Fenofibrate-mediated inhibition of tumor proliferation and progression by modulating the PTPN14/MARK/Hippo signaling axis

PTPN14 is a non-receptor tyrosine phosphatase that functions as a tumor suppressor through negative regulation of the Hippo signaling pathway, making it a potential therapeutic target for cancer. Despite its therapeutic potential, no PTPN14-targeting small-molecules have been developed to date. In this study, we discovered fenofibrate (FF), a small-molecule commonly used as a lipid-lowering agent, exhibits potent anti-proliferative and anti-migratory properties. Mechanistically, FF was found to directly bind the PPEY motif of PTPN14, facilitating formation of a complex with LATS1 and MARK3, which promotes cytoplasmic sequestration of YAP. Furthermore, genetic knockdown of PTPN14 or pharmacological inhibition of MARK3 substantially abolished the FF-mediated inhibition of malignant phenotypes, indicating the critical role of the PTPN14/MARK3/Hippo signaling axis in tumor progression. Notably, our data provide evidence for the potential of FF to sensitize the efficacy of conventional chemotherapeutics across melanoma, colorectal and ovarian carcinoma models. In conclusion, our results demonstrate that PTPN14 is a promising target for drug development in treating melanoma. These findings broaden our understanding of FF beyond its conventional functions, presenting a promising novel therapeutic strategy for treating melanoma.