细胞代谢中组蛋白和非组蛋白赖氨酸 (K) 残基的翻译后修饰及其在癌症进展中的作用之间已建立的联系已有充分记录。然而，三阴性乳腺癌 (TNBC) 中的乳酰化表达特征仍未得到充分探索。我们对八对 TNBC 样本及其匹配的邻近组织进行了全面的乳酰蛋白质组分析。这是通过 4 维无标记定量蛋白质组学与乳酰化分析 (4D-LFQP-LA) 相结合实现的。使用免疫印迹和免疫组织化学 (IHC) 和特定一抗检测 TNBC 中已鉴定乳酰化蛋白的表达，并评估其临床病理学和预后意义。我们的分析鉴定了 48 个蛋白上的 58 个乳酰化位点，描绘了 TNBC 中的蛋白乳酰化改变特征。生物信息学和功能分析表明，这些乳酰化蛋白在调节 TNBC 的关键生物过程中发挥着至关重要的作用。值得注意的是，组蛋白 H4 结构域 12 位赖氨酸 (H4K12lac) 的乳酰化被发现在 TNBC 中上调。进一步研究显示，TNBC 中 H4K12lac 上调的发生率很高，TNBC 组织芯片和验证队列中的阳性率分别为 93.19%（137/147）和 92.93%（92/99）。 H4K12lac 表达与 Ki-67 呈正相关，与 TNBC 中的总生存期 (OS) 呈负相关（HR [风险比] = 2.813，95% CI [可信区间]：1.242-6.371，P = 0.0164），表明其作为独立治疗的潜力。预后标志物（HR=3.477，95%CI：1.324-9.130，P=0.011）。乳酰化是TNBC蛋白中显着的翻译后修饰。 H4K12lac 成为一种有前途的 TNBC 生物标志物，可深入了解 TNBC 蛋白的乳酰化谱，并将组蛋白修饰与 TNBC 的临床意义联系起来。版权所有 © 2024 Cui、Li、Lin、Zheng、Luo、Hu、Chen、Xiao 和 Sun。

The established link between posttranslational modifications of histone and non-histone lysine (K) residues in cell metabolism, and their role in cancer progression, is well-documented. However, the lactylation expression signature in triple-negative breast cancer (TNBC) remains underexplored.We conducted a comprehensive lactylproteome profiling of eight pairs of TNBC samples and their matched adjacent tissues. This was achieved through 4-Dimensional label-free quantitative proteomics combined with lactylation analysis (4D-LFQP-LA). The expression of identified lactylated proteins in TNBC was detected using immunoblotting and immunohistochemistry (IHC) with specific primary antibodies, and their clinicopathological and prognostic significance was evaluated.Our analysis identified 58 lactylation sites on 48 proteins, delineating the protein lactylation alteration signature in TNBC. Bioinformatic and functional analyses indicated that these lactylated proteins play crucial roles in regulating key biological processes in TNBC. Notably, lactylation of lysine at position 12 (H4K12lac) in the histone H4 domain was found to be upregulated in TNBC. Further investigations showed a high prevalence of H4K12lac upregulation in TNBC, with positive rates of 93.19% (137/147) and 92.93% (92/99) in TNBC tissue chip and validation cohorts, respectively. H4K12lac expression correlated positively with Ki-67 and inversely with overall survival (OS) in TNBC (HR [hazard ratio] =2.813, 95%CI [credibility interval]: 1.242-6.371, P=0.0164), suggesting its potential as an independent prognostic marker (HR=3.477, 95%CI: 1.324-9.130, P=0.011).Lactylation is a significant post-translational modification in TNBC proteins. H4K12lac emerges as a promising biomarker for TNBC, offering insights into the lactylation profiles of TNBC proteins and linking histone modifications to clinical implications in TNBC.Copyright © 2024 Cui, Li, Lin, Zheng, Luo, Hu, Chen, Xiao and Sun.