Sinensetin ameliorates osteoarthritis progression by modulating the NF-κB/NLRP3 signaling pathway and suppressing chondrocyte pyroptosis

Abstract

Sinensetin (SIN) is a natural flavonoid with potential anti-inflammatory effects. This study investigated whether SIN ameliorates osteoarthritis (OA) and explored its underlying mechanisms. In vitro, SIN (0.05-1 ug/mL) protected human OA chondrocytes from IL- 1p-induced viability loss. Transcriptome sequencing and molecular docking identified SERPINA3 as a candidate target of SIN. SIN reduced the expression of NLRP3, GSDMD, and ASC, inhibited pyroptotic morphology, decreased TUNEL-positive cells and LDH release, and lowered IL-1p and IL-18 secretion in IL-1p-treated chondrocytes. Knockdown of SERPINA3 reversed these effects, suggesting that SIN acts through SERPINA3 to inhibit the NLRP3 inflammasome. In a rat DMM-induced OA model, SIN (20 mg/kg/day for 6 weeks) alleviated pain, reduced Osteoarthritis Research Society International (OARSI) scores, improved cartilage matrix staining (Safranin O, Masson's trichrome), attenuated synovial hyperplasia and posterior capsule adhesions, and decreased plasma IL-1p and IL-18 levels. Western blot of rat cartilage confirmed that SIN suppressed GSDMD and NLRP3 expression. These results indicate that SIN ameliorates OA progression by inhibiting SERPINA3-mediated NF-KB/NLRP3-driven chondrocyte pyroptosis. SIN may be a potential therapeutic candidate for OA.