Lactate Dehydrogenase C4 Accelerates Triple‐Negative Breast Cancer Progression by Promoting Acetyl‐CoA Acyltransferase 2 Lactylation to Increase Free Fatty Acid Accumulation

作者：Zhaolei Cui, Chaoqiang Zheng, Yingying Lin, Zhenzhou Xiao, Yanhong Li, Wei Peng, Shijie He, Anyang Li, Xiufeng Wu, Yan Chen, Yang Sun · 发表于：Advanced Science · 年份：2025 · DOI：10.1002/advs.202511849 · 被引用次数：4 · 研究领域：Cancer, Lipids, and Metabolism、Cancer, Hypoxia, and Metabolism、Metabolomics and Mass Spectrometry Studies

Lactate-induced protein lysine (K) lactylation is inherently connected to cellular metabolism and is implicated in oncogenesis. As a crucial glycolytic enzyme in lactate metabolism, lactate dehydrogenase C4 (LDHC4) has undefined yet potentially significant biological functions and mechanistic roles in triple-negative breast cancer (TNBC) that warrant further investigation. This study aims to determine whether and how LDHC4 affects TNBC progression by regulating protein lactylation. LDHC4 expression in human TNBC tissues and adjacent nontumor tissues is analyzed through immunoblotting and immunohistochemistry (IHC). Functional experiments verified the biological features of LDHC4 in human TNBC cells both in vitro and in vivo (subcutaneous, orthotopic, and pulmonary metastatic mouse models). 4D label-free lactylproteome expression analysis (4D-LFQP-LA), immunoblotting, and immunoprecipitation are utilized to confirm lactylation at specific lysine sites in acetyl-CoA acyltransferase 2 (ACAA2) following LDHC4 induction. Targeted lipidomic analysis is performed to characterize ACAA2-induced metabolite alterations. Immunoblotting, immunofluorescence, and transmission electron microscopy are performed to investigate the mechanisms underlying LDHC4-induced ACAA2 lactylation and tumor progression in TNBC. LDHC4 expression is upregulated in TNBC, and LDHC4 is an independent predictive factor for prognosis. Both in vitro and in vivo experiments demonstrated that LDHC4 promotes TNBC prog...