SOX9 reprograms lipid metabolism via FASN to promote metastasis in colorectal cancer

Colorectal cancer (CRC) is one of the most common malignant tumors worldwide, and metabolic reprogramming is increasingly recognized as a driver of CRC progression, but how lipid metabolism is transcriptionally regulated during metastasis remains incompletely understood. SRY-box transcription factor 9 (SOX9) has been reported to participate in tumor development, yet its role in lipid metabolism during CRC metastasis remains largely unclear. Integrated transcriptomic and targeted lipidomic analyses, along with Nile Red staining, flow cytometry, transmission electron microscopy and Nanolive lipid droplet imaging, were used to explore and verify SOX9 overexpression-induced fatty acid synthesis, lipid accumulation and intracellular lipid deposition. Migration, invasion and lung metastatic colonization assays (with FASN inhibition for rescue), CUT&Tag sequencing and luciferase reporter assays were performed to evaluate SOX9’s pro-metastatic effect and its regulatory role in FASN promoter activity. We identified SOX9 as a regulator of de novo lipogenesis in CRC. In this study, we demonstrated that SOX9 was upregulated in CRC tissues, enriched in metastatic lesions, and associated with poor patient outcomes. Integrated transcriptomic and targeted lipidomic analyses showed that SOX9 overexpression increased fatty acid synthesis and lipid accumulation. Consistently, Nile Red staining, flow cytometry, transmission electron microscopy and Nanolive lipid droplet imaging confirmed that SOX9 overexpression dramatically enhanced intracellular lipid deposition. Moreover, SOX9 promoted migration, invasion and lung metastatic colonization, which could be significantly attenuated by inhibition of fatty acid synthase. Mechanistically, CUT&Tag sequencing identified SOX9 occupancy near the FASN promoter, and luciferase reporter assays supported SOX9-mediated regulation of FASN promoter activity. Further reporter analyses supported sequence-dependent regulation of the proximal FASN promoter by SOX9. Collectively, these findings illustrate that SOX9–FASN axis contributes to lipid metabolic remodeling and metastasis in CRC, highlighting this axis as a potential metabolic vulnerability in CRC.