Breast cancer cells have an increased ferroptosis risk induced by system x−c blockade after deliberately downregulating CYTL1 to mediate malignancy

Sep 21, 2026

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Cytokine-like protein 1 (CYTL1) expression is deliberately downregulated during cancer progression, yet the metabolic logic behind this remains unclear in breast cancer. Metabolism comparisons show that low CYTL1 suppresses CBS-driven transsulfuration and decreases de novo cysteine synthesis. Mechanistically, CYTL1 activates Nrf2 via autophagic Keap1 degradation, promoting CBS transcription. Limited cysteine causes hypersensitivity to system x−c blockade-induced ferroptosis in vitro and in vivo. Silencing CBS reverses CYTL1-mediated ferroptosis resistance, highlighting a metabolic vulnerability.

LanguageEnglish

CategoryResearch & Report

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Pages12

Reading Time30 min

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Introduction

Cancer metabolism and therapeutic vulnerabilities

CYTL1 in cancer progression

Redox Biology 70 (2024) 103034 Contents lists available at ScienceDirect Redox Biology journal [homepage:](homepage: www.elsevier.com/locate/redox)[ www.elsevier.com/locate/redox](homepage: www.elsevier.com/locate/redox) | Breast cancer cells have an increased ferroptosis risk induced by system x−c blockade after deliberately downregulating CYTL1 to mediate malignancy
Wenwen Xuea, 1, Ying Yu a, 1, Yongzhong Yao b, 1, Lin Zhou a, Ying Huang a, Yixuan Wang a, Zhixiu Chena, Liwei Wang a, Xinran Lia, c, Xiaoning Wang a, Ronghui Dua, c, ***, Yan Shena, **, Qiang Xu a, *
a State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Drum Tower Hospital, School of Life Sciences, Nanjing University, Nanjing, China b Department of Breast Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing University, Nanjing, China c Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, China | | | | --- | --- | --- | | A R T I C L E I N F O | | A B S T R A C T | | Keywords:
CYTL1
Breast cancer Transsulfuration pathway CBS
Ferroptosis | | Cytokine-like protein 1 (CYTL1) expression is deliberately downregulated during the progression of multiple types of cancers, especially breast cancer. However, the metabolic characteristics of cancer progression remain unclear. Here, we uncovered a risk of breast cancer cells harboring low CYTL1 expression, which is metabolically controlled during malignant progression. We performed metabolism comparison and revealed that breast cancer cells with low CYTL1 expression have highly suppressed transsulfuration activity that is driven by cystathionine β-synthase (CBS) and contributes to de novo cysteine synthesis. Mechanistically, CYTL1 activated Nrf2 by promoting autophagic Keap1 degradation, and Nrf2 subsequently transactivated CBS expression. Due to the lack of cellular cysteine synthesis, breast cancer cells with low CYTL1 expression showed hypersensitivity to system x−c blockade-induced ferroptosis in vitro and in vivo. Silencing CBS counteracted CYTL1-mediated ferroptosis resistance. Our results show the importance of exogeneous cysteine in breast cancer cells with low CYTL1 expression and highlight a potential metabolic vulnerability to target. | 1. Introduction Alterations in cellular metabolism are hallmarks of cancer and support cancer cell proliferation and stress adaptation [1,2]. Understanding cancer-specific metabolism can provide new therapeutic options by targeting unique metabolic pathways. For instance, tumor-initiating cells are highly dependent on exogeneous methionine, and pharmacological inhibition of the methionine cycle is sufficient to cripple their tumor-initiating capability [3].“Glutamine addiction” is a characteristic of some Myc-expressing cancers, and they cannot be sustained in the absence of a glutamine source [4]. In addition, gene amplification of phosphoglycerate dehydrogenase (PHGDH, the first enzyme of theserine-glycine pathway) is observed in breast cancer and melanoma, and PHGDH inhibition causes a strong decrease in cell proliferation [5,6]. Thus, metabolic characteristics endow cancers with therapeutically exploitable vulnerabilities. Cytokine-like protein 1 (CYTL1) is a widely expressed and secreted protein [7]. Although the tertiary structure of the CYTL1 protein and its receptors remain unknown, increasing evidence suggests that CYTL1 is involved in the regulation of cartilage homeostasis, immunity and tumor progression [8–10]. Bioinformatics analysis based on the TCGA and GEO databases indicates a robust decrease in CYTL1 expression in multiple types of cancers, including breast, lung and prostate cancer [8,10,11]. DNA hypermethylation and/or a low copy number of cytl1 could account for low CYTL1 expression in cancers. Ectopic expression of CYTL1 in lung or breast cancer cells inhibits cell invasion and tumor metastasis in vivo [8]. Our previous study

FAQs

What is the central role of CYTL1 in this study of breast cancer?

CYTL1 is shown to be deliberately downregulated during breast cancer progression, and low CYTL1 expression is linked to distinct metabolic control that affects ferroptosis sensitivity.

How does low CYTL1 influence cysteine synthesis and transsulfuration?

Low CYTL1 suppresses CBS-driven transsulfuration activity, leading to highly reduced de novo cysteine synthesis.

What happens when breast cancer cells are treated with system x−c blockade?

Cells with low CYTL1 expression become hypersensitive to ferroptosis induced by system x−c blockade in both vitro and in vivo experiments.

Sep 21, 2026

Uploaded by Logic