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ORIGINAL RESEARCH ARTICLE

Unsaturated fatty acid metabolism and FADS2 as candidate factors in triple-negative breast cancer

Ying Chen1 ,  Yu-Hui Ma1 ,  Zhi-hui Hu1 ,  Qi Liu1 ,  Bin Song1* ,  He Hao1*
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1 Cancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital, Taiyuan, Shanxi , China
CP, 026340053 https://doi.org/10.36922/CP026340053
Received: 23 August 2026 | Revised: 27 September 2026 | Accepted: 10 October 2026 | Published online: 2 November 2026
© 2026 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

Triple-negative breast cancer (TNBC) is aggressive and lacks effective targeted therapies. Using estrogen receptor  (ER)-negative breast cancer as a proxy for TNBC, we explored circulating metabolite associations and downstream candidate genes. A two-sample Mendelian randomization (MR) analysis used large-scale metabolome genome-wide association study data (~1,400 metabolites). Candidate metabolites underwent Kyoto Encyclopedia of Genes and Genomes enrichment. Computationally predicted targets were intersected with common differentially expressed genes from three Gene Expression Omnibus datasets and Weighted Gene Co-expression Network Analysis modules. Least absolute shrinkage and selection operator-Cox and random survival forest prioritized genes in the Cancer Genome Atlas–TNBC. Single-cell RNA-seq (GSE176078) explored heterogeneity and pathways. MR identified 38 candidate metabolites nominally associated with ER-negative breast cancer risk, enriched in unsaturated fatty acid and arachidonic acid metabolism. Integration yielded 39 candidate genes, and survival-based machine learning prioritized KRAS, MGST3, FADS2, UGT8, IDO1, and SRC. Single-cell analysis showed higher FADS2 in a presumed malignant epithelial subpopulation (log2FC = 2.53, false discovery rate < 0.05), associated with cholesterol biosynthesis, sterol metabolism, and cell-cycle programs. These exploratory findings nominate abnormal circulating unsaturated fatty acid metabolism and FADS2 as candidate factors in ER-negative/TNBC biology. FADS2 is a candidate biomarker and potential target requiring TNBC-specific genetic, patient-aware single-cell, prognostic, and experimental validation.

Keywords
Triple negative breast cancer
Estrogen receptor-negative breast cancer proxy
Mendelian randomization
Unsaturated fatty acid metabolism
FADS2
Single cell transcriptomics
Exploratory computational analysis
Funding
This work was supported by the Shanxi Bethune Hospital Research Initiation Grant 2025RC001, Research Project Supported by Shanxi Scholarship Council of China 2025-224, and 2025 Sanjin Talents Program for Young Top-notch Talents in Medical and Health Field (Grant No. SJYC2025528).
Conflict of interest
The authors declare that they have no competing interests.
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Cancer Plus, Electronic ISSN: 2661-3840 Print ISSN: 2661-3832, Published by AccScience Publishing
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