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Peer-reviewedCC BY-NC-ND 4.0Cell Communication and Signaling : CCS

Metabolic-extracellular matrix crosstalk in hepatocellular carcinoma: mechanisms and targeted intervention

  • Yusufukadier Maimaitinijiati1,2
  • Tanqing Long3,4,5
  • Yuan Meng1
  • Xiong Chen1
  • Xiaoyan Xing6
  • Zhihua Lu7
  • Yingcai Zhang1
  • Qi Wang3
  • Juan Liu3,4
7 affiliations
  1. 1Hepatopancreatobiliary Center, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, 830011 China
  2. 2Hepato-Pancreato-Biliary Center, Key Laboratory of Digital Intelligence Hepatology (Ministry of Education), School of Clinical Medicine, Tsinghua Medicine, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, 102218 China
  3. 3School of Future Medicine, Beijing University of Chinese Medicine, Beijing, 100102 China
  4. 4Institute for Organ Transplant and Bionic Medicine, Beijing Key Laboratory of Liver Transplantation and Bionic Manufacturing, Tsinghua University, Beijing, 102218 China
  5. 5School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
  6. 6Center of Clinical Immunology, Peking University People’s Hospital, Peking University, Beijing, 100044 China
  7. 7Department of General Surgery, Cheeloo College of Medicine, Qilu Hospital (Qingdao), Shandong University, Qingdao, 266035 China
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Abstract

Bidirectional crosstalk between metabolic reprogramming and extracellular matrix (ECM) remodeling in hepatocellular carcinoma (HCC) constitutes an important metabolic–ECM regulatory network that contributes to HCC progression. Metabolic derangements disrupt ECM deposition, crosslinking, and matrix mechanical properties, with downstream consequences for tumor invasion, immune evasion, and the establishment of pre-metastatic niches. Matrix remodeling in turn provides feedback via mechanotransduction and associated signaling networks that reprogram tumor cell glycolysis, lipogenesis, and amino acid metabolism, thereby forming a self-reinforcing malignant cycle. The network hubs in this cycle may represent candidate mechanobiological biomarkers for future patient stratification and longitudinal response monitoring, although their diagnostic and prognostic utility requires further clinical validation. Interventions are therefore shifting from single-target therapeutics toward coordinated, multi-node modulation aimed at decoupling the metabolic–ECM axis, including integrin-directed therapeutics combined with those that increase tumor microenvironment permeability; focal adhesion kinase (FAK) inhibitors, including those that disrupt functional coupling to epigenetic regulation; and the use of these regimens combined with anti-angiogenic agents, immunotherapies, or metabolic inhibitors to concurrently attenuate drug delivery barriers, mechanically driven cues, and metabolic plasticity. Collectively, therapeutic strategies aimed at decoupling the metabolic–ECM axis hold translational promise for limiting HCC progression, invasion, and metastasis, but their potential to improve long-term survival remains to be validated in clinical studies.

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Cite

BibTeXRIS
BibTeX
@article{maimaitinijiati2026metabolicextracellular,
  title = {{Metabolic-extracellular matrix crosstalk in hepatocellular carcinoma: mechanisms and targeted intervention}},
  author = {Yusufukadier Maimaitinijiati and Tanqing Long and Yuan Meng and Xiong Chen and Xiaoyan Xing and Zhihua Lu and Yingcai Zhang and Qi Wang and Juan Liu},
  journal = {Cell Communication and Signaling : CCS},
  year = {2026},
  month = aug,
  doi = {10.1186/s12964-026-03134-1},
  url = {https://doi.org/10.1186/s12964-026-03134-1},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - Metabolic-extracellular matrix crosstalk in hepatocellular carcinoma: mechanisms and targeted intervention
AU  - Yusufukadier Maimaitinijiati
AU  - Tanqing Long
AU  - Yuan Meng
AU  - Xiong Chen
AU  - Xiaoyan Xing
AU  - Zhihua Lu
AU  - Yingcai Zhang
AU  - Qi Wang
AU  - Juan Liu
PY  - 2026
DA  - 2026/08/10
JO  - Cell Communication and Signaling : CCS
DO  - 10.1186/s12964-026-03134-1
UR  - https://doi.org/10.1186/s12964-026-03134-1
AB  - Bidirectional crosstalk between metabolic reprogramming and extracellular matrix (ECM) remodeling in hepatocellular carcinoma (HCC) constitutes an important metabolic–ECM regulatory network that contributes to HCC progression. Metabolic derangements disrupt ECM deposition, crosslinking, and matrix mechanical properties, with downstream consequences for tumor invasion, immune evasion, and the establishment of pre-metastatic niches. Matrix remodeling in turn provides feedback via mechanotransduction and associated signaling networks that reprogram tumor cell glycolysis, lipogenesis, and amino acid metabolism, thereby forming a self-reinforcing malignant cycle. The network hubs in this cycle may represent candidate mechanobiological biomarkers for future patient stratification and longitudinal response monitoring, although their diagnostic and prognostic utility requires further clinical validation. Interventions are therefore shifting from single-target therapeutics toward coordinated, multi-node modulation aimed at decoupling the metabolic–ECM axis, including integrin-directed therapeutics combined with those that increase tumor microenvironment permeability; focal adhesion kinase (FAK) inhibitors, including those that disrupt functional coupling to epigenetic regulation; and the use of these regimens combined with anti-angiogenic agents, immunotherapies, or metabolic inhibitors to concurrently attenuate drug delivery barriers, mechanically driven cues, and metabolic plasticity. Collectively, therapeutic strategies aimed at decoupling the metabolic–ECM axis hold translational promise for limiting HCC progression, invasion, and metastasis, but their potential to improve long-term survival remains to be validated in clinical studies.
SN  - 1478-811X
ER  -