Nicotine exacerbates intervertebral disc degeneration via NF-κB/MAPK-dependent inflammatory activation and cellular senescence

Cigarette smoking constitutes a major modifiable risk factor for intervertebral disc degeneration (IVDD), yet the mechanistic underpinnings remain incompletely elucidated. This study aimed to elucidate the pathological effects of nicotine-the primary addictive component in tobacco-on IVDD, focusing on its role in inflammation, extracellular matrix (ECM) disruption, and cellular senescence. Utilizing in vivo models (smoke exposure, nicotine injection, and disc puncture) and in vitro human nucleus pulposus cell (NPC) cultures, we employed multi-omics approaches (metabolomics, transcriptomics, imaging, and functional assays) to investigate nicotine's impact on ECM metabolism, inflammatory signaling, and senescence. Nicotine and its primary metabolite, cotinine, accumulated in avascular disc tissue following inhalation or systemic administration. Nicotine dose- and time-dependently inhibited aggrecan and collagen II synthesis, concomitant with MMP-13 upregulation, indicating a catabolic shift in ECM homeostasis. In vivo, nicotine exacerbated puncture-induced IVDD, with synergistic ECM degradation and inflammation. RNA-seq revealed NF-κB and MAPK pathway activation, confirmed by rapid p65 and p38 phosphorylation and elevated IL-1β and IL-6 expression. Pharmacological inhibition of these pathways attenuated nicotine-induced ECM degradation and inflammation. Notably, nicotine triggered NPC senescence with a pro-inflammatory senescence-associated secretory phenotypes (SASP), synergizing with pre-existing disc injury to accelerate IVDD. Our study uncovers a dual-pathway mechanism in which nicotine activates NF-κB and MAPK signaling to amplify inflammatory cascades and SASP, synergistically accelerating IVDD progression. These insights underscore the urgency of smoking cessation, particularly in early-stage IVDD, and propose targeted inhibition of these pathways as a therapeutic strategy.