ADAM12 Stabilizes EIF3B to Promote Glycolysis and Tumor Progression in Hepatocellular Carcinoma

Background: Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with poor prognosis and limited therapeutic options. A disintegrin and metalloproteinase 12 (ADAM12) is aberrantly expressed in multiple cancers and has been implicated in tumor progression. However, its biological role and underlying mechanism in HCC remain unclear. Methods: Public HCC datasets and bioinformatics analyses were used to evaluate ADAM12 expression and its clinical significance. The effects of ADAM12 on HCC cell viability, colony formation, migration, invasion, and apoptosis were assessed in vitro, and its role in tumor growth was examined in a xenograft model. The underlying mechanism was investigated by immunoprecipitation-mass spectrometry, co-immunoprecipitation, cycloheximide chase, ubiquitination, and metabolic assays. Results: ADAM12 was significantly upregulated in HCC tissues and was associated with unfavorable overall survival. ADAM12 knockdown inhibited cell viability, colony formation, migration, and invasion, promoted apoptosis in vitro, and suppressed xenograft tumor growth in vivo without obvious body weight loss. Mechanistically, EIF3B was identified as an ADAM12-interacting protein. ADAM12 knockdown decreased EIF3B protein abundance without affecting its mRNA level, accelerated EIF3B degradation, and increased its ubiquitination, indicating that ADAM12 stabilizes EIF3B by limiting ubiquitin–proteasome-mediated degradation. Moreover, ADAM12 depletion reduced PKM2 and LDHA expression, decreased extracellular acidification rate, lactate production, and glucose uptake, and increased oxygen consumption rate, indicating a shift from glycolysis toward oxidative phosphorylation. These effects were largely rescued by EIF3B overexpression or PKM2 restoration. Conclusion: ADAM12 promotes glycolytic reprogramming and tumor progression in HCC by stabilizing EIF3B and regulating the EIF3B/PKM2 axis. The ADAM12–EIF3B pathway may therefore represent a potential therapeutic target in HCC. Diagram showing ADAM12 and EIF3B interaction affecting tumor progression and suppression via stabilization and ubiquitination. Keywords: hepatocellular carcinoma, A disintegrin and metalloproteinase 12, eukaryotic translation initiation factor 3B, glycolysis inhibition, cancer therapy