Capsaicin attenuates ferroptosis and pyroptosis in nucleus pulposus cells by disrupting the IL-1β/NF-κB-PTGS2 positive feedback loop

Abstract

Abstract Background The pathogenesis of intervertebral disc degeneration (IDD), a chronic disease of the spine, remains poorly understood despite its high disability rates, significant financial burden, and association with low back pain. Importantly, pyroptosis and ferroptosis in nucleus pulposus cells (NPCs) have emerged as critical mechanisms underlying the development of IDD. Methods Through bioinformatics analysis, we identified PTGS2 as a key gene involved in a positive feedback loop (IL-1β/NF-κB-PTGS2), driving IDD progression by regulating NPCs ferroptosis and pyroptosis. We evaluated this loop's expression in degenerated/non-degenerated human intervertebral disc tissue samples using RT-qPCR, immunohistochemistry, and western blotting. Our findings were further confirmed through cell and rat IDD models. Furthermore, a pharmacological network analysis was performed on PTGS2 target genes to investigate how capsaicin disrupts the IL-1β/NF-κB-PTGS2 feedback loop for attenuating NPCs ferroptosis and pyroptosis both in vivo and in vitro. Results The biogenic analysis revealed the presence of an IL-1β/NF-κB-PTGS2 positive feedback loop, which triggered NPCs pyroptosis and ferroptosis. Then, we validated the upregulated expression of this loop in surgical specimens from patients with IDD, and further substantiated its increased expression by establishing cellular and animal models of IDD. Furthermore, we found that capsaicin disrupted the IL-1β/NF-κB-PTGS2 positive feedback loop by inhibiting PTGS2 mRNA transcription, NF-κB signaling activity, and mitochondria reactive oxygen species production in vitro. And it could effectively delay the progression of IDD in vivo. Conclusions The capsaicin compound alleviates IDD by disrupting the IL-1β/NF-κB-PTGS2 positive feedback loop, thereby inhibiting ferroptosis and pyroptosis in NPCs.