Brevilin A, a novel LRRC15 inhibitor, exerts potent anti-rheumatoid arthritis effects by inhibiting the LRRC15/STAT3 signaling pathway.

PURPOSE

Leucine-rich repeat-containing 15 (LRRC15) is a transmembrane protein that is highly expressed in the synovium of patients with rheumatoid arthritis (RA). Brevilin A (BrA), an active compound isolated from , exerts potent anti-inflammatory effects. However, the anti-RA effect of BrA and its underlying mechanism of action of BrA have not been fully elucidated.

METHODS

Transcriptome analysis was performed to explore biomarkers of RA. An lipopolysaccharide (LPS)-induced RAW264.7 macrophage model, a TNF-α-stimulated RA fibroblast-like synoviocytes (RA-FLSs) model, as well as a collagen-induced arthritis (CIA) rat model were used to explore the anti-RA effects of BrA. Moreover, inhibition or overexpression of LRRC15 was performed to explore the role of LRRC15 signaling in the anti-RA effects of BrA.

RESULTS

Transcriptome analysis of patients with RA revealed that LRRC15 expression was significantly upregulated in the synovial tissue of RA patients. BrA significantly downregulated the expression of inflammation-related markers in cell models, and inhibited their proliferation and migration; Moreover, it significantly reduced joint swelling and cartilage damage in CIA rats. Further mechanistic studies suggest that inhibition of LRRC15 inhibits cell proliferation and migration; and overexpression of LRRC15 increases the protein levels of STAT3’s downstream metastasis-related markers.

CONCLUSIONS

Our findings suggest that BrA, a novel LRRC15 inhibitor, has promising anti-RA activity and potently inhibits LRRC15/STAT3 signaling pathway both in vivo and in vitro. This study not only supports the development of BrA as a novel therapeutic agent for RA treatment, but also paves the way for the development of other LRRC15-targeting therapeutic strategies.

SUPPLEMENTARY INFORMATION

The online version contains supplementary material available at 10.1186/s13075-025-03629-1.