial pathology, with preservation of joint architecture and articular cartilage. Conclusion These findings identify SHP2—STAT3 signaling as a key regulator of pathogenic FLS behavior, stromal—immune interactions, and RA progression. Targeted degradation of SHP2 or STAT3 represents a promising therapeutic strategy to limit synovial inflammation and joint destruction in RA. Funding Source NIAMS R21 AR081642, NIDDK R01DK138630 Topic Categories Immune Mechanisms of Human Disease (HUM)