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Fatty acid metabolism reprogramming in ccRCC: mechanisms and potential targets

Abstract

Lipid droplet formation is a defining histological feature in clear-cell renal cell carcinoma (ccRCC) but the underlying mechanisms and importance of this biological behaviour have remained enigmatic. De novo fatty acid (FA) synthesis, uptake and suppression of FA oxidation have all been shown to contribute to lipid storage, which is a necessary tumour adaptation rather than a bystander effect. Clinical studies and mechanistic investigations into the roles of different enzymes in FA metabolism pathways have revealed new metabolic vulnerabilities that hold promise for clinical effect. Several metabolic alterations are associated with worse clinical outcomes in patients with ccRCC, as lipogenic genes drive tumorigenesis. Enzymes involved in the intrinsic FA metabolism pathway include FA synthase, acetyl-CoA carboxylase, ATP citrate lyase, stearoyl-CoA desaturase 1, cluster of differentiation 36, carnitine palmitoyltransferase 1A and the perilipin family, and each might be potential therapeutic targets in ccRCC owing to the link between lipid deposition and ccRCC risk. Adipokines and lipid species are potential biomarkers for diagnosis and treatment monitoring in patients with ccRCC. FA metabolism could potentially be targeted for therapeutic intervention in ccRCC as small-molecule inhibitors targeting the pathway have shown promising results in preclinical models.

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Fig. 1: H&E staining of ccRCC and normal adjacent kidney tissues.
Fig. 2: VHL and HIF pathway regulation in ccRCC.
Fig. 3: Fatty acid metabolism pathways in clear-cell renal cell carcinoma and potential therapeutic targets.

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Acknowledgements

This work was supported in part by a grant from the National Institutes of Health R01CA254409 to S.M.W.

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Tan, S.K., Hougen, H.Y., Merchan, J.R. et al. Fatty acid metabolism reprogramming in ccRCC: mechanisms and potential targets. Nat Rev Urol (2022). https://doi.org/10.1038/s41585-022-00654-6

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