Fangfang Lai

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint inflammation and tissue damage, driven by dysregulated cytokine signaling and immune cell hyperactivation. Bruton's tyrosine kinase (BTK) mediates pathogenic B‐cell activation and autoantibody production, while Janus kinase 3 (JAK3) orchestrates cytokine‐driven inflammation through signal transducer and activator of transcription 5 (STAT5) phosphorylation, exacerbating macrophage and monocyte activation. Here, we report Wj1113, a novel dual inhibitor that potently blocks BTK (IC₅₀ = 0.7 nM) and JAK3 (IC₅₀ = 26.2 nM). Wj1113 inhibits B‐cell activation via BTK blockade and suppresses JAK3‐dependent STAT5 phosphorylation, reducing proinflammatory cytokine secretion and monocyte chemotaxis. In vitro, it suppresses macrophage activation and modulates inflammatory mediator expression. In the collagen‐induced arthritis mouse model, Wj1113 treatment dose‐dependently reduces joint inflammation, macrophage infiltration, and levels of TNF‐α (tumor necrosis factor‐α), IL(interleukin)‐6, anti‐cyclic citrullinated peptide antibody (ACPA) and rheumatoid factor (RF), while elevating anti‐inflammatory IL‐10. Histopathological and micro‐CT analyses confirm attenuation of cartilage/bone erosion and synovial hyperplasia. Mechanistically, Wj1113 inhibits BTK/JAK3 signaling in vivo and alleviates arthritis in joints. Collectively, these findings establish Wj1113 as a promising dual‐target therapeutic candidate for RA, addressing both B‐cell and cytokine‐driven pathogenic pathways.

The extracellular heat shock protein 90α (eHSP90α) has been reported to promote cancer cell motility. However, whether pancreatic cancer (PC) cells expressed membrane-bound or secreted HSP90α, as well as its underlying mechanism for PC progression, were still unclear. Our study demonstrated that the amounts of secreted HSP90α proteins were discrepant in multiple PC cells. In addition, highly invasive Capan-2 cells have a higher level of secreted HSP90α compared with those of less invasive PL45 cells. The conditioned medium of Capan-2 cells or recombinant HSP90α treatment stimulated the migration and invasion of PC cells, which could be prevented with a neutralizing anti-HSP90α antibody. Furthermore, secreted HSP90α promoted elements of epithelial–mesenchymal transition in PL45 cells, including increases in vimentin and Snail expressions, decreases in E-cadherin expression, and changes in cell shape towards a mesenchymal phenotype, but these phenomena were reversed by the anti-HSP90α antibody in Capan-2 cells. In addition, high levels of low-density lipoprotein receptor-related protein 1 (LRP1) were associated with worsened patient survival in pancreatic adenocarcinoma. We demonstrated LRP1 as a receptor of eHSP90α for its stimulatory role in metastasis, by activating the AKT pathway. In addition, silencing LRP1 enhanced the chemosensitivity to gemcitabine and doxorubicin in Capan-2 cells. Therefore, our study indicated that blocking secreted HSP90α underlies an aspect of metastasis and chemoresistance in PC.