Fatty Acid Oxidation in Cancer Metabolism

Fatty acid oxidation (FAO) has emerged as a pivotal metabolic pathway in the adaptation and progression of diverse malignancies. By catabolising long-chain fatty acids within mitochondria, FAO provides tumour cells with ATP, reducing equivalents and essential biosynthetic precursors, thereby supporting proliferation, survival under stress and metastatic dissemination. The enzyme carnitine palmitoyl transferase 1a (CPT1A) governs the rate-limiting step of mitochondrial FAO, controlling fatty acid import and coupling lipid catabolism to energy production. Dysregulation of FAO fosters metabolic plasticity, allowing cancer cells to shift between glycolysis and lipid oxidation in response to nutrient availability, therapy-induced stress or microenvironmental cues. FAO-derived acetyl-CoA influences epigenetic programmes and redox balance, while reactive oxygen species generated during FAO can activate adaptive transcriptional networks such as those driven by nuclear factor erythroid 2-related factor 2 (Nrf2). Moreover, FAO modulates the tumour immune microenvironment, influencing immune checkpoint expression and macrophage phagocytic activity. Together, these features underscore FAO as an integrative hub linking energy metabolism, epigenetic regulation and treatment resistance, and highlight FAO modulation as a promising axis for therapeutic intervention.

Research from Nature Portfolio

Recent studies have explored the therapeutic potential of targeting FAO to overcome resistance in diverse cancer types. In HER2-positive breast cancer models, genetic ablation of CPT1A delayed tumour initiation and metastasis, yet tumour cells adapted by increasing glucose uptake and activating Nrf2-mediated antioxidant pathways. Combined blockade of FAO with a ketogenic high-fat diet or anti-HER2 monoclonal antibody synergistically enhanced apoptosis, limited metastatic spread and reshaped the immune milieu towards antitumour inflammation. In glioblastoma, upregulation of FAO enzymes including CPT1A and CPT2 was linked to radioresistance and immune escape via induction of the immune-checkpoint receptor CD47. Inhibition of FAO, either pharmacologically or by CRISPR-mediated deletion of key FAO enzymes, reduced CD47 expression, enhanced macrophage-mediated phagocytosis and improved radiation control of recurrent tumours. These findings demonstrate that disrupting FAO not only impairs tumour bioenergetics but also restores immune surveillance to improve therapeutic outcomes.

Fatty Acid Oxidation in Cancer Metabolism publication trend

The graph below shows the total number of articles in fatty acid oxidation in cancer metabolism across all publications each year (not limited to Nature Index journals).

Technical terms

Fatty acid oxidation (FAO): Mitochondrial process of catabolising long-chain fatty acids to generate acetyl-CoA, NADH and FADH₂ for energy production.

Carnitine palmitoyl transferase 1a (CPT1A): Rate-limiting mitochondrial enzyme that transports long-chain fatty acids into mitochondria for β-oxidation.

Acetyl-CoA: Central metabolic intermediate that links FAO and glycolysis to the tricarboxylic acid cycle and serves as a substrate for histone acetylation.

Nuclear factor erythroid 2-related factor 2 (Nrf2): Transcription factor that regulates antioxidant response elements to maintain redox homeostasis.

CD47: Cell surface immune-checkpoint receptor that inhibits phagocytosis by macrophages when engaged by its ligand.

References

1. Targeting fatty acid oxidation enhances response to HER2-targeted therapy. Nature Communications (2024).
2. Fatty Acid Oxidation Supports Lymph Node Metastasis of Cervical Cancer via Acetyl‐CoA‐Mediated Stemness. Advanced Science (2024).
3. Hepatocyte-derived Igκ promotes HCC progression by stabilizing electron transfer flavoprotein subunit α to facilitate fatty acid β-oxidation. Journal of Experimental & Clinical Cancer Research (2024).
4. Fatty acid oxidation and carnitine palmitoyltransferase I: emerging therapeutic targets in cancer. Cell Death & Disease (2016).
5. The carnitine system and cancer metabolic plasticity. Cell Death & Disease (2018).
6. Fatty acid oxidation fuels glioblastoma radioresistance with CD47-mediated immune evasion. Nature Communications (2022).