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<p>Lactylation, a newly identified post-translational modification of lactate metabolism, has been implicated in degenerative diseases. However, its roles in intervertebral disc degeneration (IVDD) remain unexplored. This study aimed to identify database- and literature-derived lactylation-associated candidate hub genes (abbreviated as “lactylation-associated candidate hub genes”) in IVDD, characterize their biological functions, and validate potential targeted therapeutic compounds. Differential expression analysis of the GSE56081 dataset identified 3305 differentially expressed genes (DEGs). Weighted gene co-expression network analysis (WGCNA) screened IVDD-associated key module genes, which were intersected with 327 known lactylation-associated candidate hub proteins to obtain 42 overlapping genes. Protein–protein interaction (PPI) network analysis (STRING/Cytoscape) identified hub genes, followed by GO/KEGG enrichment, immune infiltration (CIBERSORT), molecular docking, and in vitro validation (CCK-8, LDH, RT-qPCR). Five core lactylation-associated candidate hub genes (RBM39, HNRNPU, SFPQ, HNRNPL, DDX5) may potentially regulate IVDD progression through involvement in RNA metabolism, ferroptosis, HIF-1 signaling, and immune microenvironment remodeling (increased CD8<sup>+</sup> T cells, Th17 cells, Tregs, macrophages, neutrophils; decreased monocytes, B cells), though direct mechanistic evidence is still needed. Curcumin exhibited strong binding affinity with hub proteins, especially SFPQ (− 7.8&#xa0;kcal/mol) and regulated their expression in nucleus pulposus cells, maintaining cell viability and reducing cytotoxicity. This study is the first to systematically identify lactylation-associated candidate hub genes that are potentially involved in IVDD pathogenesis via multiple pathways and immune microenvironment modulation. Curcumin shows favorable binding potential with these hub proteins and may serve as a candidate targeted therapeutic agent for IVDD. Our findings provide novel insights into the molecular mechanisms of IVDD and a preliminary basis for guiding the development of lactylation-related precision treatment strategies.</p>

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Discovery of lactylation-associated candidate hub genes and potential curcumin targets in intervertebral disc degeneration

  • 期刊论文

  • 发表日期：

    2026年4月28日

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  • Weiye Cai,
  • Yingjin Luo,
  • Jiangping Wang,
  • Jian Kong,
  • Yujiang Liu,
  • Binjie Lu,
  • Boen Song,
  • Yue Lu,
  • Bo Xu,
  • Xiaofeng Shen

摘要

Lactylation, a newly identified post-translational modification of lactate metabolism, has been implicated in degenerative diseases. However, its roles in intervertebral disc degeneration (IVDD) remain unexplored. This study aimed to identify database- and literature-derived lactylation-associated candidate hub genes (abbreviated as “lactylation-associated candidate hub genes”) in IVDD, characterize their biological functions, and validate potential targeted therapeutic compounds. Differential expression analysis of the GSE56081 dataset identified 3305 differentially expressed genes (DEGs). Weighted gene co-expression network analysis (WGCNA) screened IVDD-associated key module genes, which were intersected with 327 known lactylation-associated candidate hub proteins to obtain 42 overlapping genes. Protein–protein interaction (PPI) network analysis (STRING/Cytoscape) identified hub genes, followed by GO/KEGG enrichment, immune infiltration (CIBERSORT), molecular docking, and in vitro validation (CCK-8, LDH, RT-qPCR). Five core lactylation-associated candidate hub genes (RBM39, HNRNPU, SFPQ, HNRNPL, DDX5) may potentially regulate IVDD progression through involvement in RNA metabolism, ferroptosis, HIF-1 signaling, and immune microenvironment remodeling (increased CD8+ T cells, Th17 cells, Tregs, macrophages, neutrophils; decreased monocytes, B cells), though direct mechanistic evidence is still needed. Curcumin exhibited strong binding affinity with hub proteins, especially SFPQ (− 7.8 kcal/mol) and regulated their expression in nucleus pulposus cells, maintaining cell viability and reducing cytotoxicity. This study is the first to systematically identify lactylation-associated candidate hub genes that are potentially involved in IVDD pathogenesis via multiple pathways and immune microenvironment modulation. Curcumin shows favorable binding potential with these hub proteins and may serve as a candidate targeted therapeutic agent for IVDD. Our findings provide novel insights into the molecular mechanisms of IVDD and a preliminary basis for guiding the development of lactylation-related precision treatment strategies.