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Clear cell renal cell carcinoma (ccRCC) is characterized by accumulation of neutral lipids and adipogenic transdifferentiation. We assessed adipokine expression in ccRCC and found that tumor tissues and patient plasma exhibit obesity-dependent elevations of the adipokine chemerin. Attenuation of chemerin by several approaches led to significant reduction in lipid deposition and impairment of tumor cell growth in vitro and in vivo. A multi-omics approach revealed that chemerin suppresses fatty acid oxidation, preventing ferroptosis, and maintains fatty acid levels that activate hypoxia-inducible factor 2α expression. The lipid coenzyme Q and mitochondrial complex IV, whose biogeneses are lipid-dependent, were found to be decreased after chemerin inhibition, contributing to lipid reactive oxygen species production. Monoclonal antibody targeting chemerin led to reduced lipid storage and diminished tumor growth, demonstrating translational potential of chemerin inhibition. Collectively, the results suggest that obesity and tumor cells contribute to ccRCC through the expression of chemerin, which is indispensable in ccRCC biology.Significance:Identification of a hypoxia-inducible factor–dependent adipokine that prevents fatty acid oxidation and causes escape from ferroptosis highlights a critical metabolic dependency unique in the clear cell subtype of kidney cancer. Targeting lipid metabolism via inhibition of a soluble factor is a promising pharmacologic approach to expand therapeutic strategies for patients with ccRCC.See related commentary by Reznik et al., p. 1879.This article is highlighted in the In This Issue feature, p. 1861

Differential expression of genes between ccRCC cluster and normal cluster

Differential expression matrix

Supplementary data

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.