乳酸化修饰在肿瘤中的研究进展

来源期刊：广州医药 | 1237-1245 发布时间：2024-11-20 收稿时间：2025/2/11 15:24:55 阅读量：52

作者：: 洪雅滢,

郑莉,

谢涛,

赵善超,

关键词：: 乳酸化修饰增殖迁移免疫逃逸肿瘤; lactation modification proliferation migration immune escape tumor

DOI：: 10. 20223 / j. cnki. 1000-8535. 2024. 11. 001

收稿时间：: 2024-05-30
修订日期：
接收日期：
引用总数：: 2

乳酸以往被视为不具备生物学功能的代谢废物。随着人们对乳酸的深入研究,发现乳酸有多种作用。乳酸化修饰是近期发现一种与乳酸有关的蛋白质翻译后修饰过程。乳酸化修饰主要有两种,一种是与乳酸相关的直接修饰,另外一种是与丙酮酸相关的间接修饰。这两种乳酸化修饰均可能受到糖酵解、乳酸转运与堆积、蛋白质串扰以及神经系统等多方面的调控。乳酸化修饰可以通过直接或间接修饰组蛋白或非组蛋白,从而在肿瘤组织的代谢重编程、增殖、迁移及免疫逃逸中发挥着重要作用。乳酸化修饰的深入研究,有望为肿瘤的诊断和治疗开辟新的路径。因此,为了明确乳酸化修饰在肿瘤方面的研究进展,本文就蛋白乳酸化修饰的分子机制及其在肿瘤中作用的研究进展作一综述。

赵善超 南方医科大学第五附属医院副院长，泌尿外科教授、主任医师、博士研究生导师、博士后合作导师、医学博士，国务院特殊津贴专家，国家重点研发计划项目首席科学家。入选国家级领军人才，广东省卫生健康领军人才，广东省杰出青年医学人才。获评《南粤优秀教师》《广东医师奖》《国之名医》等。担任国家自然科学基金同行评议专家、国家科学技术奖励评审专家、国家教育部学位中心评审专家；担任中华医学会男科学分会第六、七届青委会副主任委员、中国性学会前列腺疾病分会副主任委员、广东省医学会男科学分会候任主任委员等学术任职。主要研究方向：前列腺癌的发病机制及诊治研究。以第一作者或通讯作者发表论文70余篇，其中以第一作者或通讯作者/共同通讯作者发表SCI论文50余篇，单篇最高影响因子37.3分并入选高被引论文。主持国家重点研发计划项目1项、国家自然科学基金5项、中华医学会专项基金1项、广东省课题基金7项、广州市重大专项1项。以第一完成人获得广东省科技进步一等奖、中华医学科技奖二等奖、广东医学科技奖一等奖等奖项。

乳酸是细胞在缺氧条件下进行无氧糖酵解时产生的代谢产物，以往被视为不具备生物学功能的代谢废物。然而，近年来的研究发现，乳酸可作为一种多功能信号转导分子在炎症和癌症等众多病理生理过程中发挥重要作用。早在20世纪20年代，德国科学家Warburg发现了肿瘤细胞在有氧条件下能以高效的速率吸收葡萄糖进行糖酵解，并产生大量的乳酸，这一现象在1972年被命名为Warburg效应^［1］。乳酸不仅能直接影响肿瘤细胞，其还可通过乳酸化修饰来影响肿瘤的进展^［2］。本文旨在总结乳酸化修饰对肿瘤的影响。

1 乳酸化修饰的发现与鉴定

1980年，文献首次报道了从马下颌腺分离出具有乳酰基的神经氨酸^［3］。1993年，文献进一步报道了在胃里面发现了具有乳酸修饰的神经氨酸（9-O-乳酰基-N-乙酰神经氨酸），这标志着乳酸化修饰被正式发现。随着液相色谱和质谱的飞速发展（LC/MS），蛋白质翻译后修饰的研究不断取得突破，乳酸化修饰的研究也日渐深入。2019年，Yingming Zhao团队在Nature上发表了一篇研究论文，揭示了人和鼠中组蛋白赖氨酸的乳酸化修饰现象^［4］。通过质谱检测，他们发现组蛋白尾部赖氨基酸残基的质量偏移了72.021Da，通过质谱图谱对比，他们发现这是由于赖氨酸残基上添加了乳酸基团所致，用同位素13Ｃ进行代谢追踪证实外源性或内源性乳酸皆可参与组蛋白赖氨酸的乳酸化修饰^［4］。
随着蛋白乳酸化修饰研究的不断深入，越来越多的乳酸化修饰位点被揭示。2020年，研究人员通过蛋白质组学及液相二级质谱在灰霉病菌（一种破坏性的坏死性营养真菌病原体）中成功鉴定出了166种蛋白质中的273个乳酸化位点，约2/3的乳酸化蛋白分布在细胞质中，而27%乳酸化蛋白则分布在线粒体中。此外，被鉴定出的乳酸化蛋白约有1/3与蛋白翻译紧密相关，表明乳酸化修饰与核糖体相关蛋白亚群有紧密联系，乳酸化修饰很可能在调控蛋白的表达水平上发挥重要作用^［5］。同时，在一项非酶促乳酸化的研究中鉴定了350种乳酸化修饰蛋白，通过DAVID数据库（The Database for Annotation，Visualization and Integrated Discovery）和KEGG（Kyoto Encyclopedia of Genes and Genomes）数据库的分析，发现乳酸化修饰蛋白主要富集在糖酵解和碳代谢通路上^［6］。这进一步表明乳酸化修饰可能通过多种途径调控生物活动，对生命体的活动具有重要意义。

近年来，生物信息技术的飞速发展，为研究人员探索生命过程提供了极大的便利。虽然质谱及液相质谱可以鉴定出蛋白质的乳酸化修饰位点，但这些方法相对耗时且费力。为了提高预测蛋白乳酸化修饰位点的效率，科学家们研发了一系列网站来预测蛋白乳酸化位点，例如基于少样本学习的乳酸化预测网站（http：//kla.zbiolab.cn/）^［7］、联合神经网络及网络服务器的DeepKla（http：//lin-group.cn/server/DeepKla）^［8］以及采用自动机器学习的Auto-Kla（http：//tubic.org/Kla）^［9］。这些工具的出现，为研究人员提供了更加便捷和高效的手段来探索乳酸化修饰的作用。

2 乳酸化修饰的途径及影响因素

乳酸存在两种立体异构体，即L-乳酸和D-乳酸^［10］。大多数哺乳动物糖酵解产生L-乳酸，而肿瘤细胞中经过Warburg效应会产生大量的L-乳酸^［10］。D-乳酸是L-乳酸的的光学异构体，在正常情况下生物体中D-乳酸的含量显著低于L-乳酸^［10］。而体内也存在两种乳酸化修饰途径：L-乳酸化与D-乳酸化^［10］，也分别被称为直接乳酸化与间接乳酸化^［11］。直接乳酸化是以L-乳酸为前体，由乳酰辅酶 A提供乳酰基（用于乳酸化修饰的基团），在一系列酶促反应的作用下完成乳酸化修饰^［4］。酶促反应主要涉及三种酶，分别是写入酶（writer）、擦除酶（eraser）和阅读酶（reader）^［12］。写入酶负责将乳酰基附着在蛋白质的特定位点，而擦除酶是负责清除蛋白质上的乳酸化修饰，而阅读酶含有特殊结构域，主要负责识别特定的表观遗传标记来发挥相应的作用^［12］。研究发现，在HCT116和HEK293T细胞中沉默p300可以降低组蛋白乳酸化的水平，表明p300是潜在的乳酸化写入酶^［13］。同时，组蛋白乙酰转移酶（HAT）和KAT8也可作为写入酶在乳酸化修饰上发挥作用^［14-15］。Ⅰ类和Ⅲ类组蛋白去乙酰酶（histone deacetylase，HDAC）例如HDAC1-3和SIRT1-3是常见的乳酸化擦除酶，其中HDAC1和3去除乳酸化能力尤为突出，可去除L-乳酸化和D-乳酸化的修饰^［10］。然而，目前尚不明确哪些蛋白在乳酸化修饰中充当着阅读酶的角色以及他们发挥的具体作用。

