This study published in Genes & Diseases by researchers from Chongqing Medical University uncovers a previously unrecognized hypoxia–m⁶A–Gal-1 regulatory axis that fuels HCC progression by stabilizing Galectin-1 (Gal-1) mRNA and promoting malignant phenotypes.

The researchers report that Gal-1, a β-galactoside–binding lectin implicated in proliferation, metastasis, immune evasion, and epithelial–mesenchymal transition, is markedly up-regulated in HCC tissues and strongly correlates with poor clinical prognosis. Functional experiments confirmed that Gal-1 enhances HCC cell proliferation, migration, invasion, and EMT-driven phenotypic plasticity, establishing it as a critical mediator of liver cancer progression.

The study provides the first evidence that Gal-1 expression is regulated through m⁶A-dependent RNA stability. Under normoxic conditions, the m⁶A demethylase ALKBH5 and the m⁶A reader YTHDF2 coordinate to control Gal-1 mRNA turnover. However, hypoxic stress significantly elevates ALKBH5 expression while suppressing YTHDF2, resulting in reduced m⁶A levels on Gal-1 transcripts and preventing their degradation. This shift in RNA methylation enhances Gal-1 mRNA stability and drives its overexpression in HCC cells.
Importantly, the authors identify hypoxia-inducible factors (HIF-1α and HIF-2α) as key upstream regulators of this process. HIF-1α directly induces ALKBH5 expression, while HIF-2α represses YTHDF2, linking hypoxic signaling to m⁶A-mediated post-transcriptional control. Together, these coordinated changes establish a hypoxia–m⁶A–Gal-1 regulatory circuit that promotes tumor cell proliferation, invasiveness, and EMT activation.

In vivo studies further validated the functional relevance of this axis. Gal-1 knockdown suppressed tumor growth and reduced expression of proliferation and EMT markers. Moreover, lipid nanoparticle–delivered siGal-1 efficiently accumulated in the liver and significantly inhibited orthotopic tumor progression and metastasis, highlighting Gal-1 as a promising therapeutic target.

Overall, this study reveals that hypoxia-induced m⁶A demethylation is a major driver of Gal-1 overexpression and HCC malignancy. By elucidating how ALKBH5, YTHDF2, and HIFs converge to regulate Gal-1, the authors provide new mechanistic insights into hypoxia-driven tumor evolution and identify a targeted therapeutic avenue for combating liver cancer.

Reference

Title of Original Paper
Hypoxia-induced m6A demethylation promotes hepatocellular carcinoma progression by preventing the degradation of Gal-1 mRNA

Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.

DOI: https://doi.org/10.1016/j.gendis.2025.101860

Funding Information:
The National Natural Science Foundation of China (No. 82370672, No. 8207034238)

# # # # # #
Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.

Scopus Cite Score: 8.4
Impact Factor: 9.4

# # # # # #

More information: https://www.keaipublishing.com/en/journals/genes-and-diseases/
Editorial Board: https://www.keaipublishing.com/en/journals/genes-and-diseases/editorial-board/
All issues and articles in press are available online in ScienceDirect (https://www.sciencedirect.com/journal/genes-and-diseases).
Submissions to Genes & Diseases may be made using Editorial Manager (https://www.editorialmanager.com/gendis/default.aspx).

Print ISSN: 2352-4820
eISSN: 2352-3042
CN: 50-1221/R

Contact Us: editor@genesndiseases.cn
X (formerly Twitter): @GenesNDiseases (https://x.com/GenesNDiseases)

# # # # # #