Beyond lipid-lowering effects: Challenges and insights in fenofibrate repurposing for oncology

Fenofibrate, a well-established peroxisome proliferator-activated receptor alpha (PPARα) agonist, is widely used clinically for managing hypercholesterolemia and hyperlipidemia. In recent years, its potential anti-tumor properties have garnered considerable attention. Accumulating evidence demonstrates that fenofibrate inhibits the growth of various malignancies, including breast, liver, prostate, and lung cancers, by modulating lipid metabolism, suppressing cancer cell proliferation, and inducing apoptosis. The anti-tumor mechanisms of fenofibrate involve both PPARα-dependent pathways through direct regulation of PPARα and associated lipid metabolic enzymes, and PPARα-independent pathways, such as inhibition of the Akt/mTOR, TNF-α/NF-κB, and Cx43/EGF/ERK1/2 signaling axes. Furthermore, fenofibrate exhibits synergistic effects with conventional chemotherapeutic agents (e.g., paclitaxel and docetaxel) by enhancing T-cell viability, activating immune responses, and thereby improving chemotherapy sensitivity. This review comprehensively summarizes the efficacy and underlying mechanisms of fenofibrate against diverse cancer types and discusses the potential applications and challenges associated with its repurposing for cancer therapy. A deeper understanding of fenofibrate's anti-cancer capabilities and molecular targets may provide novel insights for the development of innovative therapeutic strategies.