间接乳酸化是以丙酮醛为前体，在高水平糖酵解的组织中通过S-D-乳酰谷胱甘肽间接提供乳酰基团完成非组蛋白的乳酸化修饰，由于这一过程无需生物酶的参与，所以也被称作“非酶促赖氨酸乳酰化”，在人胚肾细胞中可以检测到350种非酶促赖氨酸乳酸化的蛋白质^［6］。此外，L-乳酸可以通过抑制乳酰谷胱甘肽降解从而上调其表达水平，因此L-乳酸可以促进直接和间接蛋白乳酸化修饰^［6］。

乳酸化修饰可受多种因素的影响。首先，乳酸化修饰与糖酵解紧密相关。糖酵解过程中可产生两种乳酸化修饰的前体（L-乳酸和丙酮醛），从而促进乳酸化修饰。因此糖酵解与细胞中的乳酸化修饰显著正相关。使用线粒体呼吸抑制剂鱼藤酮促进细胞进行糖酵解，不仅会增加细胞内乳酸含量，同时也会上调组蛋白乳酸化水平^［4］。其次，乳酸转运也会对乳酸化修饰产生影响^［16］。L-乳酸和 D-乳酸都可由单羧酸转运蛋白（monocarboxylate transporter，MCT）家族转运进出细胞，从而调控细胞内的乳酸水平^［17］。MCT4促进L-乳酸从细胞内流出，MCT1、MCT2促进L-乳酸从细胞外流入^{［18–20］}。研究表明，MCT能促使巨噬细胞摄取细胞外乳酸以乳酸化 HMGB1，而使用 MCT抑制剂则可阻断这个过程，从而抑制高乳酸水平诱导的乳酸化修饰^［21］。此外，直接乳酸化修饰受生物酶的调控，因此酶的活性对直接乳酸化修饰具有重要作用^［10］。同时，乳酸化修饰还可能受神经系统的影响。社交挫败应激（SDS）模型的小鼠大脑中，乳酸的含量及乳酸化修饰水平与神经元活动呈显著正相关，表明乳酸化修饰在神经活动及调控抑郁或焦虑中发挥着重要作用^［11］。蛋白质存在多种翻译后修饰的方式，它们之间可以相互影响和交互，这一现象被称为串扰，其也是影响乳酸化修饰的一个重要因素。目前已经发现乳酸化修饰和乙酰化修饰可竞争结合组蛋白H3的赖氨酸残基^［11］此外，乳酸化METTL16可以促进FDX1mRNA的m6A修饰，从而上调FDX1的蛋白水平，促进胃癌细胞的铜死亡过程^［22］。以上研究结果表明，乳酸化修饰是一个复杂的过程，其可受到多种因素的调控和影响。

3 乳酸化修饰对肿瘤的影响

随着人类对肿瘤领域的不断探索与深化研究，肿瘤所展现的众多复杂特性逐渐被揭示，其中尤为引人注目的是其高度的可塑性^［23］。这种可塑性体现在肿瘤能够发起一系列精妙反应，诸如免疫逃逸机制以及向周边组织、血管系统的侵袭与转移能力，极大地挑战了现有的医疗策略^［24］。在肿瘤微环境中，Warburg效应导致的乳酸堆积是癌症的一个普遍现象。这种乳酸堆积进一步促进了蛋白质的乳酸化修饰过程，进而影响肿瘤的可塑性。在此，我们总结了蛋白乳酸化修饰对肿瘤的具体影响，以期更深入的了解其在肿瘤学中的具体作用。

3.1 乳酸化修饰影响肿瘤代谢重编程

为了能够满足肿瘤快速生长对能量的巨大需求，大部分肿瘤细胞会进行代谢重编程以适应这种环境^［25］。经过代谢重编程后，肿瘤细胞会增强糖酵解途径，导致乳酸的堆积进而促进蛋白质的乳酸化修饰。这种乳酸化修饰也会反过来促进肿瘤的代谢重编程。从而形成，“代谢重编程-乳酸化”的正向反馈调节通路，从而加速肿瘤的进展。在胰腺癌中，肿瘤微环境中的乳酸促进了核仁和纺锤体相关蛋白 1（nucleolar and spindle-associated protein 1，NUSAP1）的乳酸化修饰从而上调了NUSAP1的蛋白水平^［26］。而NUSAP1与c-Myc和HIF-1α形成复合物并与乳酸脱氧酶A（lactate dehydrogenase，LDHA）的启动子区域相结合，进而促进LDHA的转录和翻译从而促进肿瘤细胞的糖酵解及肿瘤环境中的乳酸堆积，由此形成乳酸化NUSAP1-LDHA-乳酸的正反馈调节通

路，推动了胰腺癌的发展^［26］。组蛋白的乳酸化修饰也能够影响代谢相关基因的表达。在非小细胞肺癌中，乳酸可影响糖酵解酶HK-1和三羧酸循环酶SDHA启动子区域组蛋白的乳酸化水平进而调控糖酵解，促进肿瘤细胞的增殖^［27］。在乙型肝炎病毒相关肝癌的队列研究中发现，肝癌细胞中乳酸化的组蛋白可影响三羧酸循环、氨基酸、脂肪酸及核苷酸代谢等多种代谢途径^［28］。此外，缺氧环境下诱导线粒体AARS2积累，通过乳酸化氧化磷酸化的关键酶来抑制氧化磷酸化过程^［29］。乳酸化可稳定DCBLD1从而激活磷酸戊糖通路，促进宫颈癌的进展^［30］。上述结果提示，乳酸化修饰在肿瘤的代谢重编程中发挥重要的作用，与肿瘤的发展密切相关。

3.2 乳酸化修饰促进肿瘤增殖和迁移

增殖和迁移是肿瘤细胞常见的恶性生物学行为，其中蛋白乳酸化修饰在肿瘤增殖过程发挥着重要作用。研究表明，前蛋白转化酶枯草溶菌素9（proprotein convertase subtilisin 9，PCSK9）可促进结直肠癌的增殖及迁移，而降低PCSK9可显著抑制结直肠癌中蛋白质的乳酸化修饰，因此乳酸化修饰可能参与肿瘤的增殖及迁移过程^［31］。类似的，组蛋白乳酸化可稳定c-Myc的表达，从而促进乳腺癌的增殖^［32］。相反，研究表明抑制蛋白质的乳酸化可抑制肿瘤的增殖。例如，三萜类抗肿瘤化合物去甲泽拉木醛可以抑制组蛋白H3K9和H3K56的乳酸化修饰水平从而抑制肝癌细胞的增殖^［33］。此外，发挥擦除酶作用的SIRT3可通过抑制细胞周期蛋白E2的乳酸化修饰从而诱导肝癌细胞的凋亡^［34］。然而，也有研究指出，乳酸可以通过诱导葡萄膜黑色素瘤的H3K18的乳酸化来抑制细胞增殖^［35］。

蛋白乳酸化修饰在肿瘤的迁移中也发挥着重要作用。研究报道，肾透明细胞癌中，希佩尔林道（VHL）抑癌基因的缺失会诱导H3K18的乳酸化水平的上升，从而促进血小板衍生生长因子受体β（PDGFRβ）的转录，这种受体又能够诱导H3K18的乳酸化，形成正向反馈循环，推动肿瘤的增殖和迁移^［36］。Xia Jiazeng等人报道，乳酸化H3K18上调VCAM1表达从而激活AKT-mTOR-CXCL1促进胃癌的进展和转移^［37］。腺苷酸激酶2（adenylate kinase 2，AK2）是调控ATP及ADP关键酶，其在肿瘤的发生发展中发挥着重要作用^［28］。AK2的K28位点的乳酸化修饰会抑制AK2的功能从而下调了细胞内的凋亡途径来促进肿瘤细胞的增殖，同时乳酸化的AK2可能干扰ATP的代谢影响细胞外围的局部ATP供应，从而增强HepG2细胞的迁移能力^［28］。在结直肠癌中，革兰氏阴性细菌来源的脂多糖通过促进LINC00152启动子与乳酸化组蛋白进行结合，同时降低抑制因子 YY1与LINC00152启动子的结合效率，从而上调了 LINC00152的表达，进而促进了肿瘤细胞的迁移和侵袭^［38］。
非组蛋白乳酸化修饰可通过稳定蛋白表达促进肿瘤进展。在前列腺癌中，单羧酸转运蛋白 1（MCT1）将细胞外的乳酸转运到前列腺癌细胞内，上调HIF-1α乳酸化水平并稳定其表达，从而促进KIAA1199的转录并促进血管生成，最终促进肿瘤细胞的转移^［39］。缺氧条件下，乳酸堆积会上调β-catenin乳酸化水平，稳定β-catenin的表达并激活Wnt信号通路，从而促进结直肠癌的增殖^［40］。综上所述，乳酸化在肿瘤的增殖和迁移中扮演着重要角色，但乳酸化修饰在不同的肿瘤中具有不同作用，还需要研究学者们不断深入研究。

