High Fat Diet-Induced PPARα Suppression Disrupts Mitochondrial Bioenergetics and Fuels ROS-NF-κB-driven Colorectal Tumorigenesis

Here, we integrated epidemiological analysis of the National Health and Nutrition Examination Survey (NHANES), multi-omics Mendelian randomization (MR), a murine colitis-related cancer model, and human colonic epithelial cells to investigate the role of the lipid sensor peroxisome proliferator-activated receptor α (PPARα) in HFD-associated CRC.

Self-reported high-fat dietary behavior was associated with increased CRC risk (OR = 2.43, 95% CI 1.08–5.49, P = 0.033), and MR analyses indicated that genetically predicted PPARα levels were negatively associated with CRC risk. In both human transcriptomes and HFD-fed mice, HFD suppressed colonic PPARα and its fatty-acid oxidation network, impairing oxidative phosphorylation, depolarizing the mitochondrial membrane potential, and driving excessive mitochondrial reactive oxygen species (ROS) that hyperactivated NF-κB signaling.