Nutritional c‐Fos Induction Rewires Hepatic Metabolism and Can Promote Obesity‐Associated Hepatocellular Carcinoma

Abstract The transcription factor c‐Fos plays a key role in liver metabolism, stress responses, and carcinogenesis. Here, the role of hepatic c‐Fos in the pathophysiology of metabolic dysfunction‐associated steatotic liver disease and hepatocellular carcinoma (HCC) is investigated. In chow‐fed mice, hepatic c‐Fos is induced by insulin after feeding and suppressed by glucagon during fasting. Adenovirus‐mediated hepatic c‐Fos ectopic expression is sufficient to induce insulin resistance in chow‐fed mice. In models of diet‐induced obesity and inducible hepatocyte‐specific Fos ‐expressing mice, elevated c‐Fos expression is associated with transcriptomic changes in PPAR signaling and fatty acid metabolism pathways. Mechanistically, ectopic c‐Fos expression enhances glycolysis and activates stress‐related MAPK and insulin‐related PI3K‐Akt signaling, which can contribute to metabolic dysregulation. In HCC, persistent c‐Fos expression correlates with activation of PI3K‐Akt, MAPK, and calcium signaling pathways. Functional studies show that c‐Fos knockdown reduces proliferation and restores apoptotic sensitivity in HCC cells under lipotoxic or endoplasmic reticulum stress conditions. These findings identify c‐Fos as a transcriptional regulator responsive to metabolic and hormonal cues, with potential roles in liver metabolic dysfunction and tumorigenesis.