bims-merabr 2026-10-11 papers

Front Oncol. 2026 ;16 1959579

CPT1A as a metabolic gatekeeper linking fatty acid oxidation, ferroptosis resistance, and breast cancer stemness.

Feng Zeng, Xinghan Chen, Kaiguo Long, Benjun Yu, Yuhuai Cai, Yulan Cai, Chuyu Liu.

Breast cancer stem-like cells sustain residual disease, metastatic recurrence and resistance to systemic and local therapies. Their defining metabolic feature is not a fixed preference for glycolysis or oxidative phosphorylation, but the capacity to reallocate substrates while preserving energy and redox homeostasis. Carnitine palmitoyltransferase 1A (CPT1A), which controls mitochondrial entry of long-chain fatty acids, is increasingly linked to breast cancer stemness, metastatic competence, radioresistance and endocrine resistance. Ferroptosis creates a complementary therapeutic opportunity because stem-like cells depend on tightly regulated iron, phospholipid and antioxidant metabolism. Yet the direct relationship between CPT1A and ferroptosis in breast cancer stem cells remains incompletely resolved. Here, we distinguish direct causal evidence in breast cancer from pathway-level observations and cross-cancer mechanisms, and propose that CPT1A functions as a context-dependent metabolic gatekeeper. By allocating long-chain fatty acids among mitochondrial oxidation, neutral-lipid storage and peroxidation-prone membrane phospholipids, CPT1A may coordinate adenosine triphosphate (ATP) supply, redox buffering, phenotypic plasticity and the ferroptosis threshold. Direct breast cancer evidence links CPT1A to stemness in miR-328-3p-regulated, luminal and radiation-selected models, and to ferroptosis resistance downstream of peroxisome proliferator-activated receptor-γ (PPARγ) in triple-negative breast cancer (TNBC), whereas CPT1B contributes to leptin-STAT3-driven stemness and is co-regulated with CPT1A following OVOL2 loss. Breast cancer stem-cell ferroptosis is independently constrained by DKK1-SLC7A11, ZMYND8-dependent activation of nuclear factor erythroid 2-related factor 2 (NRF2), lysosomal iron handling and hypoxia-adapted cysteine metabolism. We integrate these findings into a subtype- and treatment-aware framework for combining CPT1A inhibition with ferroptosis induction. Critical barriers include CPT1 isoform specificity, pharmacological off-target effects, tumor-host metabolic interactions, normal-tissue toxicity and the absence of validated functional biomarkers. Resolving these issues will determine whether the CPT1A-ferroptosis-stemness axis can be translated from a mechanistic model into a therapeutic vulnerability.

Keywords: CPT1a; breast cancer; breast cancer stem cells; fatty acid oxidation; ferroptosis; lipid peroxidation; metabolic plasticity; therapy resistance

DOI: https://doi.org/10.3389/fonc.2026.1959579

Biochim Biophys Acta Rev Cancer. 2026 Oct 05. pii: S0304-419X(26)00205-2. [Epub ahead of print]1881(6): 189733

Metabolic reprogramming and plasticity in breast Cancer: Mechanisms driving tumor progression, metastasis, and therapeutic resistance.

Jie Yuan, Hua Zhang, Jun Huang, Bei Wang, Minghua Wang, Li Yang.