3.3 乳酸化修饰促进肿瘤免疫逃逸

乳酸化修饰在肿瘤免疫逃逸中也发挥着重要作用。巨噬细胞作为先天性免疫系统的重要组成成员，在肿瘤发展的各个阶段发挥着重要作用。M1巨噬细胞通过激活T细胞和自然杀伤细胞的强大杀伤能力来启动免疫反应进而发挥促炎作用，它们可以破坏组织的完整性并阻碍肿瘤的进展^［41-42］。相对而言，M2巨噬细胞主要承担抗炎和组织重塑的职责，并促进肿瘤增殖、侵袭、转移、血管生成和免疫抑制^［41-42］。乳酸可以诱导M1巨噬细胞表达M2型相关蛋白例如精氨酸酶1（arginase 1，Arg1）并推动巨噬细胞向M2型极化^［43］。此外，B细胞磷酸肌醇 3-激酶衔接蛋白（B-cell adapter for phosphoinositide 3-kinase，BCAP）也能通过调控糖酵解及组蛋白乳酸化修饰进一步促进巨噬细胞表达损伤修复蛋白例如Arg1［44］，使得巨噬细胞从抑癌状态向促癌状态转化变。另外一项研究表明，Arg1的表达水平与肿瘤相关巨噬细胞中组蛋白乳酸化水平呈正相关^［4］。此外，组蛋白乳酸化水平和巨噬细胞迁移抑制因子（MIF）表达的降低有助于促进M1型巨噬细胞的极化，从而抑制了结肠癌的进展和转移^［31］。然而，有研究指出组蛋白的乳酸化修饰与M2型巨噬细胞的活化并无直接关联，而是与巨噬细胞的死亡呈正相关^［45］。

Treg细胞在维持肿瘤微环境中的免疫抑制发挥重要作用。乳酸可通过乳酸化MOSEIN（细胞膜与细胞骨架的连接蛋白）中Lys72来调节Treg细胞的生成，并改善MOESIN与转化生长因子β受体和下游SMAD3的信号传导，从而稳定Treg细胞的功能，促进肿瘤细胞免疫逃逸^［46］。肿瘤浸润性髓系细胞（tumor-infiltrating myeloid cells，TIMs）是参与肿瘤免疫逃逸的关键细胞群，其功能受多种表观遗传机制的调控。乳酸通过乳酸化TIMs中的H3K18增强METTL3转录，从而介导了 TIMs 中Jak1 mRNA上的m6A修饰，m6A-YTHDF1轴提高了JAK1 蛋白的翻译效率，并随后增强了 STAT3 的磷酸化，促进了肿瘤的进展^［47］。在恶性胸腔积液的冷肿瘤微环境（CD8+ T细胞和NK细胞的抗肿瘤活性受到抑制，Treg细胞活性增强）中发现了一种名为 FOXP3+自然杀伤T样细胞（natural killer T（NKT）-like cells，NKT）样的特殊细胞群，它们通过较高蛋白乳酸化水平以维持免疫抑制功能［48］。此外，Ikaros家族锌指1（IKZF1）K164乳酸化可以直接影响Th17相关基因的表达，如Runt相关转录因子（Runx1）、Toll样受体4（Tlr4）、白细胞介素-2（IL-2）和白细胞介素-4（IL-4）来增强Th17的分化^［49］。此外，STAT5通过促进组蛋白的乳酸化来促进血液恶性肿瘤程序性死亡配体（programmed death-ligand，PD-L1）的表达，从而促进肿瘤的免疫逃逸^［50］。据报道，乳酸对树突状细胞、T细胞、自然杀伤细胞等免疫细胞的功能也具有抑制作用^［51-52］，但蛋白乳酸化与这些免疫细胞之间的关系尚未明确。以上结果研究表明，乳酸化修饰在肿瘤免疫逃逸中扮演着复杂的角色，探究其对肿瘤作用的机制可为肿瘤治疗提供新的思路。

4 乳酸化修饰的临床意义

乳酸化修饰水平可以作为预测患者生存预后的关键指标。缺失的Numb/Parkin能促进组蛋白泛乳酸化、H3K18乳酸化水平的上调，同时影响Syn和 NSE等神经内分泌相关基因的转录，从而对神经内分泌前列腺癌和肺腺癌的预后产生不良影响^［53］。相比与癌旁组织，组蛋白乳酸化在胃癌和乳腺癌组织中显著升高，其水平与预后相关，这表明组蛋白乳酸化是胃癌和乳腺癌潜在的预后标志物^［54-55］。Lu Ling等人报道，Treg细胞中的MOESIN 乳酸化水平与免疫治疗的疗效呈负相关，抗PD-1和乳酸脱氢酶抑制剂联合治疗比单独使用抗PD-1展现出了更强的抗肿瘤作用^［46］。研究表明，使用PI3K的抑制剂降低了肿瘤相关巨噬细胞中组蛋白乳酸化水平，与抗PD-1的药物联用可增强巨噬细胞对前列腺癌的杀伤作用^［56］。此外，Oxamate可以通过抑制CCR8的乳酸化水平从而增强CAR-T对胶质母细胞瘤的疗效^［57］。这表明抑制乳酸化修饰可能改善肿瘤免疫治疗效果。不仅如此，乳酸化H3K18可上调RUBCNL的蛋白水平来增强结直肠癌对贝伐珠单抗的耐药性^［58］。同时，组蛋白乳酸化也会促进膀胱癌对顺铂耐药的能力^［59］。因此，乳酸化修饰对改善肿瘤治疗效果具有重要意义。
乳酸的堆积会促使蛋白质的乳酸化修饰，因此，抑制乳酸的生成对于抑制肿瘤的发展至关重要。乳酸脱氢酶作为乳酸生成的关键酶，其抑制剂的研发具有重要作用。基于蛋白乳酸化的机制，目前针对乳酸化修饰靶点的新药研究进展如火如荼。目前，已研发出几种有效的乳酸脱氢酶抑制剂如Oxamate和FX-11，它们可以抑制乳酸的产生并降低乳酸化修饰^［60-61］。然而，使用乳酸脱氢酶进行非靶向的抗癌治疗也可能会带来一些副作用，例如抑制乳酸的生成可能导致乳酸的前体丙酮酸的增多，从而诱导胶原羟基化来驱动细胞外基质重塑，从而促进乳腺癌的转移性生长^［62］。此外，糖酵解过程也是肌肉细胞正常生命活动的关键环节，若是无针对性的抑制乳酸脱氢酶可能会影响细胞的正常功能，造成不良反应。因此，研发出靶向阻断乳酸脱氢酶的药物具有重要意义。

