Liang Zhi-Qiang, Luo Wang-Sheng, Tang Chen-Chen, Zhong Yi-Lang, Xu Chen-Qin, Ma Chao, Jia Cheng-Lin, Cai Tong-Kai, Cao Yong-Bing, Li Ji, Chen Jian
Institute of Vascular Anomalies, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China.
Department of Cardiology, the First Affiliated Hospital of University of South China, Hengyang, China.
Life Sci. 2025 Sep 15;377:123777. doi: 10.1016/j.lfs.2025.123777. Epub 2025 May 29.
This study investigates the role of macrophage histone lactylation-a protein modification-in atherosclerosis progression, particularly in peripheral artery disease (PAD), and evaluates the therapeutic potential of the herbal formula Ruan Jian Qing Mai (RJQM).
Weighted gene co-expression network analysis (WGCNA), functional enrichment, and machine learning were used to explore regulatory mechanisms and develop a predictive model for subclinical atherosclerosis. Experimental validation included ApoE-/- mice treated with RJQM and molecular docking to assess drug-protein interactions.
Our analysis identified 2853 histone lactylation-related genes, of which 117 were significantly correlated with macrophage infiltration across carotid, femoral, and infrapopliteal arteries. WGCNA revealed a strong correlation (r = 0.93, P = 7e-47) between the turquoise module and macrophage infiltration, indicating the potential regulatory role of histone lactylation in inflammatory processes. Functional enrichment analysis highlighted the involvement of these proteins in immune responses, particularly cytokine signaling, with hub proteins such as PTPN6 and CASP1 being pivotal. Furthermore, we developed a consensus signature using machine learning methodologies that demonstrated robust predictive power (average area under the curve, AUC > 0.817) for subclinical atherosclerosis. Experimental validation in ApoE-/- mice indicated that the RJQM effectively reduced plaque area by 39 % (P < 0.05) and modulated macrophage pyroptosis and inflammation.
This research uncovers novel insights into the regulatory mechanisms of macrophage histone lactylation in atherosclerosis and validates the potential of RJQM as a therapeutic strategy, warranting further exploration of its protein modifications and underlying molecular pathways.
本研究调查巨噬细胞组蛋白乳酰化（一种蛋白质修饰）在动脉粥样硬化进展中的作用，特别是在外周动脉疾病（PAD）中的作用，并评估中药方剂软坚清脉（RJQM）的治疗潜力。
采用加权基因共表达网络分析（WGCNA）、功能富集和机器学习来探索调控机制并建立亚临床动脉粥样硬化的预测模型。实验验证包括用RJQM治疗的ApoE-/-小鼠以及分子对接以评估药物-蛋白质相互作用。
我们的分析确定了2853个与组蛋白乳酰化相关的基因，其中117个与颈动脉、股动脉和腘下动脉的巨噬细胞浸润显著相关。WGCNA显示绿松石模块与巨噬细胞浸润之间存在强相关性（r = 0.93，P = 7e-47），表明组蛋白乳酰化在炎症过程中具有潜在的调控作用。功能富集分析强调了这些蛋白质参与免疫反应，特别是细胞因子信号传导，关键蛋白如PTPN6和CASP1起关键作用。此外，我们使用机器学习方法开发了一种共识特征，该特征对亚临床动脉粥样硬化具有强大的预测能力（平均曲线下面积，AUC > 0.817）。在ApoE-/-小鼠中的实验验证表明，RJQM有效地将斑块面积减少了39%（P < 0.05），并调节了巨噬细胞焦亡和炎症。
本研究揭示了巨噬细胞组蛋白乳酰化在动脉粥样硬化调控机制方面的新见解，并验证了RJQM作为一种治疗策略的潜力，值得进一步探索其蛋白质修饰和潜在的分子途径。
