Bulk and single-cell transcriptome profiling reveal extracellular matrix mechanical regulation of lipid metabolism reprograming through YAP/TEAD4/ACADL axis in hepatocellular carcinoma

Int J Biol Sci. 2023 Apr 9;19(7):2114-2131. doi: 10.7150/ijbs.82177. eCollection 2023.


Emerging studies have revealed matrix stiffness promotes hepatocellular carcinoma (HCC) development. We studied metabolic dysregulation in HCC using the TCGA-LIHC database (n=374) and GEO datasets (GSE14520). HCC samples were classified into three heterogeneous metabolic pathway subtypes with different metabolic profiles: Cluster 1, an ECM-producing subtype with upregulated glycan metabolism; Cluster 2, a hybrid subtype with partial pathway dysregulation. Cluster 3, a lipogenic subtype with upregulated lipid metabolism; These three subtypes have different prognosis, clinical features and genomic alterations. We identified key enzymes that respond to matrix stiffness and regulate lipid metabolism through bioinformatic analysis. We found long-chain acyl-CoA dehydrogenase (ACADL) is a mechanoreactive enzyme that reprograms HCC cell lipid metabolism in response to extracellular matrix stiffness. ACADL is also regarded as tumor suppressor in HCC. We found that increased extracellular matrix stiffness led to activation of Yes-associated protein (YAP) and the YAP/TEA Domain transcription factor 4 (TEAD4) transcriptional complex was able to directly repress ACADL at the transcriptional level. The ACADL-dependent mechanoresponsive pathway is a potential therapeutic target for HCC treatment.

Keywords: ACADL; Hepatocellular carcinoma; YAP; extracellular matrix.

MeSH terms

  • Acyl-CoA Dehydrogenase / genetics
  • Acyl-CoA Dehydrogenase / metabolism
  • Adaptor Proteins, Signal Transducing / metabolism
  • Carcinoma, Hepatocellular* / metabolism
  • Cell Line, Tumor
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic / genetics
  • Humans
  • Lipid Metabolism / genetics
  • Liver Neoplasms* / metabolism
  • Phosphoproteins / metabolism
  • TEA Domain Transcription Factors
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • YAP-Signaling Proteins


  • Acyl-CoA Dehydrogenase
  • Adaptor Proteins, Signal Transducing
  • YAP-Signaling Proteins
  • Phosphoproteins
  • Transcription Factors
  • TEAD4 protein, human
  • TEA Domain Transcription Factors