FBXW8-mediated degradation of PPT1 suppresses epithelial-mesenchymal transition and metastasis in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality, characterized by its aggressive growth, high metastatic potential, and resistance to therapeutic interventions. Dysregulation of the ubiquitin-proteasome system (UPS) is recognized as a hallmark of cancer; however, its precise functional contributions to HCC pathogenesis remain incompletely elucidated. In the present study, we identify F-box and WD repeat domain-containing 8 (FBXW8), an F-box protein component of the Cullin-RING ligase (CRL) complex, as a pivotal tumor suppressor in HCC. Through a combination of in vitro and in vivo models, we demonstrate that FBXW8 depletion facilitates HCC cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT), whereas FBXW8 overexpression exerts inhibitory effects on these malignant phenotypes. Proteomic and mechanistic analyses reveal that FBXW8 targets palmitoyl-protein thioesterase 1 (PPT1), a lysosomal hydrolase, for ubiquitination and subsequent proteasomal degradation. Elevated PPT1 expression correlates with poor clinical prognosis in HCC patients and is positively associated with the activation of EMT and oncogenic signaling pathways. Our data further reveal that PPT1 promotes EMT in part by enhancing the expression of critical EMT transcription factors, notably Snail Family Transcriptional Repressor 1 (SNAIL) and Zinc Finger E-box Binding Homeobox 1 (ZEB1), with a more pronounced effect on SNAIL. Mechanistically, FBXW8-mediated degradation of PPT1 inhibits EMT, reducing metastatic potential, whereas PPT1 silencing reverses the tumor-promoting effects of FBXW8 loss. These findings establish the FBXW8-PPT1 axis as a pivotal regulatory pathway linking UPS-mediated proteostasis to HCC progression and metastasis. Our study highlights the therapeutic potential of targeting PPT1 or restoring FBXW8 activity to disrupt oncogenic signaling and improve outcomes in HCC patients.