Forsythiaside A attenuates intervertebral disc degeneration by suppressing PI3K/AKT/NF-κB-mediated NLRP3 inflammasome activation and pyroptosis

Intervertebral disc degeneration (IVDD) is a major cause of low back pain, characterized by inflammatory responses and NLRP3 inflammasome-driven Pyroptosis. Forsythiaside A (FTA), a primary bioactive compound derived from Forsythia suspensa, possesses anti-inflammatory, antioxidant, and antipyroptotic properties. However, its role in IVDD remains unclear. This study aimed to investigate whether FTA alleviates IVDD by inhibiting NLRP3 inflammasome activation via the PI3K/Akt/NF-κB pathway. Network pharmacology and molecular docking were used to predict FTA targets and binding affinities. In vitro, lipopolysaccharide-stimulated rat nucleus pulposus cells were treated with FTA to assess extracellular matrix degradation, inflammatory cytokine release, and Pyroptosis. In vivo, a puncture-induced rat IVDD model was established to evaluate the therapeutic effects of FTA. Mechanisms were examined using Western blotting, immunofluorescence, RT-qPCR, ELISA, histology, and radiography. Network pharmacology revealed an enrichment of FTA targets in the PI3K/Akt/NF-κB pathway. Molecular docking confirmed strong binding between FTA and PI3K/p65. FTA dose-dependently inhibited lipopolysaccharide-induced extracellular matrix degradation (reduced MMP-13 and ADAMTS-5), suppressed inflammatory cytokines (IL-1β and IL-18), and down-regulated Pyroptosis markers (NLRP3, cleaved-caspase-1, and GSDMD). Mechanistically, FTA inhibited PI3K/Akt phosphorylation and NF-κB p65 nuclear translocation, thereby suppressing NLRP3 inflammasome activation. In vivo, FTA treatment preserved disc height, improved MRI signals, reduced histological degeneration, and decreased MMP-13 and NLRP3 expression while enhancing Collagen II synthesis. FTA mitigates IVDD by inhibiting PI3K/Akt/NF-κB signaling, thereby suppressing NLRP3 inflammasome-mediated Pyroptosis and extracellular matrix degradation. These findings suggest FTA as a promising therapeutic agent for IVDD.