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

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.