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Fatty acid binding protein 5 suppression attenuates obesity-induced hepatocellular carcinoma by promoting ferroptosis and intratumoral immune rewiring.

Authors :
Sun J
Esplugues E
Bort A
Cardelo MP
Ruz-Maldonado I
Fernández-Tussy P
Wong C
Wang H
Ojima I
Kaczocha M
Perry R
Suárez Y
Fernández-Hernando C
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.)

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