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

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 μg/mL) protected human OA chondrocytes from IL‑1β‑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‑1β and IL‑18 secretion in IL‑1β‑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 OARSI scores, improved cartilage matrix staining (Safranin O, Masson's trichrome), attenuated synovial hyperplasia and posterior capsule adhesions, and decreased plasma IL‑1β 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‑κB/NLRP3‑driven chondrocyte pyroptosis. SIN may be a potential therapeutic candidate for OA.