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<p>Intervertebral disc degeneration (IVDD) is a major contributor to lumbar degenerative diseases and chronic low back pain, while the role of ferroptosis in its pathogenesis remains incompletely understood. In this study, we integrated transcriptomic and single-cell RNA sequencing analyses to systematically identify ferroptosis-related key gene networks and explore potential pharmacological interventions. Bioinformatics analysis identified seven core hub genes, including JUN, TGFB1, MAPK1, CDKN1A, DUSP1, TIMP1, and HSF1, which were mainly enriched in ErbB, HIF-1, FoxO, and MAPK signaling pathways. Single-cell analysis revealed 12 major cell subpopulations, among which inflammatory and chondrocyte-like nucleus pulposus (NP) cells were significantly enriched in degenerated discs. CytoTRACE trajectory inference indicated that regenerative and notochordal-like NP cells exhibited higher differentiation potential. The hub genes showed highly heterogeneous expression patterns across cell types, and the interaction strength between inflammatory NP cells and macrophages was markedly increased, suggesting their involvement in the degenerative microenvironment and ferroptosis regulation. Based on drug prediction and molecular docking, resveratrol demonstrated strong binding affinities with most core targets, with binding energies below − 5&#xa0;kcal/mol. In vitro experiments further confirmed that resveratrol significantly improved IL-1β-induced reduction of NP cell viability as assessed by CCK-8 assays. RT-qPCR analysis showed that resveratrol effectively suppressed the overexpression of JUN, TGFB1, MAPK1, DUSP1, TIMP1, and HSF1, while upregulating the expression of CDKN1A, thereby exerting a protective effect. Collectively, this study systematically elucidates the ferroptosis-related molecular networks and their distribution across cellular subpopulations in IVDD, and demonstrates the potential of resveratrol as a candidate therapeutic agent, providing novel insights for targeted intervention strategies.</p>

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Unraveling the ferroptosis landscape in intervertebral disc degeneration through integrated bioinformatics and single-cell sequencing

  • 期刊论文

  • 发表日期：

    2025年11月25日

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  • Gangbo Qu,
  • Zhijiang Zeng,
  • Bing Luo,
  • Lu Zhao,
  • Jun Yuan

摘要

Intervertebral disc degeneration (IVDD) is a major contributor to lumbar degenerative diseases and chronic low back pain, while the role of ferroptosis in its pathogenesis remains incompletely understood. In this study, we integrated transcriptomic and single-cell RNA sequencing analyses to systematically identify ferroptosis-related key gene networks and explore potential pharmacological interventions. Bioinformatics analysis identified seven core hub genes, including JUN, TGFB1, MAPK1, CDKN1A, DUSP1, TIMP1, and HSF1, which were mainly enriched in ErbB, HIF-1, FoxO, and MAPK signaling pathways. Single-cell analysis revealed 12 major cell subpopulations, among which inflammatory and chondrocyte-like nucleus pulposus (NP) cells were significantly enriched in degenerated discs. CytoTRACE trajectory inference indicated that regenerative and notochordal-like NP cells exhibited higher differentiation potential. The hub genes showed highly heterogeneous expression patterns across cell types, and the interaction strength between inflammatory NP cells and macrophages was markedly increased, suggesting their involvement in the degenerative microenvironment and ferroptosis regulation. Based on drug prediction and molecular docking, resveratrol demonstrated strong binding affinities with most core targets, with binding energies below − 5 kcal/mol. In vitro experiments further confirmed that resveratrol significantly improved IL-1β-induced reduction of NP cell viability as assessed by CCK-8 assays. RT-qPCR analysis showed that resveratrol effectively suppressed the overexpression of JUN, TGFB1, MAPK1, DUSP1, TIMP1, and HSF1, while upregulating the expression of CDKN1A, thereby exerting a protective effect. Collectively, this study systematically elucidates the ferroptosis-related molecular networks and their distribution across cellular subpopulations in IVDD, and demonstrates the potential of resveratrol as a candidate therapeutic agent, providing novel insights for targeted intervention strategies.