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Fatty acid binding protein 5 suppression attenuates obesity-induced hepatocellular carcinoma by promoting ferroptosis and intratumoral immune rewiring.
- Source :
-
Nature metabolism [Nat Metab] 2024 Apr; Vol. 6 (4), pp. 741-763. Date of Electronic Publication: 2024 Apr 25. - Publication Year :
- 2024
-
Abstract
- Due to the rise in overnutrition, the incidence of obesity-induced hepatocellular carcinoma (HCC) will continue to escalate; however, our understanding of the obesity to HCC developmental axis is limited. We constructed a single-cell atlas to interrogate the dynamic transcriptomic changes during hepatocarcinogenesis in mice. Here we identify fatty acid binding protein 5 (FABP5) as a driver of obesity-induced HCC. Analysis of transformed cells reveals that FABP5 inhibition and silencing predispose cancer cells to lipid peroxidation and ferroptosis-induced cell death. Pharmacological inhibition and genetic ablation of FABP5 ameliorates the HCC burden in male mice, corresponding to enhanced ferroptosis in the tumour. Moreover, FABP5 inhibition induces a pro-inflammatory tumour microenvironment characterized by tumour-associated macrophages with increased expression of the co-stimulatory molecules CD80 and CD86 and increased CD8 <superscript>+</superscript> T cell activation. Our work unravels the dual functional role of FABP5 in diet-induced HCC, inducing the transformation of hepatocytes and an immunosuppressive phenotype of tumour-associated macrophages and illustrates FABP5 inhibition as a potential therapeutic approach.<br /> (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
- Subjects :
- Animals
Mice
Male
Tumor Microenvironment immunology
Humans
Mice, Inbred C57BL
Tumor-Associated Macrophages metabolism
Tumor-Associated Macrophages immunology
Carcinoma, Hepatocellular metabolism
Carcinoma, Hepatocellular etiology
Fatty Acid-Binding Proteins metabolism
Fatty Acid-Binding Proteins genetics
Liver Neoplasms metabolism
Liver Neoplasms etiology
Obesity complications
Obesity metabolism
Ferroptosis
Neoplasm Proteins
Subjects
Details
- Language :
- English
- ISSN :
- 2522-5812
- Volume :
- 6
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Nature metabolism
- Publication Type :
- Academic Journal
- Accession number :
- 38664583
- Full Text :
- https://doi.org/10.1038/s42255-024-01019-6