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

## TL;DR

A high-fat diet reduces ACSL4 levels in lung cancer, impairing cell death and increasing cancer spread.

## Contribution

Identifies ACSL4 as a tumor suppressor in lung adenocarcinoma linked to ferroptosis and diet.

## Key findings

- ACSL4 is downregulated in lung adenocarcinoma and correlates with worse prognosis.
- ACSL4 overexpression reduces tumor invasiveness and promotes ferroptosis.
- High-fat diets inhibit ferroptosis by reducing ACSL4 expression.

## Abstract

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.

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.

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.

The online version contains supplementary material available at 10.1186/s13062-021-00294-7.