To investigate the metabolism of clear cell renal cell carcinoma (ccRCC) and elucidate the effect of malonyl-CoA decarboxylase (MLYCD) on fatty acid (FA) anabolism in ccRCC. Experimental Design: FA anabolic reprogramming in ccRCC was evaluated in the public database. MLYCD expression was measured in clinical samples, cell lines, and Sunitinib-resistant ccRCC cell lines from the mouse model. The effect of MLYCD absence on FA anabolism was evaluated utilizing absolute quantitative lipidomics, BODIPY staining, Seahorse assays, and C14 tracings. The impact of MLYCD absence on ccRCC endoplasmic reticulum (ER) and mitochondrial homeostasis was evaluated by multiple probe, cell death or activity assays with multiple inhibitor, and measurements of intracellular reactive oxygen species (ROS). The susceptibility of MLYCD-restoration in Sunitinib-resistant ccRCC to Sunitinib was interrogated in vitro and in vivo. Results: We identified that MLYCD, a key gene for FA anabolism, was downregulated in ccRCC and predicted poor prognosis. Restoring MLYCD expression decreased malonyl-CoA content, resulting in the inhibition of de novo FA synthesis and promotion of FA movement into mitochondria for oxidation. MLYCD-mediated FA anabolism inhibits lipid droplet (LD) accumulation, which disrupts ER and mitochondrial homeostasis, increases ROS levels, and induces ferroptosis. Moreover, overexpression of MLYCD induced a reduction in tumor growth and reversed resistance to Sunitinib in vitro and in vivo. Mechanistically, this study demonstrated that HIF inhibits MLYCD translation by upregulating eIF4G3 microexons. Conclusions: These findings demonstrate MLYCD mediated FA anabolism repressed ccRCC progression and the translational potential of targeting FA anabolism in MLYCD-null cancers.