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. 2024 Apr;6(4):741-763.
doi: 10.1038/s42255-024-01019-6. Epub 2024 Apr 25.

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

Jonathan Sun  1   2   3   4 , Enric Esplugues  1   2   3 , Alicia Bort  1   2   3 , Magdalena P Cardelo  1   2   3 , Inmaculada Ruz-Maldonado  1   2   3 , Pablo Fernández-Tussy  1   2   3 , Clara Wong  1   2   3 , Hehe Wang  5 , Iwao Ojima  5   6 , Martin Kaczocha  6   7 , Rachel Perry  2   8   9 , Yajaira Suárez  10   11   12   13 , Carlos Fernández-Hernando  14   15   16   17
Affiliations

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

Jonathan Sun et al. Nat Metab. 2024 Apr.

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.

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