ACSL4-dependent ferroptosis is not a major tumor-suppressive mechanism during HCC initiation and progression

Question Non-alcoholic fatty liver disease is a condition characterized by excess of fat in liver ranging from simple steatosis to steatohepatitis, cirrhosis, and hepatocellular carcinoma (HCC). In our study, we aimed to investigate the relevance of ferroptosis for disease progression using hepatocyte-specific ACSL4 deletion in an experimental HCC model.

Methods Primary hepatocytes from either wild-type mice or mice with hepatocyte-specific deletion of ACSL4 (ACSL4Δhepa) were treated with specific inducers (e.g., RSL3) and inhibitors (e.g., Liproxstatin-1) of ferroptosis. We used STZ (Streptozocin) with high-fat diet as HCC model, where different time points of disease progression were studied to investigate the role of ferroptosis.

Results Treatment of primary hepatocytes with RSL3 triggered increased ferroptotic cell death, which could be rescued by Liproxstatin-1 or by ACSL4 deletion. At the stage of tumor initiation in our HCC model, inhibition of ferroptosis in hepatocytes increases the severity of chronic liver disease as evidenced by elevated serum transaminase levels in ACSL4Δhepa mice. Importantly, the overall tumor burden was increased, too. Interestingly, ACSL4 deletion does not significantly affect inflammation. However, enhanced oxidative stress and remarkably decreased ferroptotic and apoptotic cell death was observed in ACSL4Δhepa mice. Moreover, evaluation of HCC progression at later stage showed no effect on overall tumor burden but significantly reduced proliferation in ACSL4Δhepa mice.

Conclusion Our results demonstrate that primary mouse hepatocytes are susceptible to ferroptosis induction and that it depends on functional ACSL4. In vivo in our HCC model, ACSL4 deletion increases tumor initiation, but has no significant impact on tumor progression.

Lecture Session V Viral Hepatitis and Immunology

29/01/2022, 11.00 am – 11.45 am, Lecture Hall

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Artikel online veröffentlicht:
26. Januar 2022