FSCN1 Modulates Fatty Acid Metabolism and the Coordinated Activation of AKT/mTOR and p38 MAPK Pathways in Colorectal...

Background: Fascin actin-bundling protein 1 (FSCN1) modulates the expression of key lipogenic enzymes fatty acid synthase (FASN) and stearoyl-CoA desaturase (SCD1) in colorectal cancer (CRC), but the underlying mechanisms remain elusive. Methods: Bioinformatics analyses were performed to evaluate FSCN1 expression and its prognostic value in CRC. Intracellular lipid levels following FSCN1 knockdown were assessed by Nile Red/DAPI co-staining and triglyceride quantification, and further validated by Oil Red O staining of xenograft tumors. Expression levels of key metabolic enzymes were measured by qRT-PCR and Western blotting. RNA sequencing identified FSCN1-associated pathways, which were functionally investigated using pharmacological inhibitors. Results: FSCN1 was significantly upregulated in CRC (p < 0.001; AUC = 0.796) and was correlated with poorer overall survival (p = 0.018). FSCN1 depletion reduced intracellular lipid accumulation, accompanied by downregulation of lipogenic mediators-sterol regulatory element-binding transcription factor 1 (SREBF1; protein product: SREBP1), FASN, and SCD1-and upregulation of peroxisomal fatty acid oxidation (FAO)-related factors-peroxisome proliferator-activated receptor alpha (PPARA; protein product: PPARα) and acyl-CoA oxidase 1 (ACOX1). Mechanistically, FSCN1 was associated with activation of the protein kinase B/mammalian target of rapamycin (AKT/mTOR) and p38 mitogen-activated protein kinase (p38 MAPK) pathways; pharmacological inhibition with LY294002 or SB203580 phenocopied the lipid-lowering effects of FSCN1 knockdown. Conclusion: Collectively, these findings link FSCN1 to the AKT/mTOR/SREBP1/(FASN/SCD1) lipogenic axis and the p38 MAPK/PPARα/ACOX1 peroxisomal FAO pathway, implicating FSCN1 in lipid metabolic regulation and CRC progression, while suggesting a putative functional regulatory axis and a promising candidate therapeutic target for CRC.