Destabilization of lipoma-preferred partner by TGF-β-induced O-GlcNAcylation promotes hepatocellular carcinoma metastasis.

Metastatic dissemination drives the lethal progression of hepatocellular carcinoma (HCC). A comprehensive elucidation of the post-translational modifications involved in this process is anticipated to facilitate the development of more effective strategies for inhibiting tumor cell dissemination. Here, we identified the lipoma-preferred partner (LPP) as an unexpected metastasis suppressor that is specifically downregulated in HCC. Mechanistically, transforming growth factor-β1 (TGF-β1) stabilizes glutamine-fructose-6-phosphate aminotransferase 1 (GFAT1), the rate-limiting enzyme of the hexosamine biosynthetic pathway, thereby elevating global O-GlcNAcylation levels. O-GlcNAc transferase (OGT) subsequently modifies LPP protein at serine 33 and 35, priming its ubiquitination-dependent proteasomal degradation. This degradation, mediated by the ubiquitin-protein ligase E3A (UBE3A), occurs at lysine 108 (K108) of LPP, which facilitates HCC cell migration and invasion both in vitro and in vivo. Mutagenesis of these glycosylation sites markedly attenuates HCC cell motility, invasion, and pulmonary colonization in tail-vein models. Conversely, LPP depletion accelerates metastatic outgrowth and associates with reduced patient survival. Collectively, our findings reveal a TGF-β/GFAT1/LPP axis that couples metabolic reprogramming to metastatic competence, and highlight O-GlcNAcylation blockade or targeted stabilization of LPP as potential therapeutic strategies against metastatic HCC.