同时，抑制乳酸的转运也可以遏制乳酸的积累，例如MCT2抑制剂A-氰基-4-羟基肉桂酸酯（A-cyano-4-hydroxycinnamate）和MCT1/2抑制剂AR-C155858体外处理皮质神经元时，能够抑制外源性乳酸诱导的乳酸化^［11］。抑制MCT-1/miR-34a/IL-6/IL-6R 信号转导通路可抑制三阴性乳腺癌的上皮间充质转化、肿瘤干性和M2巨噬细胞极化^［63］。除了抑制乳酸生成和转运，直接靶向乳酸化过程中的酶也是抑制乳酸化修饰的有效途径。P300不仅是乳酸化写入酶，也是前列腺癌和乳腺癌中重要的促癌基因^［4，64］。CCS1477是市面上唯一处于IB/IIA期临床试验的P300抑制剂，其可能在血液恶性肿瘤和晚期前列腺癌中发挥作用^［65］，但其是否通过抑制乳酸化修饰而取得良好的治疗效果，我们仍未可知。此外，还有一些植物提取物可通过抑制组蛋白乳酸化来抑制肿瘤的发展。天然果实提取物Evodiamine通过下调HIF-1α中组蛋白的乳酸化水平，来抑制前列腺癌PD-L1的表达及诱导血管生成的能力^［66］。据此，我们得出乳酸化修饰不仅可以作为肿瘤预后评估的潜在标志物，更可以作为研发肿瘤治疗的新靶点。

5 总结

随着质谱及液相质谱技术的不断发展，以及人们对蛋白质翻译后修饰研究的不断深入，蛋白乳酸化修饰越来越受到人们的关注。乳酸存在L-乳酸和D-乳酸两种模式，同时包括直接乳酸化和间接乳酸化两种形式，其调控机制涉及乳酸、神经和串扰等多种途径。研究学者发现，乳酸化修饰与肿瘤之间存在紧密的联系，能够影响肿瘤细胞的增殖、迁移、代谢重编程以及介导肿瘤免疫逃逸。虽然乳酸化修饰与肿瘤恶性生物学行为之间的关系仍未完全阐明，但乳酸化修饰与肿瘤不良预后密切相关，同时抑制乳酸的生成可提高免疫治疗的疗效已经得到广泛的证据支持。因此，深入探究乳酸化修饰与肿瘤发生发展之间的复杂关系，不仅有助于丰富肿瘤表观遗传修饰的理论基础，而且对靶向药物开发和临床转化有重要意义。

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14、王安琪，杨丽，赵乐，等．蛋白质乳酸化修饰的机制和功能的研究进展［J］．肿瘤代谢与营养电子杂志，2022，9（4）：517-523．

15、XIE%E2%80%83B%EF%BC%8CZHANG%E2%80%83M%EF%BC%8CLI%E2%80%83J%EF%BC%8Cet%E2%80%83al%EF%BC%8EKAT8-catalyzed%E2%80%83%0Alactylation%E2%80%83promotes%E2%80%83eEF1A2-mediated%E2%80%83protein%E2%80%83synthesis%E2%80%83%0Aand%E2%80%83colorectal%E2%80%83carcinogenesis%EF%BC%BBJ%EF%BC%BD%EF%BC%8EProceedings%E2%80%83of%E2%80%83the%E2%80%83%0ANational%E2%80%83Academy%E2%80%83of%E2%80%83Sciences%E2%80%83of%E2%80%83the%E2%80%83United%E2%80%83States%E2%80%83of%E2%80%83%0AAmerica%EF%BC%8C2024%EF%BC%8C121%EF%BC%888%EF%BC%89%EF%BC%9Ae2314128121%EF%BC%8E

16、黄丽娜，杨毅，王博，等．蛋白质乳酸化修饰调控机制的研究进展［J］．中国病理生理杂志，2023，39（3）：559-564．

17、ENERSON%E2%80%83B%E2%80%83E%EF%BC%8CDREWES%E2%80%83L%E2%80%83R%EF%BC%8EM%20ol%20e%20c%20ul%20a%20r%E2%80%83%0Afeatures%EF%BC%8Cregulation%EF%BC%8Cand%E2%80%83function%E2%80%83of%E2%80%83monocarboxylate%E2%80%83%0Atransporters%EF%BC%9AImplications%E2%80%83for%E2%80%83drug%E2%80%83delivery%EF%BC%BBJ%EF%BC%BD%EF%BC%8EJ%E2%80%83%0APharm%E2%80%83Sci%EF%BC%8C2003%EF%BC%8C92%EF%BC%888%EF%BC%89%EF%BC%9A1531-1544%EF%BC%8E

18、BR%C3%96ER%E2%80%83S%EF%BC%8CSCHNEIDER%E2%80%83H%E2%80%83P%EF%BC%8CBR%C3%96ER%E2%80%83A%EF%BC%8Cet%E2%80%83al%EF%BC%8E%0ACharacterization%E2%80%83%20of%E2%80%83the%E2%80%83monocarboxylate%E2%80%83transporter%E2%80%83%0A1%E2%80%83expressed%E2%80%83in%E2%80%83Xenopus%E2%80%83laevis%E2%80%83oocytes%E2%80%83by%E2%80%83changes%E2%80%83in%E2%80%83%0Acytosolic%E2%80%83pH%EF%BC%BBJ%EF%BC%BD%EF%BC%8EBiochem%E2%80%83J%EF%BC%8C1998%EF%BC%8C333%EF%BC%88Pt%E2%80%831%EF%BC%89%0A%EF%BC%88Pt%E2%80%831%EF%BC%89%EF%BC%9A167-174%EF%BC%8E

19、BR%C3%96ER%E2%80%83S%EF%BC%8CBR%C3%96ER%E2%80%83A%EF%BC%8CSCHNEIDER%E2%80%83H%E2%80%83P%EF%BC%8Cet%E2%80%83al%EF%BC%8E%0ACharacterization%E2%80%83of%E2%80%83the%E2%80%83high-affinity%E2%80%83monocarboxylate%E2%80%83%0Atransporter%E2%80%83MCT2%E2%80%83in%E2%80%83Xenopus%E2%80%83laevis%E2%80%83oocytes%EF%BC%BBJ%EF%BC%BD%EF%BC%8E%0ABiochem%E2%80%83J%EF%BC%8C1999%EF%BC%8C341%EF%BC%88Pt%E2%80%833%EF%BC%89%EF%BC%88Pt%E2%80%833%EF%BC%89%EF%BC%9A529-535%EF%BC%8E

20、WILSON%E2%80%83M%E2%80%83C%EF%BC%8CJACKSON%E2%80%83V%E2%80%83N%EF%BC%8CHEDDLE%E2%80%83C%EF%BC%8Cet%E2%80%83%0Aal%EF%BC%8ELactic%E2%80%83acid%E2%80%83efflux%E2%80%83from%E2%80%83white%E2%80%83%20skeletal%E2%80%83muscle%E2%80%83is%E2%80%83%0Acatalyzed%E2%80%83by%E2%80%83the%E2%80%83monocarboxylate%E2%80%83transporter%E2%80%83isoform%E2%80%83MCT3%EF%BC%BBJ%EF%BC%BD%EF%BC%8EThe%E2%80%83Journal%E2%80%83of%E2%80%83Biological%E2%80%83Chemistry%EF%BC%8C%0A1998%EF%BC%8C273%EF%BC%8826%EF%BC%89%EF%BC%9A15920-15926%EF%BC%8E

21、YANG%E2%80%83K%EF%BC%8CFAN%E2%80%83M%EF%BC%8CWANG%E2%80%83X%EF%BC%8Cet%E2%80%83al%EF%BC%8ELactate%E2%80%83%0Apromotes%E2%80%83macrophage%E2%80%83HMGB1%E2%80%83lactylation%EF%BC%8Cacetylation%EF%BC%8C%0Aand%E2%80%83exosomal%E2%80%83release%E2%80%83in%E2%80%83polymicrobial%E2%80%83sepsis%EF%BC%BBJ%EF%BC%BD%EF%BC%8E%0ACell%E2%80%83Death%E2%80%83Differ%EF%BC%8C2022%EF%BC%8C29%EF%BC%881%EF%BC%89%EF%BC%9A133-146%EF%BC%8E

22、SUN%E2%80%83L%EF%BC%8CZHANG%E2%80%83Y%EF%BC%8CYANG%E2%80%83B%EF%BC%8Cet%E2%80%83al%EF%BC%8ELactylation%E2%80%83of%E2%80%83%0AMETTL16%E2%80%83promotes%E2%80%83cuproptosis%E2%80%83via%E2%80%83m6A-modification%E2%80%83%0Aon%E2%80%83FDX1%E2%80%83mRNA%E2%80%83in%E2%80%83gastric%E2%80%83cancer%EF%BC%BBJ%EF%BC%BD%EF%BC%8ENature%E2%80%83%0ACommunications%EF%BC%8C2023%EF%BC%8C14%EF%BC%881%EF%BC%89%EF%BC%9A6523%EF%BC%8E

