@Article{or.2026.084987,
AUTHOR = {Zhen Li, Xinya Yu, Boning Wu, Jialin Zhang, Xinyu Ju, Yajun Wang, Jieli Song, Qiao Liu, Peng Huang, Qi Ding, Yupeng Wu},
TITLE = {FSCN1 Modulates Fatty Acid Metabolism and the Coordinated Activation of AKT/mTOR and p38 MAPK Pathways in Colorectal Cancer Cells},
JOURNAL = {Oncology Research},
VOLUME = {},
YEAR = {},
NUMBER = {},
PAGES = {{pages}},
URL = {http://www.techscience.com/or/online/detail/28021},
ISSN = {1555-3906},
ABSTRACT = {<b>Background:</b> Fascin actin-bundling protein 1 (<i>FSCN1</i>) modulates the expression of key lipogenic enzymes fatty acid synthase (<i>FASN</i>) and stearoyl-CoA desaturase (<i>SCD1</i>) in colorectal cancer (CRC), but the underlying mechanisms remain elusive. <b>Methods:</b> Bioinformatics analyses were performed to evaluate FSCN1 expression and its prognostic value in CRC. Intracellular lipid levels following <i>FSCN1</i> 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. <b>Results:</b> FSCN1 was significantly upregulated in CRC (<i>p</i> &lt; 0.001; AUC = 0.796) and was correlated with poorer overall survival (<i>p</i> = 0.018). FSCN1 depletion reduced intracellular lipid accumulation, accompanied by downregulation of lipogenic mediators—sterol regulatory element-binding transcription factor 1 (<i>SREBF1</i>; protein product: SREBP1), FASN, and SCD1—and upregulation of peroxisomal fatty acid oxidation (FAO)-related factors—peroxisome proliferator-activated receptor alpha (<i>PPARA</i>; protein product: PPARα) and acyl-CoA oxidase 1 (<i>ACOX1</i>). 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 <i>FSCN1</i> knockdown. <b>Conclusion:</b> 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.},
DOI = {10.32604/or.2026.084987}
}