Breast cancer remains the most frequently diagnosed malignancy and a leading cause of cancer-related mortality among women worldwide. Despite substantial advances in endocrine therapy, human epidermal growth factor receptor 2 (HER2)-targeted therapy, chemotherapy, and immunotherapy, therapeutic resistance and metastatic progression remain major clinical challenges. Accumulating evidence has established metabolic reprogramming as a fundamental hallmark of breast cancer, enabling tumor cells to adapt dynamically to nutrient limitation, hypoxia, oxidative stress, and therapeutic pressure. Beyond the classical Warburg effect, breast cancer cells exhibit remarkable metabolic plasticity through coordinated reprogramming of glycolysis, oxidative phosphorylation (OXPHOS), glutamine metabolism, lipid metabolism, and one‑carbon metabolism. These metabolic alterations not only sustain bioenergetic and biosynthetic demands but also reshape the tumor microenvironment (TME), promote immune evasion, maintain cancer stemness, and facilitate metastatic dissemination. Recent studies further reveal that metabolic heterogeneity varies substantially across molecular subtypes, metastatic niches, and treatment-resistant cell populations. In parallel, stromal cells, cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), and immune cells establish complex metabolic symbiotic relationships with tumor cells through metabolite exchange and immunometabolic regulation. Importantly, therapy-induced metabolic adaptation has emerged as a central mechanism underlying resistance to chemotherapy, endocrine therapy, HER2-targeted therapy, CDK4/6 inhibitors, and immune checkpoint blockade. In this review, we comprehensively summarize the molecular mechanisms governing metabolic reprogramming and metabolic plasticity in breast cancer, with particular emphasis on how they contribute to tumor progression, metastasis, immune escape, and therapeutic resistance. We further discuss emerging therapeutic strategies targeting glycolysis, mitochondrial metabolism, glutamine utilization, lipid metabolism, ferroptosis-associated pathways, and immunometabolic vulnerabilities. Finally, we highlight current challenges in clinical translation, including metabolic heterogeneity, compensatory pathway activation, and limited therapeutic selectivity, and outline future directions that integrate multi-omics profiling, spatial metabolomics, and precision metabolic targeting for individualized breast cancer therapy.

Keywords: Breast cancer; Cancer stem cells; Ferroptosis; Immunometabolism; Lipid metabolism; Metabolic plasticity; Metabolic reprogramming; Oxidative phosphorylation; Therapeutic resistance; Tumor microenvironment

DOI: https://doi.org/10.1016/j.bbcan.2026.189733

Breast Cancer (Dove Med Press). 2026 ;18 619042

Pharmacological Myristoylation Inhibition by Zelenirstat Disrupts Growth Signalling, Energy Metabolism, and Migration in Triple-Negative Breast Cancer Cells.

Rony Pain, Erwan Beauchamp, Shawn Duckett, Morris A Kostiuk, Claudia Y Acevedo-Morantes, Heather Mast, Helene Lemieux, Luc G Berthiaume.

Background: Metastatic breast cancer cells rely on oxidative phosphorylation (OXPHOS) for energy production, yet selectively targeting mitochondrial metabolism in cancer cells remains a major therapeutic challenge. Myristoylation, the modification of proteins with the 14-carbon fatty acid myristate by N-myristoyltransferases NMT1 and NMT2, dually impacts cancer cell signalling and metabolism. The pan-NMT inhibitor zelenirstat selectively inhibits these enzymes to prevent the myristoylation of target proteins.
Methods: We assessed the effects of zelenirstat on the protein levels and metabolic activity of multiple triple-negative breast cancer (TNBC) cell lines. NDUFAF4 knockout (KO) MDA-MB-231 cells were engineered using CRISPR/Cas9. Functional assays included multiple types of respirometry, cell migration measurements, and spheroid formation.
Results: Zelenirstat treatment depleted myristoylated complex I assembly factor NDUFAF4 levels in four different TNBC cell lines. This loss effectively abrogated mitochondrial OXPHOS through impairment of complex I, resulting in reduced cellular energy production. Zelenirstat treatment resulted in NADH accumulation, loss of AMPK, and decreased glycolysis. Given that zelenirstat impacted cell signalling and OXPHOS, we further demonstrated that it also significantly impaired migration and invasion. Importantly, both zelenirstat treatment and NDUFAF4 KO TNBC MDA-MB-231 cells dramatically reduced mammosphere formation, indicating potent activity against breast cancer stem cells (BCSCs).
Conclusion: In addition to the previously shown inhibitory effect of zelenirstat on TNBC cell growth in vitro and in vivo, our new data demonstrate the widespread effects of zelenirstat on both aggressive TNBC cells and BCSCs. These findings highlight the potential of zelenirstat as an anti-metastatic agent, warranting further clinical trial evaluation in patients with TNBC.

Keywords: OXPHOS; TNBC; cancer metabolism; cancer stem cells; myristoylation; zelenirstat

DOI: https://doi.org/10.2147/BCTT.S619042