SOX4 reprograms fatty acid metabolism through the CHREBP to inhibit ferroptosis in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality, characterized by aggressive progression and poor prognosis. Pathological angiogenesis in HCC is closely linked to metabolic reprogramming, particularly concerning fatty acid metabolism. The interplay between fatty acid metabolism and ferroptosis, a type of cell death driven by lipid peroxidation, is emerging as a crucial area of study. The transcription factor SOX4 is known to be overexpressed in various cancers, including HCC, and may play a key role in these processes. We assessed SOX4 expression in HCC using clinical samples and data from online databases. Next-generation RNA sequencing was employed to explore the effects of SOX4 on fatty acid metabolism, focusing on the CHREBP pathway. Functional assays, including lipid peroxidation and angiogenesis studies, were conducted to investigate the role of SOX4 in regulating ferroptosis and angiogenesis in HCC. SOX4 was found to be significantly upregulated in HCC and associated with enhanced angiogenesis. Mechanistically, SOX4 activated the CHREBP/SCD1 pathway, leading to increased production of monounsaturated fatty acids, which in turn inhibited ferroptosis. This suppression of ferroptosis contributed to the promotion of angiogenesis and tumor progression in HCC. In conclusion, SOX4 reprograms fatty acid metabolism via the CHREBP/SCD1 pathway, thereby inhibiting ferroptosis and promoting angiogenesis in HCC. These findings suggest that targeting the SOX4-CHREBP axis could represent a novel therapeutic strategy for HCC.