BACKGROUND: Previous studies have identified the long non-coding RNA (lncRNA) Uc002kfo as significantly upregulated in hepatocellular carcinoma (HCC) tissues, particularly in advanced stages, compared to adjacent non-cancerous tissues. This study aims to further explore the molecular mechanisms by which Uc002kfo promotes HCC metastasis, focusing on its regulation of α-SMA expression. METHODS: The study investigate the effects of Uc002kfo on proliferation, migration, and invasion in HCC cells using in vitro assays. Additionally, we also explored the molecular mechanism by which Uc002kfo indirectly regulates α-SMA gene transcription through its targeting of Sp1. Finally, we conducted preliminary validation in mice model to assess the potential for Uc002kfo-targeted silencing to inhibit HCC cell invasion and metastasis. RESULTS: The results of the study demonstrate that the Uc002kfo/Sp1/α-SMA pathway plays a role in regulating HCC metastasis. Uc002kfo inhibits the degradation of Sp1 protein, thereby promoting Sp1 binding to the α-SMA promoter and enhancing its transcription. Consequently, silencing Uc002kfo can indirectly suppress α-SMA expression, effectively inhibiting HCC cell proliferation, invasion, and migration in vitro, as well as liver metastasis in mice through the spleen. CONCLUSION: Uc002kfo plays a critical role in promoting HCC metastasis, making it a potential a promising therapeutic target for inhibiting tumor progression and metastasis in HCC.