23、何丹，成炜，刘铭．肿瘤可塑性与药物治疗抵抗［J］．广州医药，2024，55（3）：213-220，230．

24、P%C3%89REZ-GONZ%C3%81LEZ%E2%80%83A%EF%BC%8CB%C3%89VANT%E2%80%83K%EF%BC%8CBLANPAIN%E2%80%83%0AC%EF%BC%8ECancer%E2%80%83cell%E2%80%83plasticity%E2%80%83during%E2%80%83tumor%E2%80%83progression%EF%BC%8C%0Ametastasis%E2%80%83and%E2%80%83response%E2%80%83to%E2%80%83therapy%EF%BC%BBJ%EF%BC%BD%EF%BC%8ENature%E2%80%83%0ACancer%EF%BC%8C2023%EF%BC%8C4%EF%BC%888%EF%BC%89%EF%BC%9A1063-1082%EF%BC%8E

25、CERTO%E2%80%83M%20%EF%BC%8C%20LLIBRE%E2%80%83A%20%EF%BC%8C%20LEE%E2%80%83W%20%EF%BC%8C%20et%E2%80%83al%20%EF%BC%8E%0AUnderstanding%E2%80%83lactate%E2%80%83sensing%E2%80%83and%E2%80%83signalling%EF%BC%BBJ%EF%BC%BD%EF%BC%8E%0ATrends%E2%80%83in%E2%80%83Endocrinology%E2%80%83and%E2%80%83Metabolism%EF%BC%9ATEM%EF%BC%8C%0A2022%EF%BC%8C33%EF%BC%8810%EF%BC%89%EF%BC%9A722-735%EF%BC%8E

26、NUSAP1-LDHA-Glycolysis-Lactate%E2%80%83feedforward%E2%80%83loop%E2%80%83%0Apromotes%E2%80%83warburg%E2%80%83effect%E2%80%83and%E2%80%83metastasis%E2%80%83in%E2%80%83pancreatic%E2%80%83%0Aductal%E2%80%83adenocarcinoma%E2%80%83-%E2%80%83PubMed%EF%BC%BBEB%2FOL%EF%BC%BD%EF%BC%8E%0A%EF%BC%BB2024-03-30%EF%BC%BD%EF%BC%8Ehttps%EF%BC%9A%2F%2Fpubmed%EF%BC%8Encbi%EF%BC%8Enlm%EF%BC%8E%0Anih%EF%BC%8Egov%2F37354982%2F%EF%BC%8E

27、JIANG%E2%80%83J%EF%BC%8CHUANG%E2%80%83D%EF%BC%8CJIANG%E2%80%83Y%EF%BC%8Cet%E2%80%83al%EF%BC%8ELactate%E2%80%83%0AModulates%E2%80%83%20Cellular%E2%80%83%20Metabolism%E2%80%83%20Through%E2%80%83%20Histone%E2%80%83%0ALactylation-Mediated%E2%80%83Gene%E2%80%83Expression%E2%80%83in%E2%80%83Non-Small%E2%80%83%0ACell%E2%80%83Lung%E2%80%83Cancer%EF%BC%BBJ%EF%BC%BD%EF%BC%8EFrontiers%E2%80%83in%E2%80%83Oncology%EF%BC%8C2021%0A%EF%BC%8811%EF%BC%89%EF%BC%9A647559%EF%BC%8E

28、YANG%E2%80%83Z%EF%BC%8CYAN%E2%80%83C%EF%BC%8CMA%E2%80%83J%EF%BC%8Cet%E2%80%83al%EF%BC%8ELactylome%E2%80%83analysis%E2%80%83%0Asuggests%E2%80%83lactylation-dependent%E2%80%83mechanisms%E2%80%83of%E2%80%83metabolic%E2%80%83%0Aadaptation%E2%80%83in%E2%80%83hepatocellular%E2%80%83carcinoma%EF%BC%BBJ%EF%BC%BD%EF%BC%8ENature%E2%80%83%0AMetabolism%EF%BC%8C2023%EF%BC%8C5%EF%BC%881%EF%BC%89%EF%BC%9A61-79%EF%BC%8E

29、MAO%E2%80%83Y%EF%BC%8CZHANG%E2%80%83J%EF%BC%8CZHOU%E2%80%83Q%EF%BC%8Cet%E2%80%83al%EF%BC%8EHypoxia%E2%80%83%0Ainduces%E2%80%83%20mitochondrial%E2%80%83%20protein%E2%80%83lactylation%E2%80%83to%E2%80%83limit%E2%80%83%0Aoxidative%E2%80%83phosphorylation%EF%BC%BBJ%EF%BC%BD%EF%BC%8ECell%E2%80%83Research%EF%BC%8C%0A2024%EF%BC%8C34%EF%BC%881%EF%BC%89%EF%BC%9A13-30%EF%BC%8E

30、MENG%E2%80%83Q%EF%BC%8CSUN%E2%80%83H%EF%BC%8CZHANG%E2%80%83Y%EF%BC%8Cet%E2%80%83al%EF%BC%8ELactylation%E2%80%83%0Astabilizes%E2%80%83DCBLD1%E2%80%83activating%E2%80%83the%E2%80%83%20pentose%E2%80%83%20phosphate%E2%80%83%0Apathway%E2%80%83to%E2%80%83promote%E2%80%83cervical%E2%80%83cancer%E2%80%83progression%EF%BC%BBJ%EF%BC%BD%EF%BC%8E%0AJournal%E2%80%83of%E2%80%83Experimental%E2%80%83%26%E2%80%83Clinical%E2%80%83Cancer%E2%80%83Research%EF%BC%9A%0ACR%EF%BC%8C2024%EF%BC%8C43%EF%BC%881%EF%BC%89%EF%BC%9A36%EF%BC%8E

31、WANG%E2%80%83L%EF%BC%8CLI%E2%80%83S%EF%BC%8CLUO%E2%80%83H%EF%BC%8Cet%E2%80%83al%EF%BC%8EPCSK9%E2%80%83%20promotes%E2%80%83%0Athe%E2%80%83%20progression%E2%80%83and%E2%80%83metastasis%E2%80%83of%E2%80%83colon%E2%80%83cancer%E2%80%83cells%E2%80%83through%E2%80%83%20regulation%E2%80%83of%E2%80%83EMT%E2%80%83and%E2%80%83PI3K%2FAKT%E2%80%83signaling%E2%80%83in%E2%80%83%0Atumor%E2%80%83cells%E2%80%83and%E2%80%83phenotypic%E2%80%83polarization%E2%80%83of%E2%80%83macrophages%0A%EF%BC%BBJ%EF%BC%BD%EF%BC%8EJournal%E2%80%83%20of%E2%80%83Experimental%E2%80%83%26%E2%80%83Clinical%E2%80%83Cancer%E2%80%83%0AResearch%EF%BC%9ACR%EF%BC%8C2022%EF%BC%8C41%EF%BC%881%EF%BC%89%EF%BC%9A303%EF%BC%8E

32、PANDKAR%E2%80%83M%E2%80%83R%EF%BC%8CSINHA%E2%80%83S%EF%BC%8CSAMAIYA%E2%80%83A%EF%BC%8Cet%E2%80%83al%EF%BC%8E%0AOncometabolite%E2%80%83%20lactate%E2%80%83%20enhances%E2%80%83%20breast%E2%80%83%20cancer%E2%80%83%0Aprogression%E2%80%83by%E2%80%83orchestrating%E2%80%83histone%E2%80%83lactylation%02dependent%E2%80%83c-Myc%E2%80%83expression%EF%BC%BBJ%EF%BC%BD%EF%BC%8ETranslational%E2%80%83%0AOncology%EF%BC%8C2023%EF%BC%8C37%EF%BC%9A101758%EF%BC%8E

