Fenofibrate-induced mitochondrial dysfunction and metabolic reprogramming reversal: the anti-tumor effects in gastric...

Cancer cells reprogram their metabolism to adapt to fast growth and environmental demands, which differ them from normal cells. Mitochondria are central to the malignant metabolism reprogramming process. Here, we report that PPARα was highly expressed in gastric cancer tissues and negatively correlated with prognosis. Fenofibrate, a common drug used to treat severe hypertriglyceridemia and mixed dyslipidemia, reversed cellular metabolism and mitochondrial dysfunction in gastric cancer cells through PPARα. Our results show that fenofibrate altered glucose and lipid metabolism, inhibited gastric cancer cell proliferation, and promoted apoptosis in gastric cancer cells. We further show that fenofibrate induced mitochondrial reprogramming via CPT1 and the fatty acid oxidation pathway, as well as by activating the AMPK pathway and inhibiting the HK2 pathway. Additionally, fenofibrate inhibited subcutaneous gastric cancer cell tumor growth without obvious toxicity in mice. Collectively, our results indicate that fenofibrate exhibits anti-tumor activity in vitro and in vivo via the mitochondria and metabolic reprogramming, demonstrating that mitochondrial regulation and the normalization of cancer cell metabolism are novel therapeutic strategies for cancer.