High-fat diet impairs ferroptosis and promotes cancer invasiveness via downregulating tumor suppressor ACSL4 in lung adenocarcinoma

Biol Direct. 2021 May 31;16(1):10. doi: 10.1186/s13062-021-00294-7.


Background: Long-chain acyl-CoA synthetase-4 (ACSL4) is involved in fatty acid metabolism, and aberrant ACSL4 expression could be either tumorigenic or tumor-suppressive in different tumor types. However, the function and clinical significance of ACSL4 in lung adenocarcinoma remain elusive.

Results: ACSL4 was frequently downregulated in lung adenocarcinoma when analyzing both the TCGA database and the validation samples, and the lower ACSL4 expression was correlated with a worse prognosis. Using gene set enrichment analysis, we found that high ACSL4 expression was frequently associated with the oxidative stress pathway, especially ferroptosis-related proteins. In vitro functional studies showed that knockdown of ACSL4 increased tumor survival/invasiveness and inhibited ferroptosis, while ACSL4 overexpression exhibited the opposite effects. Moreover, high-fat treatment could also inhibit erastin-induced ferroptosis by affecting ACSL4 expression. The anti-tumor effects of ferroptosis inducers and the anti-ferroptosis effects of the high-fat diet were further validated using the mouse xenograft model.

Conclusions: ACSL4 plays a tumor-suppressive role in lung adenocarcinoma by suppressing tumor survival/invasiveness and promoting ferroptosis. Our study provided a theoretical reference for the application of ferroptotic inducers and dietary guidance for lung adenocarcinoma patients.

Keywords: Ferroptosis; High-fat diet; Long-chain acyl-CoA synthetase-4; Lung adenocarcinoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Adenocarcinoma of Lung / genetics
  • Adenocarcinoma of Lung / pathology*
  • Animals
  • Cell Line, Tumor
  • Coenzyme A Ligases / genetics*
  • Coenzyme A Ligases / metabolism
  • Diet, High-Fat / adverse effects*
  • Down-Regulation
  • Ferroptosis / drug effects*
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Lung Neoplasms / genetics
  • Lung Neoplasms / pathology*
  • Mice
  • Neoplasm Invasiveness / genetics
  • Neoplasm Invasiveness / pathology


  • Coenzyme A Ligases
  • long-chain-fatty-acid-CoA ligase