ORIGINAL RESEARCH article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1611375
This article is part of the Research TopicFerroptosis and regulation mechanism in the tumor immune microenvironment for tumor progression and treatmentView all 8 articles
FASN promotes the stemness of cancer stem cells and protects colorectal cancer cells from ferroptosis by inhibiting the activation of SREBP2
Provisionally accepted
- The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing , China, Beijing, China
Select one of your emails
You have multiple emails registered with Frontiers:
Notify me on publication
Please enter your email address:
If you already have an account, please login
You don't have a Frontiers account ? You can register here
This study examined the role and underlying mechanisms of fatty acid synthase (FASN) in colorectal cancer (CRC). Utilizing data from TCGA and conducting cellular experiments, it was determined that FASN is markedly overexpressed in CRC, with the highest levels observed in HCT116 cells, which were subsequently chosen for further investigation. The research demonstrated that FASN is upregulated in three-dimensional tumor spheroids and CD133+CD44+ cancer stem cells (CSCs) within CRC. Silencing FASN expression led to a reduction in 3D spheroid formation, suppression of in vivo tumor growth, and a decrease in the proportion of CD133+CD44+ cells, suggesting that FASN enhances CSC characteristics and facilitates tumor progression. Mechanistically, FASN knockdown resulted in decreased cholesterol levels and promoted the activation of sterol-regulatory element binding protein 2 (SREBP2), a critical regulator of cholesterol metabolism. The SREBP inhibitor fatostatin counteracted the suppressive effects of FASN knockdown on malignant phenotypes of CRC cells, such as proliferation, migration, and invasion, thereby confirming that FASN advances CRC progression by inhibiting SREBP2 activation. Furthermore, FASN knockdown induced ferroptosis in CRC cells through increased lipid peroxidation, as indicated by elevated levels of ferrous ions, ROS, and lipid peroxidation products, as well as impaired mitochondrial function. These effects could be partially reversed by fatostatin. Co-immunoprecipitation experiments confirmed a direct interaction between FASN and SREBP2. In summary, FASN plays a critical role in CRC progression by enhancing CSC characteristics, regulating SREBP2-mediated cholesterol metabolism, and modulating ferroptosis, highlighting it as a potential target for CRC therapy.
Keywords: colorectal cancer, ferroptosis, FASN, Lipid Metabolism, cancer stem cells
Received: 14 Apr 2025; Accepted: 21 Jul 2025.
Copyright: © 2025 Wang, Ge, Wu, Su, Dong, Xu and Shi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Shiping Xu, The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing , China, Beijing, China
Hui Shi, The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing , China, Beijing, China
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.