Obesity-Dependent Adipokine Chemerin Suppresses Fatty Acid Oxidation to Confer Ferroptosis Resistance

Abstract

Lipid droplet formation is a defining histological feature in clear cell renal cell carcinoma (ccRCC) but the importance of this biological behavior remains enigmatic. As adipogenic trans-differentiation is an important component of ccRCC tumorigenesis, we assessed adipokine expression in ccRCC and found an obesity-dependent elevation of adipokine chemerin in ccRCC as compared to normal kidney. The roles of chemerin in regulating lipid metabolism and tumor growth were investigated in this dissertation. To functionally dissect its role in cancer, chemerin was attenuated by several approaches in vitro and in vivo, all of which led to significant impairments of tumor growth. A multi-omic approach revealed that chemerin functions by suppressing mitochondrial fatty acid oxidation, and maintains fatty acid levels which transcriptionally activate HIF-2a expression. Chemerin silencing, also led to reduction of lipid CoQ and mitochondrial complex IV, whose biogenesis are lipid-dependent, enhancing lipid reactive oxygen species production and contributed to ferroptosis. This result highlights a critical metabolic dependency unique in ccRCC.&nbsp; Collectively, targeting lipid metabolism via inhibition of a soluble adipokine is a promising pharmacological approach to greatly expand therapeutic strategies for ccRCC patients.</p