Unveiling the Therapeutic Potential of Baicalin in Intervertebral Disc Degeneration: Integrative Bulk and Single-Cell Transcriptome Analysis with Experimental Validation of PANoptosis Inhibition

Background: Programmed cell death (PCD), including pyroptosis, apoptosis, and necroptosis, plays a critical role in the pathogenesis of intervertebral disc degeneration (IVDD). PANoptosis, a recently identified form of PCD integrating pyroptosis, apoptosis, and necroptosis, may represent a more comprehensive target for therapeutic intervention in IVDD. Objective: To explore the role of PANoptosis in IVDD and investigate the therapeutic potential and underlying mechanism of baicalin in regulating PANoptosis to alleviate disc degeneration. Methods: We performed integrative analyses of bulk transcriptomic datasets (GSE167199, GSE245147, GSE266883) and a single-cell RNA-seq dataset (GSE244889) to identify PANoptosis-related genes involved in IVDD. The expression and function of key genes were validated using clinical samples, an IL-1β-induced NPC degeneration model in vitro, and a puncture-induced rat IVDD model in vivo treated with baicalin. Results: Five core PANoptosis-related genes (FOS, CASP1, H1-2, BCL2L11, and H2AC6) were significantly upregulated in degenerated discs. Baicalin treatment effectively downregulated these genes at both mRNA and protein levels. Moreover, baicalin alleviated IL-1β-induced cell death in NPCs and improved histological features in the rat IVDD model. Conclusion: Our findings reveal a critical role of PANoptosis in IVDD progression and demonstrate that baicalin alleviates disc degeneration by inhibiting PANoptosis. This study provides novel insights into PANoptosis as a promising therapeutic target for IVDD.