Betaine induces ferroptotic stress by enhancing KEAP1-mediated NRF2 degradation in breast cancer cells
- Cell Signal. 2026 Oct:146:112664. doi: 10.1016/j.cellsig.2026.112664.
- 1. Department of Breast Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361001, PR China.
- 2. Department of Laboratory Medicine, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, PR China.
- 3. Department of Orthopedics, Harbin First Hospital, Heilongjiang 150010, PR China.
- 4. Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230001, PR China. Electronic address: [email protected].
- 5. Department of Pathology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361001, PR China. Electronic address: [email protected].
Background: Breast Cancer remains a leading cause of cancer-related mortality in women, largely due to therapeutic resistance. Ferroptosis, a regulated form of cell death driven by lipid peroxidation, represents a promising strategy to suppress tumor progression, yet its regulatory mechanisms in breast Cancer are not fully defined. This study aimed to investigate the anti-cancer effects of betaine (BET) and its potential involvement in Ferroptosis.
Methods: Network pharmacology, bioinformatics analyses of The Cancer Genome Atlas and Gene Expression Omnibus datasets, and molecular docking were used to identify potential BET targets and construct a BET-target-breast Cancer interaction network. Functional assays in MDA-MB-231 and MCF-7 cells evaluated proliferation, migration, oxidative stress, mitochondrial function, and Ferroptosis.
Results: BET treatment was associated with inhibition of cell proliferation, clonogenicity, and migration, while increasing Reactive Oxygen Species and lipid peroxidation. Mechanistically, BET enhanced Keap1-Nrf2 interaction, thereby increasing NRF2 ubiquitination and proteasomal degradation. Consequently, NRF2 nuclear accumulation was reduced, leading to suppression of downstream antioxidant and ferroptosis-protective targets, including xCT and GPX4. The resulting depletion of glutathione and accumulation of lipid peroxidation products promoted ferroptosis-associated cellular damage. BET also disrupted mitochondrial membrane potential and Oxidative Phosphorylation, further exacerbating oxidative stress. Notably, the KEAP1 R483S mutation or NRF2 overexpression partially rescued BET-induced oxidative stress and ferroptosis-associated phenotypes, supporting a role for enhanced KEAP1-dependent NRF2 turnover in mediating BET activity.
Conclusions: BET may promote ferroptosis-associated cell death and suppress breast Cancer cell malignant phenotypes, potentially through modulation of the KEAP1/NRF2/xCT/GPX4 pathway. These findings suggest a possible therapeutic relevance of BET in breast Cancer, although further validation in additional in vivo models and clinical studies is required.