ArticleBreast cancer research : BCR2025
CPT1A/HIF-1α positive feedback loop induced fatty acid oxidation metabolic pathway contributes to the L-ascorbic acid-driven angiogenesis in breast cancer.
Article in Breast cancer research : BCR, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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6 citing papers in PubMed.
- Single-cell and spatial transcriptomics map lung-adaptive metastasis programs through Exoc4, Cd36-vasculogenic mimicry, and Cxcr2 signaling in triple-negative breast cancer.Cell death & disease · 2026Article
- Hypoxia and lactate metabolism-related gene COL5A3 promotes triple negative breast cancer progression via DDR1/FAK/PI3K/AKT pathway.Biology direct · 2026Article
- Metabolic reprogramming in cancer: dysregulation of glucose, lipid, and amino acid pathways and therapeutic opportunities.Molecular biomedicine · 2026Review
- Dynamic Metabolic States in TNBC: Orchestrating Spatiotemporal Adaptation and Therapy.Oncology research · 2026Review
- CPT1A facilitated ferroptosis by forming feedback loop with Nrf2 via PI3K/AKT pathway in colorectal cancer.Apoptosis : an international journal on programmed cell death · 2025Article
- A lipid metabolism-related gene signature for risk stratification and prognosis prediction in patients with breast cancer.Scientific reports · 2025Article
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Abstract
backgroundIn tumors rich in adipose tissue, angiogenesis is a critical factor in promoting cancer cell metastasis. However, the connection between angiogenesis and the mechanisms driving adipose metabolic remodeling in breast cancer (BC) remains insufficiently understood. This research seeks to explore whether and how CPT1A, a crucial rate-limiting enzyme in fatty acid oxidation (FAO), supports angiogenesis through metabolic pathways in BC.
methodsFirst, cell functional assays and animal models were employed to elucidate the pro-carcinogenic effects of CPT1A on BC and its role in metabolic alterations. Following this, the reciprocal regulatory relationship between CPT1A and HIF-1α was elucidated using transcriptomic studies, ubiquitination analysis, and dual-luciferase assays. Matrigel tube formation assays, vasculogenic mimicry assays, and chick chorioallantoic membrane (CAM) assays were utilized to evaluate the effect of CPT1A on the pro-angiogenic properties of BC. Subsequently, untargeted metabolomics was employed to identify specific metabolic changes in supernatants with and without CPT1A expression and verified by functional recovery experiments. Finally, the prognostic significance of CPT1A and the vascular marker VEGF in BC tissues was evaluated using tissue microarrays and public databases.
resultsCPT1A overexpression significantly enhanced cell proliferation, motility, and angiogenesis via activating the FAO metabolic pathway, as demonstrated by both in vivo and in vitro experiments. Mechanistically, CPT1A regulates the ubiquitination level of hypoxia-inducible factor-1α (HIF-1α), which directly binds to the CPT1A promoter. Mutations at the 63-74 and 434-445 regions significantly reduced CPT1A promoter activity, indicating that these sites are critical for its transcriptional regulation. Ultimately, this interaction creates a reinforcing feedback loop between CPT1A and HIF-1α. Subsequently, this feedback loop alters changes in extracellular L-ascorbic acid (LAA) levels. Interestingly, LAA affects ROS homeostasis through the Nrf2/NQO1 pathway, specifically influencing angiogenesis in BC and HUVECs, while having no significant effect on their proliferation or EMT process. Moreover, increased expression levels of CPT1A and vascular endothelial growth factor (VEGF) were significantly associated with lymph node metastasis and adverse outcomes in BC patients.
conclusionThe CPT1A/HIF-1α positive feedback loop critically regulates angiogenesis through activation of the Nrf2/NQO1 pathway, modulated by LAA. These findings highlight CPT1A and VEGF as promising therapeutic targets and prognostic biomarkers for angiogenesis in BC.
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