CP-25 ameliorates dysfunction in the MR-IPR-Ca-AQP5 signaling pathway by inhibiting ERS in primary Sjögren's syndrome.

Abstract

Primary Sjögren's syndrome (pSS) is an autoimmune disease with incompletely elucidated pathological mechanisms and a current lack of effective therapeutic agents. CP-25, a structurally modified derivative of paeoniflorin, demonstrates significant therapeutic effects in experimental Sjögren's syndrome (ESS) mouse models; however, its underlying mechanism remains elusive. In this study, we constructed an ESS mouse model induced by autoantigen immunization to explore the biological effects of CP-25 on pSS and its potential mechanisms. The study first revealed the overactivation of endoplasmic reticulum stress (ERS) and the impaired function of MR-IPR-Ca-AQP5 signaling pathway in human labial gland tissue. Critically, inhibiting ERS (using 4-PBA) was found to directly ameliorate the impaired MR-IPR-Ca-AQP5 signaling pathway function, as evidenced by normalized MR expression, restored IPR and AQP5 levels, and enhanced intracellular Caintensity in IFNα-stimulated HSGECs, resulting in significantly increased salivary flow rate and reduced salivary gland inflammation in vivo. Furthermore, CP-25 exerted its therapeutic effect by upregulating the MR-IPR-Ca-AQP5 signaling pathway function, regulating MR membrane expression, and critically inhibiting ERS. Crucially, the beneficial effects of CP-25 on both ERS suppression and pathway restoration were demonstrated to be mechanistically dependent on disrupting the pathological interaction between the key ERS chaperone GRP78 and the IPR calcium channel. In summary, impaired MR-IPR-Ca-AQP5 signaling contributes to pSS pathogenesis. CP-25 treats pSS by restoring this pathway through regulating MR membrane expression, inhibiting ERS, reducing apoptosis, and decreasing GRP78-IPR co-expression in HSGECs. This study provides experimental support for CP-25's mechanism and potential clinical application in pSS.