Fedratinib treatment correlates with suppressed STAT3/AKT/calpain-1 signaling and inhibits hepatocellular carcinoma progression.

Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death, and effective targeted therapies remain limited. Fedratinib, a clinically approved JAK2 inhibitor, has shown antitumor activity in hematologic malignancies, however, its role in HCC remains unclear. This study aimed to investigate the antitumor effects of fedratinib in HCC. Methods: The effects of fedratinib were examined in Huh7 and Hepa1-6 HCC cells using proliferation, migration, invasion, apoptosis, and cell cycle assays. Cell-based surface plasmon resonance (SPR) was used to assess concentration-dependent whole-cell association signals between fedratinib and intact HCC cell monolayers. Results: Fedratinib markedly inhibited proliferation, migration and invasion of HCC cells while inducing apoptosis and cell cycle arrest in a dose-dependent manner. SPR demonstrated concentration-dependent whole-cell association signals between fedratinib and intact HCC cell monolayers. In the allograft model, fedratinib significantly reduced tumor growth and bioluminescence signal intensity without causing obvious short-term systemic toxicity. In terms of molecular changes, fedratinib decreased the phosphorylation levels of STAT3 and AKT without affecting total protein expression, reduced calpain-1 expression and enzymatic activity, as well as downregulation of the anti-apoptotic protein Bcl-2. Conclusions: These results demonstrate that fedratinib treatment is associated with reduced STAT3 and AKT phosphorylation, diminished calpain-1 expression and enzymatic activity, and impaired malignant phenotypes in HCC, providing preliminary evidence supporting further evaluation of fedratinib as a candidate therapeutic agent for HCC.