Hypoxia-driven HIF1A-HK2-dependent glycolytic reprogramming contributes to sorafenib tolerance in hepatocellular carcinoma
Year: 2026
Type: preprint
Abstract: Background Hepatocellular carcinoma (HCC) is characterized by pronounced hypoxia and suboptimal response to sorafenib, but how hypoxia in defined malignant cell subsets drives metabolic adaptation and drug tolerance remains unclear. This study aimed to identify hypoxia-dominant tumor populations, derive a hypoxia-related risk signature, and determine whether a HIF1A-HK2 axis mediates glycolytic reprogramming and sorafenib resistance through tumor cell-intrinsic mechanisms. Methods Single-cell RNA sequencing from ten HCC samples was integrated with bulk transcriptomic cohorts to define a hypoxia-enriched epithelial subcluster, construct a seven-gene hypoxia-related risk model, and screen for a stable metabolic node, followed by hypoxia modelling (1% O₂/CoCl₂), HK2 knockdown/overexpression, co-immunoprecipitation, promoter-focused structural modelling, and functional assays of glycolysis, sorafenib sensitivity and endothelial tube formation. Results The analysis identified a hypoxia-high malignant subcluster whose gene set generated a seven-gene signature that stratified survival and reflected activation of hypoxia and glycolysis pathways; HK2 was consistently retained across subcluster screening, risk modelling and pathway annotation, and in vitro HIF1A stabilization increased HK2 expression, glycolytic flux and sorafenib survival, while HK2 knockdown reduced glycolysis and partially restored sorafenib sensitivity and HK2 overexpression in normoxia reproduced a hypoxia-like metabolic and drug-response profile without major effects on endothelial tube formation. Conclusions These findings indicate that a hypoxia-associated HIF1A-HK2 axis acts as a tumor cell-intrinsic driver of glycolytic support for sorafenib tolerance and suggest that hypoxia- and glycolysis-related features may refine risk stratification and inform metabolic co-targeting strategies in HCC.
Source: Research Square
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7139134867