Targeting ICAM1 through LIF-mediated NF-κB/JAK2-STAT3 crosstalk protects nucleus pulposus from IL-1β-driven pyroptosis to ameliorate intervertebral disc degeneration

Intervertebral disc degeneration (IDD) is a prevalent condition contributing to back pain and disability. Leukemia inhibitory factor (LIF) has emerged as a protective gene in IDD, prompting further investigation into its role and mechanisms. This study employs bioinformatics analysis combined with experimental validation to explore the role of LIF in IDD. Gene expression datasets from the GEO database were analyzed to identify genes associated with IDD, and the effects of LIF on nucleus pulposus (NP) cell NLRP3 activation and pyroptosis were assessed both in vitro and in vivo. Elevated L IF expression was observed in mildly degenerated discs and decreased in severely degenerated discs. In vitro studies demonstrated that L IF can alleviate IL-1 β-mediated pyroptosis of NP cells and NLRP3 activation by regulating ICAM1 expression. This process is achieved by inhibiting the NF- κB and JAK2/STAT3 pathways. Furthermore, in vivo studies confirmed these findings, showing that the progression of IDD can be ameliorated by expressing LIF or inhibiting ICAM1. LIF and ICAM 1 play significant roles in the pathogenesis of IDD, closely linked to NP cell pyroptosis and NLRP3 activation. Targeting LIF or ICAM1 could offer a novel therapeutic strategy for IDD.