# Targeting FTL regulates ferroptosis and remodels lymph node metastasis microenvironment in esophageal squamous cell carcinoma

## TL;DR

This study shows that targeting FTL, a gene linked to ferroptosis, can reduce esophageal cancer growth and metastasis by altering the tumor environment.

## Contribution

The paper identifies FTL as a key regulator of ferroptosis and metastasis in ESCC, and demonstrates its therapeutic potential using Brusatol.

## Key findings

- FTL is highly expressed in ESCC and linked to poor prognosis and macrophage activity in the tumor microenvironment.
- FTL promotes tumor growth, oxidative stress tolerance, and metastasis by activating the NRF2 pathway and inhibiting ferroptosis via NCOA4.
- Brusatol, an FTL inhibitor, significantly reduces ESCC growth and metastasis in vivo.

## Abstract

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. In vivo treatment, Brusatol, was found to inhibit FTL expression and have a significant inhibitory effect on ESCC growth and metastasis.