Nedd4 family interacting protein 1 (NDFIP1) is a novel target of PF-429242 in promoting autophagy in hepatocellular carcinoma cells

Our previous study demonstrates that PF-429242, an experimental membrane-bound transcription factor site-1 protease (MBTPS1) inhibitor, induces autophagy and exhibits potential anticancer activity in hepatocellular carcinoma (HCC) cells through mechanisms independent of its original target. However, the direct target of PF-429242 is still unclear. Using quantitative proteomics, cellular thermal shift assays, and gene/protein expression analyses, we show that PF-429242 stabilizes Nedd4 family interacting protein 1 (NDFIP1) protein and upregulates its expression at both transcriptional and post-transcriptional levels. Knockdown experiments and pathway analysis confirm that PF-429242-induced autophagy partially occurs via a NDFIP1-dependent pathway. Additionally, NDFIP1 overexpression correlates with improved progression-free survival in HCC patients, as revealed by TCGA and a Taiwanese cohort. In conclusion, this study further identifies NDFIP1 as a novel target of PF-429242, partially responsible for its induction of autophagy in HCC cells. These findings offer a promising therapeutic avenue for treating HCC.