ArticleCell death & disease2026
SOX4-STAT6-MTHFD2 axis drives hepatocellular carcinoma progression and treatment resistance.
Article in Cell death & disease, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
1 citing paper in PubMed.
- Let-7a and miR-34a Interplay Potent Suppressive Roles in Hepatocellular Carcinoma via Co-TargetingInternational journal of molecular sciences · 2026Article
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Authors and funding
10 authors.
Funding
Abstract
Hepatocellular carcinoma (HCC) is a major global health burden. Despite recent advances in immunotherapy, tyrosine kinase inhibitors (TKIs) treatment or combined therapies, therapeutic resistance and disease progression remain significant challenges. SOX4, a transcription factor frequently overexpressed in HCC and other cancers, has been linked to drug resistance and poor prognosis; however, the underlying molecular mechanisms remain unexplored. In this study, we identify STAT6 as a novel transcriptional target and interacting partner of SOX4 in HCC cells. Genetic ablation or knockdown of SOX4 induced hypermethylation of the STAT6 promoter, suppressing its expression, while treatment with the DNA methyltransferase inhibitor 5-Aza-2'-deoxycytidine restored STAT6 levels, indicating an epigenetic mechanism of regulation. In addition, SOX4 is physically associated with STAT6, as confirmed by co-immunoprecipitation and immunofluorescence. SOX4 depletion impaired interleukin-4 (IL-4)-induced phosphorylation of STAT6 at tyrosine residue 641 (Y641), implicating SOX4 in IL-4-mediated STAT6 activation. Chromatin immunoprecipitation (ChIP) assays demonstrated that SOX4 and STAT6 co-occupy the promoter of MTHFD2, a key enzyme in folate metabolism, regulating NADH/NADPH production and nucleotide biosynthesis. Knockdown of SOX4 or STAT6, or mutation of their binding sites within the MTHFD2 promoter, reduced MTHFD2 expression, NADPH levels, and nucleotide synthesis. Transcriptomic analyses from TCGA-LIHC and our independent cohort revealed a strong positive correlation between SOX4, STAT6, and MTHFD2, with MTHFD2 overexpression linked to poor overall survival. Clinically, elevated SOX4/STAT6/MTHFD2 axis activity was associated with resistance to immunotherapy or TKIs, either in our enrolled cohort or transcriptome data obtained from GSE109211. Metabolomic profiling further revealed increased NADPH and nucleotide biosynthesis in tumors with high SOX4/STAT6/MTHFD2 expression. Targeting STAT6 or MTHFD2 suppressed tumor growth in TKIs-resistant patient-derived xenograft models. Collectively, our findings identify the SOX4-STAT6-MTHFD2 axis as a critical driver of HCC progression and therapeutic resistance, offering a promising target for intervention in refractory HCC.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.