KLF2-Mediated Modulation of oxidative stress and pyroptosis by Vanillic acid in intervertebral disc degeneration

Intervertebral disc degeneration (IDD) is a major contributor to chronic low back pain, yet current treatments primarily offer symptom relief without addressing the underlying pathology. In this study, we demonstrate that vanillic acid (VA), a natural phenolic compound, protects nucleus pulposus (NP) cells from inflammation-induced pyroptosis, oxidative stress, and extracellular matrix (ECM) degradation. VA markedly reduced both intracellular and mitochondrial reactive oxygen species (ROS) levels and inhibited NLRP3 inflammasome-mediated pyroptosis. Transcriptomic analysis identified KLF2 as a significantly upregulated transcription factor in response to VA treatment. Molecular docking suggested a potential structural interaction between VA and KLF2. Mechanistically, KLF2 was found to mediate VA-induced activation of NRF2 signaling, as KLF2 knockdown abolished NRF2 nuclear translocation. In a lumbar instability mouse model of IDD, VA preserved disc structure and ECM integrity, accompanied by increased expression of KLF2 and NRF2 and reduced pyroptosis. These findings indicate that VA attenuates IDD progression by activating the KLF2/NRF2 axis and suppressing the ROS/NLRP3 cascade, and suggest that VA may serve as a potential compound for the development of KLF2-targeting therapies.