上海交通大学医学院刘军力研究组报道了丙酮酸代谢酶DLAT通过抑制亮氨酸分解代谢促进肿瘤发生。相关论文发表在2025年3月19日出版的《细胞—代谢》杂志上。

课题组开发了一种AUH^K109R-mRNA脂质纳米颗粒（LNPs）治疗策略，该策略通过恢复亮氨酸分解代谢和抑制mTOR激活在体内有效抑制肿瘤生长。总之，他们的发现揭示了DLAT作为AUH乙酰转移酶的意想不到的作用，抑制亮氨酸分解代谢。利用AUH^K109R-mRNA LNP恢复亮氨酸分解代谢可有效抑制HCC的发展，为癌症研究指明了新的方向。

据了解，丙酮酸和支链氨基酸（BCAA）代谢是肿瘤进展的关键途径，但它们之间复杂的相互作用及其对肿瘤进展的影响尚不清楚。他们的研究表明，二氢脂酰胺-乙酰转移酶（DLAT）是一种丙酮酸代谢酶，可促进亮氨酸的积累，并抑制哺乳动物肝细胞癌（HCC）中雷帕霉素（mTOR）复合物的靶细胞活化。在机制上，DLAT直接乙酰化AU RNA结合的甲基谷氨酰基辅酶A （CoA）水合酶（AUH）的K109残基，抑制其活性并导致亮氨酸积累。值得注意的是，DLAT上调与HCC患者预后不良相关。

附：英文原文

Title: Pyruvate metabolism enzyme DLAT promotes tumorigenesis by suppressing leucine catabolism

Author: Ning Wang, Sijia Lu, Ziyi Cao, Huimin Li, Junting Xu, Qian Zhou, Hanrui Yin, Qiqi Qian, Xianjing Zhang, Mijia Tao, Quanxin Jiang, Peihui Zhou, Liaoyuan Zheng, Liu Han, Hongtao Li, Limin Yin, Yunqing Gu, Xuefeng Dou, Haipeng Sun, Wei Wang, Hai-long Piao, Fuming Li, Yingjie Xu, Weiwei Yang, Suzhen Chen, Junli Liu

Issue&Volume: 2025-03-19

Abstract: Pyruvate and branched-chain amino acid (BCAA) metabolism are pivotal pathways in tumor progression, yet the intricate interplay between them and its implications for tumor progression remain elusive. Our research reveals that dihydrolipoamide S-acetyltransferase (DLAT), a pyruvate metabolism enzyme, promotes leucine accumulation and sustains mammalian target of rapamycin (mTOR) complex activation in hepatocellular carcinoma (HCC). Mechanistically, DLAT directly acetylates the K109 residue of AU RNA-binding methylglutaconyl-coenzyme A (CoA) hydratase (AUH), a critical enzyme in leucine catabolism, inhibiting its activity and leading to leucine accumulation. Notably, DLAT upregulation correlates with poor prognosis in patients with HCC. Therefore, we developed an AUHK109R-mRNA lipid nanoparticles (LNPs) therapeutic strategy, which effectively inhibits tumor growth by restoring leucine catabolism and inhibiting mTOR activation in vivo. In summary, our findings uncover DLAT’s unexpected role as an acetyltransferase for AUH, suppressing leucine catabolism. Restoring leucine catabolism with AUHK109R-mRNA LNP effectively inhibits HCC development, highlighting a novel direction for cancer research.

DOI: 10.1016/j.cmet.2025.02.008

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(25)00066-X