Secoiridoid-enriched extra virgin olive oil extracts enhance mitochondrial activity and antioxidant response in colorectal cancer cells: The role of Oleacein and Oleocanthal in PPARγ interaction.

The secoiridoid-enriched fraction of extra virgin olive oil (EVOO) provides significant health benefits, but its underlying mechanisms have not been fully elucidated. To investigate this, we analyzed the transcriptome of HCT116 colorectal cancer cells treated with secoiridoid-enriched EVOO extracts using bioinformatic tools and identified differentially expressed genes enriched in mitochondrial pathways. In vitro validation showed increased mitochondrial mass and DNA driven by enhanced biogenesis and fusion events, accompanied by higher mitochondrial respiration and ATP production. The resulting increase in reactive oxygen species (ROS) triggered a cellular response involving AMPK, NRF2, and antioxidant genes, along with PGC-1α, a master regulator of mitochondrial metabolism. To correlate the biological effects with the components of the secoiridoid-enriched EVOO extracts, we focused on Oleacein (OL) and Oleocanthal (OC). Molecular docking and dynamics simulations predicted both compounds bind to peroxisome proliferator-activated receptor gamma (PPARγ) as partial agonists, with OL exhibiting stronger affinity. Treatments with isolated OL and OC mostly replicated the results of the whole extracts. Mechanistically, we provided evidence of the crucial role played by PPARγ as the effects on the pathways analyzed were reduced by either blocking the receptor with an irreversible inhibitor and silencing the PPARG gene with specific siRNAs. This study reveals the AMPK-PGC-1α-PPARγ axis as a key regulator of OL and OC's effects on mitochondrial function and antioxidant response, supporting their potential as nutraceuticals for health promotion and opening avenues for developing novel PPARγ modulators to complement existing therapeutic strategies.