HNF4A ameliorates acute liver failure by inhibiting NCOA4-mediated ferritinophagy

Intracellular iron homeostasis imbalance is linked to cellular ferroptosis and inflammatory injury diseases. NCOA4-mediated ferritin autophagy is vital for regulating intracellular iron homeostasis, but its impact on acute liver failure (ALF) pathogenesis and regulatory mechanisms remain unclear. This study explores the role and regulatory mechanisms of NCOA4 in hepatocyte ferroptosis and ALF progression. To investigate the relationship between NCOA4 expression and acute liver failure (ALF), we compared the protein expression levels in normal and pathological liver tissues. By establishing cell and mouse models, we determined the correlation among NCOA4 expression, ferroptosis, and inflammatory liver injury. Additionally, we explored the regulatory effect of NCOA4 on hepatocyte ferroptosis by interfering with gene expression and observing mitochondrial structure changes. Finally, we evaluated the regulation of NCOA4 expression and its protective effect against acute inflammatory injury in hepatocytes. Our results showed that NCOA4 expression was significantly higher in patients with hepatitis B virus - related acute - on - chronic liver failure (HBV - ACLF) compared to those with chronic hepatitis B. Similarly, NCOA4 was upregulated in ALF model mice and inflammatory hepatocytes. Silencing NCOA4 alleviated LPS - induced ferroptosis in inflammatory hepatocytes. Mechanistic research indicated that the transcription of hepatic nuclear factor 4 A (HNF4A) negatively regulated NCOA4. HNF4A transcriptionally inhibited NCOA4 expression, reducing hepatocyte ferroptosis through anti - ferritin autophagy. This study identified the HNF4A - NCOA4 axis and ferritinophagy as crucial factors in hepatocyte ferroptosis and the pathogenesis of acute liver failure (ALF). These findings suggest that the HNF4A - NCOA4 axis could be a potential therapeutic target for ALF.