Multi-omics analyses reveal hypoxia-induced CHD2 as a key driver of malignant progression and microenvironment remodeling in HCC via the TGF-β/SMAD axis

Hepatocellular carcinoma (HCC) is characterized by remarkable molecular heterogeneity. However, the role of the chromodomain helicase DNA-binding protein 2 (CHD2) in HCC remains unclear. This study aimed to explore the biological functions and molecular mechanisms of CHD2 in HCC progression.Multi-omics datasets, including RNA-seq, single-cell RNA sequencing (scRNA-seq), and spatial transcriptomics were integrated with experimental validation to analyze the expression, biological significance and regulatory mechanisms of CHD2 in HCC. CHD2 was upregulated in HCC tissues and was associated with poor survival. Single-cell and spatial transcriptomic analyses demonstrated that CHD2 was enriched in tumor cells and positively associated with an immunosuppressive microenvironment and activation of the TGF-β/SMAD pathway. Mechanistically, HIF1-α directly activated CHD2 transcription under hypoxia. Functional experiments further showed that CHD2 promoted HCC cell proliferation, invasion, and epithelial-mesenchymal transition (EMT), while enhancing PD-L1 expression through activating the TGF-β/SMAD pathway. Our study demonstrates for the first time that CHD2 is a hypoxia-induced oncogenic factor that promotes malignant progression and immune evasion in HCC through activating the TGF-β/SMAD pathway. CHD2 may serve as a promising biomarker and potential therapeutic target for HCC.