高尔基蛋白73（GP73）在肝细胞癌（HCC）中高表达，并且作为一种分泌蛋白，被提议作为指示HCC进展的血清生物标志物。GP73促进HCC转移的潜在机制仍不清楚。在本研究中，我们发现GP73与波形蛋白相互作用，促进丝氨酸/苏氨酸蛋白磷酸酶PP1-alpha（PP1A）介导的波形蛋白S56位点的去磷酸化，并促进波形蛋白的聚合，通过TRIM56介导的波形蛋白泛素/蛋白酶体依赖途径阻断波形蛋白的降解。令人惊讶的是，氯美普兰，一种治疗抑郁症的5-羟色胺受体（5-HTR）激动剂，抑制了GP73介导的波形蛋白聚合，从而有效抑制了高GP73表达的HCC的转移，这提供了一种对抗HCC转移的新策略。最后，发现血清GP73（sGP73）与HCC原发组织中的波形蛋白呈正相关，表明sGP73可能作为HCC伴随诊断的潜在血清生物标志物。总之，本研究揭示了GP73介导的波形蛋白聚合的过程，并证明氯美普兰作为一种针对波形蛋白的潜在药物，可用于具有高sGP73水平的转移性HCC患者。© 作者。

Golgi-protein 73 (GP73) is highly expressed in hepatocellular carcinoma (HCC) and, as a secretory protein, it has been proposed as a serum biomarker indicating progression of HCC. The underlying mechanism by which GP73 may promote HCC metastasis is still poorly understood. In this study, we discovered that GP73 interacted with vimentin to facilitate Serine/Threonine-protein phosphatase PP1-alpha (PP1A)-mediated dephosphorylation of vimentin at S56 and facilitated vimentin polymerization, which blocked vimentin degradation via TRIM56-mediated ubiquitin/proteasome-dependent pathway. Strikingly, Clomipramine, a 5-hydroxytryptamine receptor (5-HTR) agonist approved for the treatment of depression, impaired GP73-mediated vimentin polymerization to effectively inhibit metastasis of HCC with high GP73 expression, which provided a new strategy against HCC metastasis. Lastly, it was found that serum GP73 (sGP73) correlated positively with vimentin in primary tissues of HCC, suggesting that sGP73 might serve as a potential serum biomarker for companion diagnosis of HCC with highly expressed vimentin. In summary, this study reveals the process of GP73-mediated vimentin polymerization and proves that Clomipramine serves as a potential drug targeting vimentin for metastatic HCC patients with high sGP73 level.© The author(s).