33、PAN%E2%80%83L%EF%BC%8CFENG%E2%80%83F%EF%BC%8CWU%E2%80%83J%EF%BC%8Cet%E2%80%83al%EF%BC%8EDemethylzeylasteral%E2%80%83%0Atargets%E2%80%83lactate%E2%80%83%20by%E2%80%83inhibiting%E2%80%83%20histone%E2%80%83lactylation%E2%80%83to%E2%80%83%0Asuppress%E2%80%83the%E2%80%83tumorigenicity%E2%80%83of%E2%80%83liver%E2%80%83cancer%E2%80%83stem%E2%80%83cells%0A%EF%BC%BBJ%EF%BC%BD%EF%BC%8EPharmacol%E2%80%83Res%EF%BC%8C2022%EF%BC%88181%EF%BC%89%EF%BC%9A106270%EF%BC%8E

34、JIN%E2%80%83J%EF%BC%8CBAI%E2%80%83L%EF%BC%8CWANG%E2%80%83D%EF%BC%8Cet%E2%80%83al%EF%BC%8ESIRT3-dependent%E2%80%83%0Adelactylation%E2%80%83%20of%E2%80%83%20cyclin%E2%80%83%20E2%E2%80%83%20prevents%E2%80%83%20hepatocellular%E2%80%83%0Acarcinoma%E2%80%83growth%EF%BC%BBJ%EF%BC%BD%EF%BC%8EEMBO%E2%80%83Reports%EF%BC%8C2023%EF%BC%8C24%0A%EF%BC%885%EF%BC%89%EF%BC%9Ae56052%EF%BC%8E

35、%20LONGHITANO%E2%80%83L%EF%BC%8CGIALLONGO%E2%80%83S%EF%BC%8CORLANDO%E2%80%83L%EF%BC%8C%0Aet%E2%80%83al%EF%BC%8ELactate%E2%80%83%20rewrites%E2%80%83the%E2%80%83metabolic%E2%80%83%20reprogramming%E2%80%83%0Aof%E2%80%83%20uveal%E2%80%83%20melanoma%E2%80%83%20cells%E2%80%83%20and%E2%80%83induces%E2%80%83%20quiescence%E2%80%83%0Aphenotype%EF%BC%BBJ%EF%BC%BD%EF%BC%8EInternational%E2%80%83%20Journal%E2%80%83of%E2%80%83Molecular%E2%80%83%0ASciences%EF%BC%8C2022%EF%BC%8C24%EF%BC%881%EF%BC%89%EF%BC%9A24%EF%BC%8E

36、YANG%E2%80%83J%EF%BC%8CLUO%E2%80%83L%EF%BC%8CZHAO%E2%80%83C%EF%BC%8Cet%E2%80%83al%EF%BC%8EA%E2%80%83%20positive%E2%80%83%0Afeedback%E2%80%83loop%E2%80%83between%E2%80%83inactive%E2%80%83VHL-triggered%E2%80%83histone%E2%80%83%0Alactylation%E2%80%83and%E2%80%83PDGFR%CE%B2%E2%80%83%20signaling%E2%80%83%20drives%E2%80%83clear%E2%80%83cell%E2%80%83%0Arenal%E2%80%83cell%E2%80%83carcinoma%E2%80%83progression%EF%BC%BBJ%EF%BC%BD%EF%BC%8EInt%E2%80%83%20J%E2%80%83%20Biol%E2%80%83%0ASci%EF%BC%8C2022%EF%BC%8C18%EF%BC%888%EF%BC%89%EF%BC%9A3470-3483%EF%BC%8E

37、ZHAO%E2%80%83Y%EF%BC%8CJIANG%E2%80%83J%EF%BC%8CZHOU%E2%80%83P%EF%BC%8Cet%E2%80%83al%EF%BC%8EH3K18%E2%80%83%0Alactylation-mediated%E2%80%83VCAM1%E2%80%83%20expression%E2%80%83%20promotes%E2%80%83%0Agast%20ric%E2%80%83%20cance%20r%E2%80%83%20p%20rog%20ression%E2%80%83%20and%E2%80%83%20metastasis%E2%80%83%20via%E2%80%83%0AAKT-mTOR-CXCL1%E2%80%83axis%EF%BC%BBJ%EF%BC%BD%EF%BC%8EBioc%20hemical%E2%80%83%0APharmacology%EF%BC%8C2024%EF%BC%8C222%EF%BC%9A116120%EF%BC%8E

38、WANG%E2%80%83J%EF%BC%8CLIU%E2%80%83Z%EF%BC%8CXU%E2%80%83Y%EF%BC%8Cet%E2%80%83al%EF%BC%8EEnterobacterial%E2%80%83%0ALPS-inducible%E2%80%83%20LINC00152%E2%80%83is%E2%80%83%20regulated%E2%80%83%20by%E2%80%83%20histone%E2%80%83%0Alactylation%E2%80%83%20and%E2%80%83%20promotes%E2%80%83%20cancer%E2%80%83%20cells%E2%80%83invasion%E2%80%83%20and%E2%80%83%0Amigration%EF%BC%BBJ%EF%BC%BD%EF%BC%8EFront%E2%80%83Cell%E2%80%83Infect%E2%80%83Microbiol%EF%BC%8C2022%0A%EF%BC%8812%EF%BC%89%EF%BC%9A913815%EF%BC%8E

39、%20LUO%E2%80%83Y%EF%BC%8CYANG%E2%80%83Z%EF%BC%8CYU%E2%80%83Y%EF%BC%8Cet%E2%80%83al%EF%BC%8EHIF1%CE%B1%E2%80%83lactylation%E2%80%83%0Aenhances%E2%80%83%20K%20IAA1199%E2%80%83%20t%20ransc%20ription%E2%80%83%20to%E2%80%83%20p%20romote%E2%80%83%0Aangiogenesis%E2%80%83%20and%E2%80%83%20vasculogenic%E2%80%83mimicry%E2%80%83in%E2%80%83%20prostate%E2%80%83%0Acancer%EF%BC%BBJ%EF%BC%BD%EF%BC%8EInternational%E2%80%83%20Journal%E2%80%83%20of%E2%80%83%20Biological%E2%80%83%0AMacromolecules%EF%BC%8C2022%EF%BC%8C222%EF%BC%88Pt%E2%80%83B%EF%BC%89%EF%BC%9A2225-2243%EF%BC%8E

40、MIAO%E2%80%83Z%EF%BC%8CZHAO%E2%80%83X%EF%BC%8CLIU%E2%80%83X%EF%BC%8EHypoxia%E2%80%83%20induced%E2%80%83%0A%CE%B2-catenin%E2%80%83lactylation%E2%80%83promotes%E2%80%83the%E2%80%83cell%E2%80%83proliferation%E2%80%83%0Aand%E2%80%83%20stemness%E2%80%83%20of%E2%80%83%20colorectal%E2%80%83%20cancer%E2%80%83through%E2%80%83the%E2%80%83%20wnt%E2%80%83signaling%E2%80%83pathway%EF%BC%BBJ%EF%BC%BD%EF%BC%8EExp%E2%80%83Cell%E2%80%83Res%EF%BC%8C2023%EF%BC%8C422%0A%EF%BC%881%EF%BC%89%EF%BC%9A113439%EF%BC%8E

41、ATRI%E2%80%83C%EF%BC%8CGUERFALI%E2%80%83F%E2%80%83Z%EF%BC%8CLAOUINI%E2%80%83D%EF%BC%8ERole%E2%80%83%20of%E2%80%83%0AHuman%E2%80%83Macrophage%E2%80%83Polarization%E2%80%83in%E2%80%83Inflammation%E2%80%83during%E2%80%83%0AInfectious%E2%80%83Diseases%EF%BC%BBJ%EF%BC%BD%EF%BC%8EInternational%E2%80%83%20Journal%E2%80%83%20of%E2%80%83%0AMolecular%E2%80%83Sciences%EF%BC%8C2018%EF%BC%8C19%EF%BC%886%EF%BC%89%EF%BC%9A1801%EF%BC%8E

