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BACKGROUND: Ligament flavum hypertrophy is the main cause of lumbar spinal stenosis, which is the result of multiple pathological factors working together. Currently, the molecular mechanism and pathway of action of ligament flavum hypertrophy are unclear, and there is a lack of effective non-surgical treatment options. OBJECTIVE: To investigate the molecular mechanisms of ligament flavum hypertrophy using methylation sequencing and transcriptome integration analysis methods. METHODS: Five normal ligament flavum tissue samples and five hypertrophic ligament flavum tissue samples were collected. Abnormal methylation sites and methylation status were recorded by methylation sequencing and abnormally expressed genes were recorded by transcriptome integration analysis. The genes that showed a negative correlation between methylation level and expression level at the intersection of the two were selected. GO and KEGG enrichment analyses were used to study the major functional pathways and molecular functions of differentially expressed genes. Key genes regulating ligamentum flavum hypertrophy were screened using protein-protein interaction analysis. RESULTS AND CONCLUSION: Methylation sequencing of the two groups of the ligament flavum showed 37 173 hypermethylation sites and 10 583 low methylation sites. Transcriptome integration analysis found 720 abnormally expressed genes, of which 463 were upregulated and 257 were down-regulated. There were 383 overlapping genes, of which 192 genes showed a negative correlation between the methylation level and the expression level. GO functional pathway analysis results showed that molecular function was enriched to 10 terms, cellular component was enriched to 15 terms, and biological process (BP) was enriched to 30 terms. The results of KEGG pathway enrichment analysis showed that 192 genes were mainly enriched to 9 pathways, such as PI3K-Akt signaling pathway, Rap1 signaling pathway, and focal adhesion signaling pathway. The protein-protein interaction analysis identified five genes, PPARG, EGFR, CNR1, TNF and COL11A2, which may be the key genes that regulate ligamentum flavum hypertrophy, and they can influence the occurrence and development of ligamentum flavum hypertrophy mainly through the regulation of tissue fibrosis, cell proliferation and differentiation, inflammatory factor levels, and collagen fiber expression. [ABSTRACT FROM AUTHOR]