Celastrol suppresses hepatocellular carcinoma tumorigenesis by targeting NEU1 and disrupting the Wnt/β-catenin axis

Neuraminidase 1 (NEU1) is a sialidase removed terminal sialic acid residues from glycoproteins and glycolipids. Although aberrant NEU1 expression has been associated with hepatocellular carcinoma (HCC) progression, the underlying molecular mechanisms remain largely unknown. Celastrol, a bioactive compound with reported hepatoprotective properties, has shown anticancer potential; however, its mechanism of action in HCC remains unclear. In this study, we investigated whether celastrol exerts anti-HCC effects by NEU1 inhibition. Clinical relevance of NEU1 in HCC was assessed using TCGA and GEO datasets. Functional assays (CCK-8, migration/invasion) and a xenograft mouse model evaluated the role of NEU1 in tumorigenesis and celastrol therapeutic effects. RNA sequencing (RNA-seq) and KEGG pathway analysis identified NEU1-regulated signaling networks. Molecular docking and co-immunoprecipitation (Co-IP) validated NEU1-β-catenin interaction. TCGA and GEO datasets analysis demonstrated that EU1 expression was significantly elevated in HCC tissues and correlated with poor patient prognosis. NEU1 deficiency inhibited proliferation, migration, and invasion in liver cancer cells. NEU1 deletion or celastrol treatment significantly inhibited tumor growth in xenograft mouse models. RNA-seq analysis identified 638 differentially expressed genes following NEU1 knockdown in HepG2 cells, and KEGG enrichment analysis revealed significant suppression of the Wnt signaling pathway. Further mechanistic studies indicated that NEU1 interacts with β-catenin and may promote HCC progression through activation of the Wnt/β-catenin signaling axis. Molecular docking analysis predicted a strong interaction between celastrol and NEU1. Our findings demonstrate that celastrol suppresses HCC progression by inhibiting NEU1-mediated activation of the Wnt/β-catenin pathway, and provides mechanistic insights into the anti-tumor activity of celastrol in HCC.