Targeting FTL regulates ferroptosis and remodels lymph node metastasis microenvironment in esophageal squamous cell carcinoma
More than half of Esophageal squamous cell carcinoma (ESCC) patients are at an advanced stage when first diagnosed, thus they do not benefit much from radical surgery. Single-cell RNA sequencing (scRNA-seq) data from patients with ESCC lymph node metastasis in our laboratory implied that ferroptosis might play an important role in ESCC metastasis. Ferroptosis was found to be a shared specific pathway between ESCC and adjacent non-tumor tissue, as well as between ESCC lymph node metastasis and adjacent non-tumor tissue, of which FTL was selected as the pivotal target gene within this common pathway. Bioinformatic analyses showed that FTL was highly expressed in both primary and metastatic sites than normal, and patients with high expression had poor prognosis, and its function was related to macrophages in TME. Functional studies have shown that FTL promoted tumor growth, tolerated oxidative stress, reduced the sensitivity of ESCC cells to ferroptosis, facilitated epithelial-mesenchymal transition (EMT) and recruited more macrophages to promote metastasis. Mechanism studies have shown that FTL promotes ESCC development and metastasis via NRF2 pathway and inhibits ferroptosis via NCOA4 protein. <i>In vivo</i> treatment, Brusatol, was found to inhibit FTL expression and have a significant inhibitory effect on ESCC growth and metastasis.
Authors
- Yanan Tan
- Jiao Huang (ORCID: https://orcid.org/0000-0002-6275-0451)
- Lanqi Gong (ORCID: https://orcid.org/0000-0002-1531-4948)
- Baifeng Zhang (ORCID: https://orcid.org/0000-0003-1966-2285)
- Xin‐Yuan Guan (ORCID: https://orcid.org/0000-0002-4485-6017)
- Xiaona Fang (ORCID: https://orcid.org/0000-0001-5325-4686)
- Yanru Qin (ORCID: https://orcid.org/0000-0001-7576-5129)
- Shuyue Zheng (ORCID: https://orcid.org/0000-0002-4805-0483)
- Yunzhi Liu (ORCID: https://orcid.org/0000-0001-6140-3522)
- Ching Ngar Wong (ORCID: https://orcid.org/0000-0002-5034-7067)
- Shan Liu (ORCID: https://orcid.org/0009-0008-6981-9731)
- Qingyun Chen (ORCID: https://orcid.org/0000-0001-6992-1447)
- Jie Luo (ORCID: https://orcid.org/0000-0002-2070-9151)
- Cuicui Huang
- Jinlin Huang (ORCID: https://orcid.org/0000-0003-1455-5966)
- Shanshan Li (ORCID: https://orcid.org/0000-0001-9704-7101)
- Yuma Yang
Institutions
- Sun Yat-sen University (CN)
- Jinan University (CN)
- Chinese University of Hong Kong (HK)
- ShanghaiTech University (CN)
- Ji Hua Laboratory (CN)
- Advanced Energy (United States) (US)
- Key Laboratory of Nuclear Radiation and Nuclear Energy Technology (CN)
- University of Hong Kong - Shenzhen Hospital (CN)
- Sun Yat-sen University Cancer Center (CN)
- First Affiliated Hospital of Zhengzhou University (CN)
- Shanghai Clinical Research Center (CN)
- Southern Medical University (CN)
- University of Hong Kong (HK)
Publication Details
- Journal
- International Journal of Biological Sciences
- Published
- 2025-10-16
- DOI
- https://doi.org/10.7150/ijbs.112017
- Primary Topic
- Ferroptosis and cancer prognosis
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Impact Fund
- National Natural Science Foundation of China