Fenofibrate-Mediated Modulation of Cancer Cell Metabolism

Fenofibrate, a clinically approved lipid-lowering agent, has emerged as a modulator of energy pathways in diverse cancer types. By engaging peroxisome proliferator-activated receptor alpha (PPARα), fenofibrate shifts cellular fuel usage from glycolysis towards fatty acid β-oxidation, imposing a metabolic bottleneck on rapidly proliferating cells. In parallel, the compound disrupts key glycolytic enzymes and alters mitochondrial function, leading to reduced ATP production, elevated reactive oxygen species and induction of programmed cell death. Beyond its PPARα-dependent actions, fenofibrate can engage stress-response pathways such as NF-κB and mitochondrial permeability transition, triggering apoptosis and necroptosis across tumour models. This multifaceted reprogramming of lipid and glucose metabolism not only suppresses primary tumour growth but also sensitises drug-resistant cells to conventional chemotherapeutics. Collectively, preclinical research highlights fenofibrate’s capacity to exploit metabolic vulnerabilities, offering a potential adjunctive approach in oncology that combines low systemic toxicity with profound effects on cancer cell energetics.

Research from Nature Portfolio

In a foundational study, fenofibrate was shown to bind the thioesterase domain of fatty acid synthase in human hepatoma Hep3B cells, mimicking the action of established enzyme inhibitors. This interaction curtailed lipid synthesis, precipitating both apoptosis and necroptosis through coordinated regulation of Bcl-2 family proteins and RIP kinases. Concomitant S and G2/M cell-cycle arrest was achieved via down-regulation of cyclin D1 and E, alongside modulation of cyclin A/Cdk2 complexes. The work underscores lipid metabolism as a critical target for fenofibrate’s antitumour effect and establishes a mechanistic basis for its repurposing in liver cancer therapy.

Fenofibrate-Mediated Modulation of Cancer Cell Metabolism publication trend

The graph below shows the total number of articles in fenofibrate-mediated modulation of cancer cell metabolism across all publications each year (not limited to Nature Index journals).

Technical terms

PPARα: A nuclear receptor that governs expression of genes involved in fatty acid uptake and oxidation.

Fatty acid β-oxidation: The mitochondrial pathway that breaks down fatty acids to generate acetyl-CoA and ATP.

Glycolysis: Cytosolic cascade converting glucose into pyruvate, often up-regulated in cancer cells.

Oxidative phosphorylation: Mitochondrial process coupling electron transport to ATP synthesis.

Apoptosis: Programmed cell death characterised by caspase activation and DNA fragmentation.

Necroptosis: A regulated form of necrosis mediated by receptor-interacting protein kinases.

References

1. PPARα modulates gene expression profiles of mitochondrial energy metabolism in oral tumorigenesis. BioMedicine (2016).
2. Fenofibrate induces apoptosis of triple-negative breast cancer cells via activation of NF-κB pathway. BMC Cancer (2014).
3. NF-κB/RelA-PKM2 mediates inhibition of glycolysis by fenofibrate in glioblastoma cells. Oncotarget (2015).
4. Fenofibrate induces human hepatoma Hep3B cells apoptosis and necroptosis through inhibition of thioesterase domain of fatty acid synthase. Scientific Reports (2019).
5. Fenofibrate Augments the Sensitivity of Drug-Resistant Prostate Cancer Cells to Docetaxel. Cancers (2019).