单位：[1]Department of Urology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China[2]Department of Urology, Henan Institute of Urology and Zhengzhou Key Laboratory for Molecular Biology of Urological Tumor Research, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China[3]Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China华中科技大学同济医学院附属协和医院[4]Department of Urology, Traditional Chinese and Western Medicine Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China[5]Department of Urology, Wuhan No.1 Hospital, Wuhan, 430030, China[6]Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China华中科技大学同济医学院附属协和医院[7]Hubei Province Key Laboratory of Molecular Imaging, Wuhan 430022, China[8]Department of Obstetrics and Gynecology, First Affiliated Hospital, Xi'an Jiao tong University, Xi'an, 710061, China[9]Department of Pediatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China[10]Department of Urology,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,Hubei,China外科学系华中科技大学同济医学院附属同济医院泌尿外科
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.
基金：
National Natural Sciences Foundation of
China (NO. 82203099 to L.J.Z, NO. 82173294 to C.H.G, and NO. 82103000 to Y.N.L),
the Joint Construction Project between Medical Science and Technology Research
Project of Henan Province (NO. LHGJ20220335 to L.J.Z), Funding for Scientific
Research and Innovation Team of The First Affiliated Hospital of Zhengzhou
University (NO.QNCXTD2023023 to C.H.G), the Training Program for Middle-aged
and Young Discipline Leaders of Health of Henan Province (NO. HNSWJW-2021004
to C.H.G).
第一作者单位：[1]Department of Urology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China[2]Department of Urology, Henan Institute of Urology and Zhengzhou Key Laboratory for Molecular Biology of Urological Tumor Research, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China[*1]Department of Urology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
共同第一作者：
通讯作者：
通讯机构：[1]Department of Urology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China[2]Department of Urology, Henan Institute of Urology and Zhengzhou Key Laboratory for Molecular Biology of Urological Tumor Research, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China[10]Department of Urology,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,Hubei,China[*1]Department of Urology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China[*2]Department of Urology, Henan Institute of Urology and Zhengzhou Key Laboratory for Molecular Biology of Urological Tumor Research, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
医学