Metabolic mRNA insufficiency of single cells: Implications for drug targeting and resistance

Yanhua Liu1,2,3, Hans V Westerhoff3,4,5,6,7

  • 1Department of Endocrinology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.

The FEBS Journal
|August 12, 2026
PubMed

Insights

This study reveals that enzyme stability, not just mRNA levels, explains cell growth. Identifying metabolic vulnerabilities in liver cancer subpopulations offers new drug targets to combat resistance.

Area of Science:

  • Metabolic Engineering
  • Cancer Biology
  • Systems Biology

Background:

  • Understanding cellular metabolism is crucial for identifying cancer vulnerabilities.
  • Subpopulation-specific metabolic networks remain poorly characterized.
  • Current models may not fully capture the drivers of cell proliferation.

Purpose of the Study:

  • To build mRNA-based metabolic maps for diverse cell populations.
  • To identify vulnerabilities in subpopulation-specific metabolic networks.
  • To discover novel drug targets for liver cancer treatment.

Main Methods:

  • Single-cell transcriptomics to construct metabolic maps.
  • Flux balance analysis (FBA) with enzyme Vmax constraints.
  • Comparative analysis of liver cancer and noncancerous liver cells.

Main Results:

  • Flux balance analysis initially predicted no growth, which was resolved by an enzyme-stability based model.
  • The enzyme-stability model indicated biomass production capacity for cell division.
  • Cholesterol synthesis (SQLEr) and arginine synthesis were identified as potential drug targets in liver cancer cells.

Conclusions:

  • Enzyme stability is a critical factor in cellular growth, complementing mRNA levels.
  • Identifying subpopulation-specific metabolic vulnerabilities can reveal novel therapeutic targets.
  • Targeting identified pathways may help reduce drug resistance in liver cancer.

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