SHP2 Allosteric Inhibitor SHP099 Alleviates Inflammation and Restores Salivary Gland Function in Sjögren's Disease-like Animals via Regulation of the IL-17RA Signaling Pathway.

Salivary gland (SG) dysfunction is a hallmark manifestation of Sjögren's disease (SjD). While SHP2 has been implicated in several autoimmune diseases, its specific function in SjD remains to be elucidated. Here, we investigated the involvement of SHP2 in SjD-induced SG damage and elucidate the underlying molecular mechanisms. Our findings revealed that SHP2 is elevated in SG tissues of SjD patients and SjD-like animals, with predominant localization to salivary gland epithelial cells (SGECs) of acini and ducts. Notably, pharmacological inhibition of SHP2 with the allosteric inhibitor SHP099 significantly alleviates SG histopathological damage and reduces inflammatory cell infiltration in SjD-like animals. In vitro studies in the human SGEC line A253 revealed that SHP2 inhibition attenuated poly(I:C)-induced SGEC apoptosis and proinflammatory cytokine production. Mechanistically, SHP099 treatment disrupted the IL-17RA/ACT1/TRAF6 signaling axis, phenocopying the effects of SHP2 knockdown and direct IL-17R antagonism, which leads to downregulation of JAK/STAT3 and NF-κB pathways. Collectively, our findings highlight the significant involvement of SHP2 in the pathogenesis of SjD and suggest that targeting SHP2 or its downstream signaling pathways may represent a promising therapeutic approach for SjD treatment.