1. Fatty acid binding protein 5 suppression attenuates obesity-induced hepatocellular carcinoma by promoting ferroptosis and intratumoral immune rewiring.
- Author
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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, and Fernández-Hernando C
- 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
- 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
+ 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., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2024
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