{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T12:06:20Z","timestamp":1790251580059,"version":"4.1.0"},"reference-count":106,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T00:00:00Z","timestamp":1790208000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:p>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-\u03b3 (PPAR\u03b3) in triple-negative breast cancer (TNBC), whereas CPT1B contributes to leptin\u2013STAT3-driven stemness and is co-regulated with CPT1A following OVOL2 loss. Breast cancer stem-cell ferroptosis is independently constrained by DKK1\u2013SLC7A11, 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\u2013host metabolic interactions, normal-tissue toxicity and the absence of validated functional biomarkers. Resolving these issues will determine whether the CPT1A\u2013ferroptosis\u2013stemness axis can be translated from a mechanistic model into a therapeutic vulnerability.<\/jats:p>","DOI":"10.3389\/fonc.2026.1959579","type":"journal-article","created":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T11:15:42Z","timestamp":1790248542000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["CPT1A as a metabolic gatekeeper linking fatty acid oxidation, ferroptosis resistance, and breast cancer stemness"],"prefix":"10.3389","volume":"16","author":[{"given":"Feng","family":"Zeng","sequence":"first","affiliation":[{"name":"Thyroid and Breast Surgery, the Second Affiliated Hospital of Zunyi Medical University","place":["Zunyi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinghan","family":"Chen","sequence":"additional","affiliation":[{"name":"Thyroid and Breast Surgery, the Second Affiliated Hospital of Zunyi Medical University","place":["Zunyi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaiguo","family":"Long","sequence":"additional","affiliation":[{"name":"Thyroid and Breast Surgery, the Second Affiliated Hospital of Zunyi Medical University","place":["Zunyi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjun","family":"Yu","sequence":"additional","affiliation":[{"name":"Thyroid and Breast Surgery, the Second Affiliated Hospital of Zunyi Medical University","place":["Zunyi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhuai","family":"Cai","sequence":"additional","affiliation":[{"name":"Thyroid and Breast Surgery, the Second Affiliated Hospital of Zunyi Medical University","place":["Zunyi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yulan","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Affiliated 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