SIK inhibitor HG-9-91-01 suppresses the pathogenic activity of fibroblast-like synoviocytes in rheumatoid arthritis

OBJECTIVES: Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterised by synovial inflammation and joint destruction, in which fibroblast-like synoviocytes (FLS) play a pivotal role through their hyperproliferative, invasive and inflammatory properties. The salt-inducible kinase (SIK) family regulates inflammatory responses, yet the role of its isoform SIK3 in RA and the therapeutic potential of its inhibition remain unclear. This study investigates the effects of HG-9-91-01, a potent SIK inhibitor, on RA-FLS pathogenicity and disease progression. METHODS: The impact of HG-9-91-01 on human MH7A cells was assessed using cell counting kit-8, 5-ethynyl-2'-deoxyuridine, flow cytometry, wound healing and Transwell assays. RNA sequencing, bioinformatics analyses and western blot analysis were employed to explore the underlying mechanisms. The therapeutic efficacy of HG-9-91-01 was evaluated in a murine collagen-induced arthritis (CIA) model through clinical scoring, histopathology and micro-CT imaging. RESULTS: SIK3 was significantly upregulated in RA synovial tissues and correlated with disease activity. HG-9-91-01 potently inhibited MH7A cell proliferation, migration and invasion while promoting apoptosis. Transcriptomic and molecular analyses revealed that these effects were mediated through the concurrent suppression of the phosphoinositide 3-kinase-protein kinase B (PI3K-Akt) and nuclear factor kappa B (NF-κB) signalling pathways, leading to downstream modulation of Bcl-2-associated X protein, B-cell lymphoma 2, inducible nitric oxide synthase, tumour necrosis factor-α and matrix metalloproteinase-9. In CIA mice, HG-9-91-01 administration markedly alleviated arthritis severity, synovitis, cartilage degradation and bone erosion. CONCLUSIONS: Our findings demonstrate that HG-9-91-01 attenuates RA progression by directly targeting FLS pathogenicity via dual inhibition of PI3K-Akt and NF-κB signalling, highlighting the therapeutic potential of SIK family inhibition in RA.