The ferroptosis mediator ACSL4 fails to prevent disease progression in mouse models of MASLD

Metabolic-dysfunction associated steatotic liver disease (MASLD) is an increasingly prevalent condition with the potential to progress to liver cirrhosis and HCC. Elevated iron levels and disrupted lipid metabolism in MASLD patients point to a potential role for ferroptosis in disease progression. Previous work by Duan et al. (PMID: 34510514) demonstrated that inhibiting ferroptosis through hepatocyte-specific deletion of Acyl-CoA synthetase long-chain family member 4 (ACSL4LPC-KO), a key pro-ferroptotic gene, reduced MASLD progression in mice offering a potential therapeutic strategy.

Our study aimed to investigate whether dietary modifications similarly affect MASLD onset. ACSL4LPC-KO and wild-type (WT) mice were fed two distinct diets—choline-deficient high-fat diet (CD-HFD) or Western diet—over 20 or 40 weeks, representing different stages of metabolic liver damage and the development of metabolic syndrome. Mice were then subjected to metabolic analyses.

In contrast to the findings by Duan et al., our results show no significant differences between ACSL4LPC-KO and WT mice in terms of MASLD progression, weight gain, glucose tolerance, and hepatic steatosis. Moreover, fibrogenesis and MASLD-associated inflammation were unaffected under both the CD-HFD and Western diet. These findings suggest that ACSL4 does not influence MASLD progression and development under these dietary conditions.

The discrepancy between our results and previously published findings could be due to differences in diets or the influence of distinct microbiomes. Therefore, the results obtained with hepatocyte-specific ACSL4LPC-KO ought to be considered with caution, underscoring the importance of publishing negative or contradictory findings.

Publication History

Article published online:
20 January 2025