42、MARTINEZ%E2%80%83F%E2%80%83O%EF%BC%8CSICA%E2%80%83A%EF%BC%8CMANTOVANI%E2%80%83A%EF%BC%8Cet%E2%80%83al%EF%BC%8E%0AMacrophage%E2%80%83activation%E2%80%83and%E2%80%83polarization%EF%BC%BBJ%EF%BC%BD%EF%BC%8EFrontiers%E2%80%83%0Ain%E2%80%83Bioscience%EF%BC%9AA%E2%80%83Journal%E2%80%83and%E2%80%83Virtual%E2%80%83Library%EF%BC%8C2008%0A%EF%BC%8813%EF%BC%89%EF%BC%9A453-461%EF%BC%8E

43、COLEGIO%E2%80%83O%E2%80%83R%EF%BC%8CCHU%E2%80%83N%E2%80%83Q%EF%BC%8CSZABO%E2%80%83A%E2%80%83L%EF%BC%8Cet%E2%80%83al%EF%BC%8E%0AFunctional%E2%80%83%20pola%20rization%E2%80%83%20of%E2%80%83%20tumou%20r-associated%E2%80%83%0Amacrophages%E2%80%83by%E2%80%83tumour-derived%E2%80%83lactic%E2%80%83acid%EF%BC%BBJ%EF%BC%BD%EF%BC%8E%0ANature%EF%BC%8C2014%EF%BC%8C513%EF%BC%887519%EF%BC%89%EF%BC%9A559-563%EF%BC%8E

44、IRIZARRY-CARO%E2%80%83R%E2%80%83A%EF%BC%8CMCDANIEL%E2%80%83M%E2%80%83M%EF%BC%8C%0AOVERCAST%E2%80%83G%E2%80%83R%EF%BC%8Cet%E2%80%83al%EF%BC%8ETLR%E2%80%83%20signaling%E2%80%83%20adapter%E2%80%83%0ABCAP%E2%80%83regulates%E2%80%83inflammatory%E2%80%83to%E2%80%83reparatory%E2%80%83macrophage%E2%80%83%0Atransition%E2%80%83by%E2%80%83promoting%E2%80%83histone%E2%80%83lactylation%EF%BC%BBJ%EF%BC%BD%EF%BC%8E%0AProceedings%E2%80%83of%E2%80%83the%E2%80%83National%E2%80%83Academy%E2%80%83of%E2%80%83%20Sciences%E2%80%83of%E2%80%83%0Athe%E2%80%83United%E2%80%83States%E2%80%83of%E2%80%83America%EF%BC%8C2020%EF%BC%8C117%EF%BC%8848%EF%BC%89%EF%BC%9A%0A30628-30638%EF%BC%8E

45、DICHTL%E2%80%83S%EF%BC%8CLINDENTHAL%E2%80%83L%EF%BC%8CZEITLER%E2%80%83L%EF%BC%8Cet%E2%80%83al%EF%BC%8E%0ALactate%E2%80%83and%E2%80%83IL6%E2%80%83define%E2%80%83separable%E2%80%83paths%E2%80%83of%E2%80%83inflammatory%E2%80%83%0Ametabolic%E2%80%83adaptation%EF%BC%BBJ%EF%BC%BD%EF%BC%8EScience%E2%80%83Advances%EF%BC%8C%0A2021%EF%BC%8C7%EF%BC%8826%EF%BC%89%EF%BC%9Aeabg3505%EF%BC%8E

46、GU%E2%80%83J%EF%BC%8CZHOU%E2%80%83J%EF%BC%8CCHEN%E2%80%83Q%EF%BC%8Cet%E2%80%83al%EF%BC%8ETumor%E2%80%83metabolite%E2%80%83%0Alactate%E2%80%83promotes%E2%80%83tumorigenesis%E2%80%83by%E2%80%83modulating%E2%80%83MOESIN%E2%80%83%0Alactylation%E2%80%83and%E2%80%83enhancing%E2%80%83TGF-%CE%B2%E2%80%83%20signaling%E2%80%83%20in%E2%80%83%0Aregulatory%E2%80%83T%E2%80%83cells%EF%BC%BBJ%EF%BC%BD%EF%BC%8ECell%E2%80%83Reports%EF%BC%8C2022%EF%BC%8C39%0A%EF%BC%8812%EF%BC%89%EF%BC%9A110986%EF%BC%8E

47、XIONG%E2%80%83J%EF%BC%8CHE%E2%80%83J%EF%BC%8CZHU%E2%80%83J%EF%BC%8Cet%E2%80%83al%EF%BC%8ELactylation-driven%E2%80%83%0AMETTL3-mediated%E2%80%83RNA%E2%80%83m6A%E2%80%83modification%E2%80%83promotes%E2%80%83%0Aimmunosuppression%E2%80%83of%E2%80%83tumor-infiltrating%E2%80%83myeloid%E2%80%83cells%0A%EF%BC%BBJ%EF%BC%BD%EF%BC%8EMolecular%E2%80%83Cell%EF%BC%8C2022%EF%BC%8C82%EF%BC%889%EF%BC%89%EF%BC%9A1660-%0A1677%EF%BC%8Ee10%EF%BC%8E

48、WANG%E2%80%83Z%E2%80%83H%EF%BC%8CZHANG%E2%80%83P%EF%BC%8CPENG%E2%80%83W%E2%80%83B%EF%BC%8Cet%E2%80%83al%EF%BC%8E%0AAltered%E2%80%83%20phenotypic%E2%80%83and%E2%80%83metabolic%E2%80%83characteristics%E2%80%83of%E2%80%83%0AFOXP3%2BCD3%2BCD56%2B%E2%80%83natural%E2%80%83killer%E2%80%83T%EF%BC%88NKT%EF%BC%89-like%E2%80%83%0Acells%E2%80%83in%E2%80%83human%E2%80%83malignant%E2%80%83pleural%E2%80%83effusion%EF%BC%BBJ%EF%BC%BD%EF%BC%8E%0AOncoimmunology%EF%BC%8C2023%EF%BC%8C12%EF%BC%881%EF%BC%89%EF%BC%9A2160558%EF%BC%8E

49、FAN%E2%80%83W%EF%BC%8CWANG%E2%80%83X%EF%BC%8CZENG%E2%80%83S%EF%BC%8Cet%E2%80%83al%EF%BC%8EGlobal%E2%80%83lactylome%E2%80%83%0Areveals%E2%80%83lactylation-dependent%E2%80%83mechanisms%E2%80%83underlying%E2%80%83%0ATH17%E2%80%83differentiation%E2%80%83in%E2%80%83experimental%E2%80%83autoimmune%E2%80%83uveitis%0A%EF%BC%BBJ%EF%BC%BD%EF%BC%8ESci%E2%80%83Adv%EF%BC%8C2023%EF%BC%8C9%EF%BC%8842%EF%BC%89%EF%BC%9Aeadh4655%EF%BC%8E

50、HUANG%E2%80%83Z%E2%80%83W%EF%BC%8CZHANG%E2%80%83X%E2%80%83N%EF%BC%8CZHANG%E2%80%83L%EF%BC%8Cet%E2%80%83al%EF%BC%8ESTAT5%E2%80%83%20promotes%E2%80%83%20PD-L1%E2%80%83%20expression%E2%80%83%20by%E2%80%83facilitating%E2%80%83%0Ahistone%E2%80%83lactylation%E2%80%83to%E2%80%83drive%E2%80%83immunosuppression%E2%80%83in%E2%80%83acute%E2%80%83%0Amyeloid%E2%80%83leukemia%EF%BC%BBJ%EF%BC%BD%EF%BC%8ESignal%E2%80%83%20Transduction%E2%80%83%20and%E2%80%83%0ATargeted%E2%80%83Therapy%EF%BC%8C2023%EF%BC%8C8%EF%BC%881%EF%BC%89%EF%BC%9A391%EF%BC%8E

51、HAAS%E2%80%83R%EF%BC%8CSMITH%E2%80%83J%EF%BC%8CROCHER-ROS%E2%80%83V%EF%BC%8Cet%E2%80%83al%EF%BC%8E%0ALactate%E2%80%83%20regulates%E2%80%83%20metabolic%E2%80%83%20and%E2%80%83%20pro-inflammatory%E2%80%83%0Acircuits%E2%80%83in%E2%80%83%20control%E2%80%83%20of%E2%80%83%20T%E2%80%83%20cell%E2%80%83%20migration%E2%80%83%20and%E2%80%83%20effector%E2%80%83%0Afunctions%EF%BC%BBJ%EF%BC%BD%EF%BC%8EPLoS%E2%80%83Biol%EF%BC%8C2015%EF%BC%8C13%EF%BC%887%EF%BC%89%EF%BC%9A%0Ae1002202%EF%BC%8E

