ArticleAging2019
HIF-2α upregulation mediated by hypoxia promotes NAFLD-HCC progression by activating lipid synthesis via the PI3K-AKT-mTOR pathway.
Article in Aging, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 69 papers.
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Who cites it
69 citing papers in PubMed, 100 citations in OpenAlex.
- Complex interactions between miR-107 and PTEN gene expression, more specifically in viral and NASH cirrhosis.Biochemistry and biophysics reports · 2026Article
- Evolving Landscape of Systemic Therapy for Hepatocellular Carcinoma: From Targeted Therapy and Combination Strategies to Emerging Therapies.Biomedicines · 2026Review
- RRP9 suppresses hepatocellular carcinoma progression by inhibiting the PI3K/AKT/mTOR pathway.International journal of oncology · 2026Article
- Combined Multi-Omics Analysis Reveals the Potential Role of Methionine in Regulating the Proliferation, Differentiation, and Lipid Deposition of Yak Intramuscular Preadipocytes.Animals : an open access journal from MDPI · 2026Article
- Signalling pathways in hepatocellular carcinoma (HCC) metastasis and invasion: Molecular mechanisms and therapeutic implications.Biochemistry and biophysics reports · 2026Review
- Trichostatin A Influences Dendritic Cells' Functions by Regulating Glucose and Lipid Metabolism via PKM2.Molecules (Basel, Switzerland) · 2026Article
- Hypoxia-inducible factors in the immunometabolism of metabolic dysfunction-associated steatotic liver disease (MASLD): molecular mechanisms and therapeutic implications.Frontiers in physiology · 2026Article
- Hypoxia-inducible factors link inflammation and lipid metabolism in atherosclerotic macrophages.Frontiers in cardiovascular medicine · 2026Review
- Kaili sour soup in alleviation of hepatic steatosis in rats via lycopene route: an experimental study.Annals of medicine · 2025Article
- Physiological roles of phosphoinositides and inositol phosphates: Implications for metabolic dysfunction-associated steatotic liver disease.Clinical science (London, England : 1979) · 2025Review
- Navigating liver cancer with mouse models: a comprehensive overview of HCC experimental systems.Journal of liver cancer · 2025Article
- Lipid Metabolism in Gastrointestinal Malignancies: Exploring Dysregulation, Biomarkers, and Treatment Strategies.Cancer medicine · 2025Review
- Establishment and verification of a prognostic signature associated with fatty acid metabolism in endometrial cancer.Molecular medicine reports · 2025Article
- Exploring the pharmacological mechanisms for alleviating OSA: Adenosine A2A receptor downregulation of the PI3K/Akt/HIF‑1 pathway (Review).Biomedical reports · 2025Review
- The PI3K/Akt/mTOR Pathway: Immuno-Metabolic Orchestration in IR/MASH-Associated Hepatocellular Carcinoma.International journal of biological sciences · 2025Review
- Rivaroxaban alleviates hepatic sinusoidal obstruction syndrome in mice by modulating the gut microbiota and inhibiting the PI3K/Akt signaling pathway.Frontiers in microbiology · 2025Article
- Research advances in traditional Chinese medicine formulae and active components targeting lipid metabolism for hepatocellular carcinoma therapy.Frontiers in pharmacology · 2025Review
- Knockdown of RASD1 improves MASLD progression by inhibiting the PI3K/AKT/mTOR pathway.Lipids in health and disease · 2024Article
- HIF-1α knockdown attenuates phenotypic transformation and oxidative stress induced by high salt in human aortic vascular smooth muscle cells.Scientific reports · 2024Article
- The impact of aerobic and anaerobic exercise interventions on the management and outcomes of non-alcoholic fatty liver disease.Physiological research · 2024Review
9 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
14 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a relevant risk factor for developing hepatocellular carcinoma (HCC). Steatohepatitic HCC (SH-HCC), characterized by HCC with steatosis, is influenced by lipid metabolism disorders. A hypoxic microenvironment is common in HCC and affects lipid metabolism. However, whether hypoxia-induced HIF-2α upregulation exacerbates lipid accumulation to contribute to SH-HCC progression remains unclear. In this study, we demonstrated that HIF-2α was elevated in tissues from NAFLD-HCC patients and was associated with survival. Under hypoxic conditions, upregulated HIF-2α was accompanied by lipid accumulation and PI3K-AKT-mTOR pathway activation. HIF-2α knockdown (KD) in steatotic HCC ameliorated triglyceride accumulation and steatosis. HIF-2α-KD steatotic HCC showed minimal lipid synthesis in a hypoxic environment, which contributes to a reduction in malignant behaviours. However, treatment with MHY1485 restored these behaviours. STAM mice, a mouse model that develops NAFLD-HCC, exhibit more rapid tumour progression upon exposure to hypoxia. STAM mice treated with INK-128 presented abrogated mTOR expression and tumour progression under hypoxic conditions with lower triglycerides and steatosis. In conclusion, in a hypoxic microenvironment, HIF-2α upregulation promotes steatotic HCC progression by activating lipid synthesis via the PI3K-AKT-mTOR pathway. Therefore, HIF-2α can be a biomarker and target in developing specific therapeutic measures for NAFLD-HCC patients.
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Registered trials
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 OpenQuestion graph.