Galectin-1 Modulates Hepatocellular Carcinoma Response to Thermal Ablation Through Regulating Glycolysis
Authors: Nguyen Tu , Shin Yonghwan , Pham Janet , Ruppa Aravinth , Chen Po-Chun , Mirmohammadi Hannah , Lu David S. K. , Raman Steven S. , Chiang Jason 
Published: December 2024

I.ABSTRACTBackground & AimsThermal ablation is the standard of care treatment modality with curative intent for early-stage hepatocellular carcinoma (HCC), but its efficacy remains moderately limited— with up to 40% of HCC patients experiencing local recurrence post-treatment. This study aimed to evaluate the prognostic value of galectin-1 (Gal-1) in predicting thermal-ablation responsiveness. We then evaluated the therapeutic potential of targeting Gal-1 in inhibition of glycolysis and subsequently enhancing thermal-ablation efficacy.MethodsLiquid-Chromatography Mass-Spectrometry (LC-MS) was employed to analyze proteomic profiles of retrospectively collected pre-ablation FFPE samples of known thermal-ablation responders and nonresponders. Anin-vitrothermal peri-ablation model was established using a heated water bath. Gal-1 inhibition via OTX008 or knockdown was utilized to investigate hyperthermic sensitivity. Hyperthermia-resistant SNU449 cells were used to establish an orthotopic murine model to evaluate the combination therapy of OTX008 and thermal ablation. Harvested tumors were analyzed by LC-MS to determine their metabolic profiles.ResultsThis study revealed that responders had significantly longer tumor progression-free survival compared to nonresponders (57.0±1.6 (median not reached) versus 8.3±0.5 months (median: 13.6 months), p<0.001). Moreover, responders were found to have significant downregulation of Gal-1 expression compared to that of nonresponders. Gal-1 inhibition or knockdown markedly increased hyperthermic sensitivity in hyperthermia-resistant HCC SNU449 cells. Targeting Gal-1 by OTX008 in combination with thermal ablation significantly reduced SNU449-derived tumor growth compared to the thermal-ablation alone groupin vivo. Metabolomic analysis revealed decreased glycolytic metabolites, fructose 1,6-bisphosphate, 3-phosphoglycerate and phosphoenolpyruvate, while western blot analysis showed decreased Gal-1 expression in the combined treatment group compared to monotherapy thermal ablation or OTX008 treatment.ConclusionsGal-1 overexpression correlates with thermal-ablation nonresponsiveness, and targeting Gal-1 enhances thermal-ablation efficacy by inhibiting glycolysis.Impact and ImplicationsDespite being a standard-of-care treatment for early-stage HCC, thermal ablation has a high local recurrence rate of approximately 40%. While thermal ablation can lead to cellular death in the central-treatment zone, its metabolic impact on cells in the peri-ablational region remains unclear. This study shows the direct association between Gal-1 overexpression and thermal-ablation nonresponsiveness. Moreover, it found that Gal-1 inhibition or knockdown increased hyperthermia sensitivityin vitro. Targeting Gal-1 in combination with thermal-ablation significantly reduced hyperthermia-resistant SNU449 tumor growth by inhibiting glycolysisin vivo. These findings suggest that the efficacy of thermal ablation in HCC can be enhanced by pharmacologically inhibiting Gal-1.Graphical abstractHighlightsProfiling pre-ablation HCC biopsies reveals Galectin-1 as a key prognostic biomarker for response prediction in thermal ablationTargeting Galectin-1 with a selective inhibitor (OTX008) enhances the efficacy of thermal ablation in HCCGalectin-1 modulates thermal-ablation response via regulating glycolysis in HCC