脂肪酸代谢重编程是明显的透明细胞肾癌（ccRCC）的突出特征。增加的脂质储存支持 ccRCC 的进展，突显了理解驱动肿瘤中脂肪酸合成改变的分子机制的重要性。本研究发现，马洛尼酰辅酶 A 解羧酶（MLYCD），作为脂肪酸合成的关键调节因子，在 ccRCC 中被下调，并且低表达与患者预后不良相关。在 ccRCC 细胞中恢复 MLYCD 的表达降低了马洛尼酰辅酶 A 的含量，阻断了脂肪酸的新生合成，促进了脂肪酸向线粒体的转运和氧化。通过 MLYCD 介导的脂肪酸氧化抑制脂滴积累，破坏内质网和线粒体的稳态，增加了活性氧水平，并诱导了铁死亡。此外，过表达 MLYCD 还可以减小肿瘤生长并逆转体外和体内对舒尼替尼的耐药性。从机理上讲，HIF2α 通过上调 eIF4G3 微外显子的表达抑制了 MLYCD 的翻译。综上所述，本研究表明，MLYCD 介导的脂肪酸分解破坏了脂质稳态，抑制了 ccRCC 的进展。激活 MLYCD 介导的脂肪酸代谢可能是治疗 ccRCC 的一种有希望的治疗策略。

Fatty acid metabolism reprogramming is a prominent feature of clear cell renal cell carcinoma (ccRCC). Increased lipid storage supports ccRCC progression, highlighting the importance of understanding the molecular mechanisms driving altered fatty acid synthesis in tumors. Here, we identified that malonyl-CoA decarboxylase (MLYCD), a key regulator of fatty acid anabolism, was downregulated in ccRCC, and low expression correlated with poor prognosis in patients. Restoring MLYCD expression in ccRCC cells decreased the content of malonyl CoA, which blocked de novo fatty acid synthesis and promoted fatty acid translocation into mitochondria for oxidation. Inhibition of lipid droplet accumulation induced by MLYCD-mediated fatty acid oxidation disrupted endoplasmic reticulum and mitochondrial homeostasis, increased reactive oxygen species levels, and induced ferroptosis. Moreover, overexpressing MLYCD reduced tumor growth and reversed resistance to sunitinib in vitro and in vivo. Mechanistically, HIF2α inhibited MLYCD translation by upregulating expression of eIF4G3 microexons. Together, this study demonstrates that fatty acid catabolism mediated by MLYCD disrupts lipid homeostasis to repress ccRCC progression. Activating MLYCD-mediated fatty acid metabolism could be a promising therapeutic strategy for treating ccRCC.