Lactic acid is a product of cell respiration. After entering into cells, glucose is metabolized to pyruvate by glycolysis. When the oxygen supply is sufficient, pyruvate is converted to acetyl coenzyme A through pyruvate dehydrogenase in the mitochondrial matrix to participate in the tricarboxylic acid cycle and provide necessary energy for cells. Pyruvate is catalysed by lactate dehydrogenase in the cytoplasm to produce lactate while cells are grown under hypoxic conditions. Lactate not only provides energy for mitochondrial respiration, but also plays important roles in inflammatory responser, wound repair, memory formation and neuroprotection as well as tumor growth and metastasis and other pathophysiological processes through autocrine, paracrine, and endocrine forms, which affects the development and prognosis of diseases. Epigenetic modification regulates gene replication, transcription and translation by covalently adding or hydrolyzing functional groups on histones and DNA through related enzymes and affects the biological effects of cells. Histones are the major structural proteins of eukaryotic chromosomes. Their post-translational modifications, such as methylation and acetylation, affect their affinity with DNA, change chromatin structures, and are widely involved in regulation of gene expression. Recent studies have found that histones can undergo lactylation, which is a new epigenetic modification by adding lactate to lysine residues on histones. As the research deepens, numerous evidences reveal that lactylation also occurs on non-histone proteins. The discovery of lactylation has expanded our understanding of lactate functions in the pathogenesis of diseases. In this review, we summarize the roles and mechanisms of lactylation in tumor, inflammatory and neural system diseases, in order to provide new ideas for the research, diagnosis and treatment of these diseases.
GE Lingling, HUANG Hongjun, LUO Yan. Research progress in the role and mechanism of lactylation in diseases. Journal of Shanghai Jiao Tong University (Medical Science)[J], 2023, 43(3): 374-379 doi:10.3969/j.issn.1674-8115.2023.03.014
甲基转移酶3（methyltransferase-like protein 3，METTL3）在结肠癌小鼠肿瘤浸润髓样细胞中表达上调，并与肿瘤进展呈正相关，条件敲除Mettl3基因后，具有抗肿瘤功能的免疫细胞数量明显增加；进一步研究发现，Mettl3启动子区域的组蛋白H3K18发生乳酰化修饰，致使METTL3表达增加；同时METTL3自身的锌指结构域也发生乳酰化，使编码JAK1的mRNA m6A甲基化修饰增加，激活JAK1-STAT3通路，启动下游免疫抑制分子的表达，有利于肿瘤细胞逃逸［11］。根据癌症基因组图谱（The Cancer Genome Atlas，TCGA）分析，结肠腺癌患者结肠组织中前蛋白转化酶枯草溶菌素转化酶9（proprotein convertase subtilisin/kexin 9，PCSK9）表达水平明显高于正常组织，且与肿瘤病理分级密切相关；体外敲低HT29和HCT116细胞中PCSK9基因后，结肠癌细胞生存、迁移和侵袭能力均降低；同时，其上清中乳酸浓度降低，胞内蛋白泛乳酰化水平降低，所以研究者推测PCSK9可能通过调节胞内蛋白乳酰化水平调节癌细胞生存、迁移和侵袭［12］。因此，乳酰化可能促进结肠癌的发生发展。
脓毒症是机体遭受病原体感染所发生的炎症级联放大反应，可进展为机体多器官功能衰竭甚至死亡；血清中乳酸升高与脓毒症患者死亡率增加具有显著相关性［15］。在脓毒症初期，为抵抗病原微生物及毒素入侵，体内将产生高水平炎症反应，而过度炎症会损害自身组织；乳酸可通过抑制炎性因子的产生缓解自身组织损伤；但脓毒症晚期，因免疫系统过度消耗使机体呈免疫抑制状态，乳酸的此种作用可能会损害机体［16］。乳酸通过小鼠巨噬细胞表面GPR81介导的信号抑制促炎因子的表达，并诱导巨噬细胞向M2型极化［17］。此外，乳酸钠处理可抑制脓毒症大鼠模型血清中IL-1β等促炎因子产生，改善脓毒症微循环障碍以及心脏和肾脏损伤［18］。因此，乳酸在脓毒症中发挥了抑制促炎因子产生的作用。高迁移率族蛋白B1（high mobility group box-1 protein，HMGB1）是一种高度保守且普遍存在的蛋白质，在脓毒症后期高表达并影响脓毒症的发展和预后［19］。与脓毒症对照小鼠相比，给予乳酸的脓毒症小鼠血清中乳酸水平和HMGB1水平显著升高，而存活率则显著降低；抑制乳酸生成可逆转上述现象，表明乳酸与脓毒症血清中HMGB1水平以及死亡率密切相关［20］；该研究还显示，给予巨噬细胞乳酸可促进HMGB1胞质转移、溶酶体定位和外泌体形式释放；进一步研究证实，乳酸可通过乙酰化酶P300/CBP使HMGB1发生乳酰化；同时，乳酸可通过激活大肿瘤抑制激酶1（large tumor suppressor kinase 1，LATS1）介导Yes相关蛋白（Yes associated protein，YAP）磷酸化和降解，抑制YAP依赖的沉默调节蛋白1（sirtuin 1，SIRT1）的表达和核转位，使HMGB1乙酰化水平显著增加。一项临床前瞻性研究［21］显示，在健康志愿者和危重患者的外周血单核细胞中均检测到乳酰化，而休克患者乳酰化水平较高。H3K18乳酰化表达与急性生理与慢性健康评估（acute physiology and chronic health evaluation，APACHEⅡ）评分、第1天序贯器官衰竭估计（Sequential Organ Failure Assessment，SOFA）评分、ICU住院时间、机械通气时间和血清乳酸水平呈正相关；与非脓毒症休克患者相比，脓毒症休克患者H3K18乳酰化水平更高，表明H3K18乳酰化可能反映危重症的严重程度。因此，乳酰化在脓毒症后期可能是有害因素。
The original manuscript was drafted by GE Lingling. The revision of the manuscript was reviewed and guided by HUANG Hongjun and LUO Yan. All the authors have read the last version of paper and consented for submission.
利益冲突声明
所有作者声明不存在利益冲突。
All authors disclose no relevant conflict of interests.
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