ArticleJournal of experimental & clinical cancer research : CR2019
SIRT4 silencing in tumor-associated macrophages promotes HCC development via PPARδ signalling-mediated alternative activation of macrophages.
Article in Journal of experimental & clinical cancer research : CR, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 papers.
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Who cites it
49 citing papers in PubMed, 63 citations in OpenAlex.
- scRNA-seq and bulk RNA-seq reveal the characteristics of macrophage copper metabolism and establish a risk signature in hepatocellular carcinoma.Translational cancer research · 2026Article
- Microglia Reprogramming in Glioblastoma: Stem Cell-Derived Factors as Emerging Immunomodulators.Cells · 2026Review
- Molecular mechanisms of tumor-associated macrophages in hepatocellular carcinoma development and therapy.World journal of gastroenterology · 2026Review
- Targeting tumor-associated macrophages to overcome immune checkpoint inhibitor resistance in hepatocellular carcinoma.Journal of experimental & clinical cancer research : CR · 2025Review
- Sphingosine 1-phosphate derived from tumor-educated hepatic stellate cells combining with S1PR4 promotes tumor associated macrophages differentiation through FAO modulation.Scientific reports · 2025Article
- SNX10 Is Involved in Ovarian Cancer Cell Metastasis by Repolarizing Tumor-Associated Macrophages Through mTOR1/Lysosomes Pathway.Biomedicines · 2025Article
- SIRT4 is associated with microvascular infiltration, immune cell infiltration, and epithelial mesenchymal transition in hepatocellular carcinoma.Histology and histopathology · 2025Article
- Macrophage metabolism in inflammatory heart disease: new insights and therapeutic implications.Frontiers in medicine · 2025Review
- Sirtuins and tumor immunity: mechanistic insights, immunotherapy prospects, and therapeutic horizons.Frontiers in immunology · 2025Review
- Metabolic reprogramming in hepatocellular carcinoma: mechanisms of immune evasion and therapeutic implications.Frontiers in immunology · 2025Review
- Mitochondrial dynamics at the intersection of macrophage polarization and metabolism.Frontiers in immunology · 2025Review
- Lipid metabolic rewiring in glioma‑associated microglia/macrophages (Review).International journal of molecular medicine · 2024Review
- Targeting metabolism to enhance immunotherapy within tumor microenvironment.Acta pharmacologica Sinica · 2024Review
- Epigenetic tuning of tumour-associated macrophages (TAMs): a potential approach in hepatocellular carcinoma (HCC) immunotherapy.Expert reviews in molecular medicine · 2024Review
- The significance of lipid metabolism reprogramming of tumor-associated macrophages in hepatocellular carcinoma.Cancer immunology, immunotherapy : CII · 2024Review
- Review
- Contributing roles of mitochondrial dysfunction and hepatocyte apoptosis in liver diseases through oxidative stress, post-translational modifications, inflammation, and intestinal barrier dysfunction.Cellular and molecular life sciences : CMLS · 2024Review
- Analysis of the Expression and Prognostic Value of SIRTs in Hepatocellular Carcinoma.International journal of general medicine · 2024Article
- Tumor-associated macrophages in anti-PD-1/PD-L1 immunotherapy for hepatocellular carcinoma: recent research progress.Frontiers in pharmacology · 2024Review
- The role of tumor-associated macrophages in hepatocellular carcinoma progression: A narrative review.Cancer medicine · 2023Review
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
Abstract
backgroundThe activation of tumour-associated macrophages (TAMs) contributes to the progression of hepatocellular carcinoma (HCC). SIRT4 acts as a tumour suppressor of tumour growth by regulating cell metabolism, inflammation, and anti-tumourigenesis. However, the involvement of SIRT4 in the activation of TAMs is unknown. Based on previous findings, the expression of SIRT4 in distinct groups of TAMs as well as the effect of SIRT4 silencing on macrophage polarization was investigated.
methodsThe expression of SIRT4 in HCC tissues and peritumour tissues was tested by qRT-PCR, western blotting and histological analysis. A Kaplan-Meier survival curve was generated based on the expression of SIRT4 in the HCC samples. Next, immunofluorescence staining was used to evaluate distinct groups of TAMs in human HCC samples, and the expression of SIRT4 in M1 and M2 TAMs was examined by flow cytometry. A homograft mouse model was used to assess the effect of SIRT4 silencing in TAMs on the development of HCC cells.
resultsSIRT4 was significantly downregulated in HCC tumour tissues, and the expression of SIRT4 in peritumour tissues was positively associated with survival in patients. We further found that downregulation of SIRT4 was associated with increased macrophage infiltration and a high ratio of M2/M1 macrophages in HCC peritumour tissues. Using gene interference, we found that SIRT4 silencing in TAMs significantly modulated the alternative activation of macrophages and promoted in vitro and in vivo HCC cell growth. Mechanistically, we revealed that HCM restricted the expression of SIRT4 in macrophages and promoted alternative activation of macrophages via the FAO-PPARδ-STAT3 axis. Furthermore, we also revealed that elevated MCP-1 expression induced by SIRT4 downregulation was responsible for increased TAM infiltration in peritumour tissues.
conclusionsOverall, our results demonstrate that downregulation of SIRT4 in TAMs modulates the alternative activation of macrophages and promotes HCC development via the FAO-PPARδ-STAT3 axis. These results could provide a new therapeutic target for the treatment of HCC.
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