Fatty acid desaturase 1 drives esophageal cancer via M1 macrophage ferroptosis and lipid metabolism remodeling

doi:10.4251/wjgo.124110

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World Journal of Gastrointestinal Oncology

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1948-5204

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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

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Copyright: ©Author(s) 2026. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution-NonCommercial (CC BY-NC 4.0) license. No commercial re-use. See permissions. Published by Baishideng Publishing Group Inc.

World J Gastrointest Oncol. Nov 15, 2026; 18(11): 124110
Published online Nov 15, 2026. doi: 10.4251/wjgo.124110

Fatty acid desaturase 1 drives esophageal cancer via M1 macrophage ferroptosis and lipid metabolism remodeling

Qian-Cheng Du, Yu Bai, De-Hua Zhou, Hua Yu, Hui Nian

Qian-Cheng Du, Hui Nian, Department of Thoracic Surgery, Shanghai Xuhui Central Hospital, Shanghai 200031, China

Yu Bai, Intensive Care Unit, Shanghai Xuhui Central Hospital, Shanghai 200031, China

De-Hua Zhou, Department of Gastrointestinal Surgery, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai 200434, China

Hua Yu, Department of Plastic Surgery, Shanghai Baoshan District Wusong Central Hospital, Shanghai 200940, China

Co-corresponding authors: Hua Yu and Hui Nian.

Author contributions: Du QC, Yu H, and Nian H contributed to writing the original draft; Du QC, Zhou DH, Yu H, and Nian H contributed to conceptualization; Du QC, Bai Y, Yu H, and Nian H contributed to investigation and validation; Du QC contributed to methodology; Bai Y, Yu H, and Nian H contributed to formal analysis; Zhou DH, Yu H, and Nian H contributed to writing - review and editing; Yu H and Nian H contributed to software, visualization, supervision, project administration, resources, and they contributed equally to this manuscript as co-corresponding authors. All the authors approved the final manuscript.

AI contribution statement: No artificial intelligence tools were utilized in the drafting, analysis, figure generation or revision of this manuscript.

Institutional review board statement: The protocol for the use of human tissue samples in this study was reviewed and approved by the Ethics Committee of Shanghai Xuhui Central Hospital, approval No. (2022) prereview (060) 001.

Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.

Data sharing statement: The data that support the findings of this study are available from the corresponding authors upon reasonable request.

Corresponding author: Hui Nian, MD, Department of Thoracic Surgery, Shanghai Xuhui Central Hospital, No. 366 Longchuan North Road, Xuhui District, Shanghai 200031, China. hnian14@fudan.edu.cn

Received: June 8, 2026
Revised: July 14, 2026
Accepted: August 28, 2026
Published online: November 15, 2026
Processing time: 141 Days and 3.9 Hours

Abstract

BACKGROUND

Esophageal cancer is a major health challenge with a poor prognosis. The tumor microenvironment, particularly the role of immune cells such as macrophages, is critical in cancer progression. The lipid metabolism enzyme fatty acid desaturase 1 (FADS1) is involved in various cancers, but its specific function in the immune regulation of esophageal cancer is unclear.

AIM

To explore whether FADS1 promotes esophageal cancer progression by remodeling the phospholipid metabolism, facilitating lipid raft assembly and triggering ferroptosis in M1 macrophages.

METHODS

We conducted a bidirectional Mendelian randomization study to identify ferroptosis-related genes linked to esophageal cancer susceptibility. Comprehensive bioinformatics analyses were performed using public transcriptomic and single-cell RNA sequencing datasets. Protein localization was examined via immunofluorescence in clinical specimens. Laboratory experiments involved the genetic manipulation of Tamm-Horsfall protein-1-derived M1 macrophages, measurement of lipid oxidation products, coculture assays, phospholipid supplementation, and disruption of lipid rafts. Virtual gene knockout and artificial intelligence-guided drug screening were also employed.

RESULTS

FADS1 was identified as a causal factor for esophageal cancer development and was overexpressed in tumor tissues, particularly in M1-polarized macrophages. Genetic inhibition of FADS1 expression in M1 macrophages reduced lipid peroxidation and ferroptosis, enhancing their cancer-killing ability in coculture with esophageal cancer cells. Mechanistically, FADS1 promoted the accumulation of 1-palmitoyl-2-stearoyl- glycerophosphocholine (16:0/18:0), which facilitated lipid raft assembly and triggered ferroptosis in M1 macrophages. Computational analysis revealed an immune-related gene network controlled by FADS1. The compound BRD-K95779464 was identified as a promising FADS1 inhibitor.

CONCLUSION

FADS1 promotes esophageal cancer progression by reprogramming the phospholipid metabolism to assemble lipid rafts, which triggers ferroptosis in M1 macrophages. This study identifies FADS1 as a potential therapeutic target for esophageal cancer immunotherapy.

Keywords: Fatty acid desaturase 1; Esophageal cancer; Ferroptosis; Phospholipid metabolism; Lipid raft

Core Tip: Esophageal cancer patients have a poor prognosis with unclear immunometabolic mechanisms. Fatty acid desaturase 1 (FADS1), a key lipid metabolism enzyme, is linked to multiple cancers, but its role in esophageal cancer immunity is unknown. In this study, FADS1, which is overexpressed in tumor-infiltrating M1 macrophages, was identified as a causal factor for esophageal cancer. Mechanistically, FADS1 accumulates 1-palmitoyl-2-stearoyl-glycerophosphocholine, promotes lipid raft assembly, and triggers ferroptosis in M1 macrophages, impairing their antitumor function. Inhibiting FADS1 expression suppressed ferroptosis and restored M1 macrophage activity. The FADS1 inhibitor BRD-K95779464 was identified by artificial intelligence screening. This work reveals a novel FADS1-mediated immunometabolic pathway in esophageal cancer.