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We performed an integrative analysis of single\u2010cell RNA sequencing (scRNA\u2010seq) and transcriptomic sequencing using public datasets (GSE230809, GSE186542) to characterise cellular heterogeneity in IDD. To elucidate the underlying pathological mechanisms, we employed senescence scoring, transcriptional entropy assessment, pseudotime trajectory inference, and hierarchical weighted gene co\u2010expression network analysis (hdWGCNA). Metabolic pathway activity was evaluated with scMetabolism, and potential therapeutics were screened using the POINT platform. We identified a key fibrochondrocyte subpopulation, FC3, which exhibits high transcriptional entropy and plays a central role in IDD. The FC3 cluster was further resolved into three functional states: fibrotic, proliferative, and metabolic. Pseudotime trajectory inference indicated that FC3 (proliferative) cells potentially represent a progenitor\u2010like state, partitioning toward fibrotic and metabolic lineages. Notably, the FC3 (metabolic) state displayed the lowest senescence score and the highest activity in the tricarboxylic acid (TCA) cycle. Through hdWGCNA and cross\u2010dataset validation, malate dehydrogenase 2 (MDH2) was established as a central hub gene linking TCA cycle activation to the FC3 (metabolic) phenotype. Functional enrichment confirmed MDH2's role in oxidative phosphorylation, fatty acid metabolism, and cellular senescence. Drug screening identified several candidate compounds, including Platycodin D, Irbesartan, and Ergothioneine, whose corresponding targets exhibited specifically enhanced activity within the FC3 (metabolic) subpopulation of degenerated tissues. Our study reveals that metabolic dysregulation in the FC3 fibrochondrocyte subpopulation, driven by aberrant MDH2\u2010mediated TCA cycle activation, is a critical mechanism promoting IDD. These findings highlight the therapeutic targeting value of the FC3 metabolic state and provide specific candidate compounds for the subsequent development of interventions against IDD.<\/jats:p>","DOI":"10.1111\/jcmm.71246","type":"journal-article","created":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T06:18:16Z","timestamp":1783059496000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Metabolic Dysregulation of\n                    <scp>FC3<\/scp>\n                    Fibrochondrocytes via\n                    <scp>MDH2<\/scp>\n                    Promotes Intervertebral Disc Degeneration"],"prefix":"10.1111","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-2953-6330","authenticated-orcid":false,"given":"Xingye","family":"Li","sequence":"first","affiliation":[{"name":"Department of Spine Surgery Beijing Jishuitan Hospital, Capital Medical University  Beijing 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