52、FISCHER%E2%80%83K%EF%BC%8CHOFFMANN%E2%80%83P%EF%BC%8CVOELKL%E2%80%83S%EF%BC%8Cet%E2%80%83al%EF%BC%8E%0AInhibitory%E2%80%83effect%E2%80%83of%E2%80%83tumor%E2%80%83cell-derived%E2%80%83lactic%E2%80%83acid%E2%80%83on%E2%80%83%0Ahuman%E2%80%83T%E2%80%83cells%EF%BC%BBJ%EF%BC%BD%EF%BC%8EBlood%EF%BC%8C2007%EF%BC%8C109%EF%BC%889%EF%BC%89%EF%BC%9A%0A3812-3819%EF%BC%8E

53、HE%E2%80%83Y%EF%BC%8CJI%E2%80%83Z%EF%BC%8CGONG%E2%80%83Y%EF%BC%8Cet%E2%80%83al%EF%BC%8ENumb%2FParkin-directed%E2%80%83%0Amitochondrial%E2%80%83fitness%E2%80%83%20governs%E2%80%83%20cancer%E2%80%83%20cell%E2%80%83fate%E2%80%83%20via%E2%80%83%0Ametabolic%E2%80%83regulation%E2%80%83of%E2%80%83histone%E2%80%83lactylation%EF%BC%BBJ%EF%BC%BD%EF%BC%8ECell%E2%80%83%0ARep%EF%BC%8C2023%EF%BC%8C42%EF%BC%882%EF%BC%89%EF%BC%9A112033%EF%BC%8E

54、JIAO%E2%80%83Y%EF%BC%8CJI%E2%80%83F%EF%BC%8CHOU%E2%80%83L%EF%BC%8Cet%E2%80%83al%EF%BC%8ELactylation-related%E2%80%83%0Agene%E2%80%83%20signature%E2%80%83for%E2%80%83%20prognostic%E2%80%83%20prediction%E2%80%83and%E2%80%83immune%E2%80%83%0Ainfiltration%E2%80%83analysis%E2%80%83in%E2%80%83breast%E2%80%83cancer%EF%BC%BBJ%EF%BC%BD%EF%BC%8EHeliyon%EF%BC%8C%0A2024%EF%BC%8C10%EF%BC%883%EF%BC%89%EF%BC%9Ae24777%EF%BC%8E

55、YANG%E2%80%83D%EF%BC%8CYIN%E2%80%83J%EF%BC%8CSHAN%E2%80%83L%EF%BC%8Cet%E2%80%83al%EF%BC%8EIdentification%E2%80%83of%E2%80%83%0Alysine-lactylated%E2%80%83substrates%E2%80%83in%E2%80%83gastric%E2%80%83cancer%E2%80%83cells%EF%BC%BBJ%EF%BC%BD%EF%BC%8E%0AiScience%EF%BC%8C2022%EF%BC%8C25%EF%BC%887%EF%BC%89%EF%BC%9A104630%EF%BC%8E

56、CHAUDAGAR%E2%80%83K%EF%BC%8CHIEROMNIMON%E2%80%83H%E2%80%83M%EF%BC%8C%0AKHURANA%E2%80%83R%EF%BC%8Cet%E2%80%83al%EF%BC%8EReversal%E2%80%83of%E2%80%83lactate%E2%80%83and%E2%80%83PD-%0A1-mediated%E2%80%83macrophage%E2%80%83immunosuppression%E2%80%83controls%E2%80%83%0Agrowth%E2%80%83of%E2%80%83PTEN%2Fp53-deficient%E2%80%83prostate%E2%80%83cancer%EF%BC%BBJ%EF%BC%BD%EF%BC%8E%0AClinical%E2%80%83Cancer%E2%80%83Research%EF%BC%9AAn%E2%80%83Official%E2%80%83Journal%E2%80%83of%E2%80%83the%E2%80%83%0AAmerican%E2%80%83Association%E2%80%83for%E2%80%83Cancer%E2%80%83Research%EF%BC%8C2023%EF%BC%8C29%0A%EF%BC%8810%EF%BC%89%EF%BC%9A1952-1968%EF%BC%8E

57、SUN%E2%80%83T%EF%BC%8CLIU%E2%80%83B%EF%BC%8CLI%E2%80%83Y%EF%BC%8Cet%E2%80%83al%EF%BC%8EOxamate%E2%80%83enhances%E2%80%83the%E2%80%83%0Aefficacy%E2%80%83%20of%E2%80%83CAR-T%E2%80%83therapy%E2%80%83%20against%E2%80%83%20glioblastoma%E2%80%83%20via%E2%80%83%0Asuppressing%E2%80%83ectonucleotidases%E2%80%83and%E2%80%83CCR8%E2%80%83lactylation%0A%EF%BC%BBJ%EF%BC%BD%EF%BC%8EJournal%E2%80%83%20of%E2%80%83Experimental%E2%80%83%26%E2%80%83Clinical%E2%80%83Cancer%E2%80%83%0AResearch%EF%BC%9ACR%EF%BC%8C2023%EF%BC%8C42%EF%BC%881%EF%BC%89%EF%BC%9A253%EF%BC%8E

58、LI%E2%80%83W%EF%BC%8CZHOU%E2%80%83C%EF%BC%8CYU%E2%80%83L%EF%BC%8Cet%E2%80%83al%EF%BC%8ETumor-derived%E2%80%83%0Alactate%E2%80%83promotes%E2%80%83%20resistance%E2%80%83to%E2%80%83bevacizumab%E2%80%83treatment%E2%80%83%0Aby%E2%80%83facilitating%E2%80%83autophagy%E2%80%83enhancer%E2%80%83%20protein%E2%80%83RUBCNL%E2%80%83%0Aexpression%E2%80%83through%E2%80%83histone%E2%80%83H3%E2%80%83lysine%E2%80%8318%E2%80%83lactylation%0A%EF%BC%88H3K18la%EF%BC%89in%E2%80%83colorectal%E2%80%83cancer%EF%BC%BBJ%EF%BC%BD%EF%BC%8EAutophagy%EF%BC%8C2024%EF%BC%8C20%EF%BC%881%EF%BC%89%EF%BC%9A114-130%EF%BC%8E

59、LI%E2%80%83F%EF%BC%8CZHANG%E2%80%83H%EF%BC%8CHUANG%E2%80%83Y%EF%BC%8Cet%E2%80%83al%EF%BC%8ESingle-cell%E2%80%83%0Atranscriptome%E2%80%83analysis%E2%80%83%20reveals%E2%80%83the%E2%80%83association%E2%80%83between%E2%80%83%0Ahistone%E2%80%83lactylation%E2%80%83and%E2%80%83cisplatin%E2%80%83%20resistance%E2%80%83in%E2%80%83bladder%E2%80%83%0Acancer%EF%BC%BBJ%EF%BC%BD%EF%BC%8EDrug%E2%80%83Resistance%E2%80%83Updates%EF%BC%9AReviews%E2%80%83%0Aand%E2%80%83Commentaries%E2%80%83in%E2%80%83Antimicrobial%E2%80%83and%E2%80%83Anticancer%E2%80%83%0AChemotherapy%EF%BC%8C2024%EF%BC%8C73%EF%BC%9A101059%EF%BC%8E

60、LAGAN%C3%81%E2%80%83G%EF%BC%8CBARRECA%E2%80%83D%EF%BC%8CCALDERARO%E2%80%83A%EF%BC%8Cet%E2%80%83%0Aal%EF%BC%8ELactate%E2%80%83dehydrogenase%E2%80%83inhibition%EF%BC%9ABiochemical%E2%80%83%0Arelevance%E2%80%83and%E2%80%83therapeutical%E2%80%83potential%EF%BC%BBJ%EF%BC%BD%EF%BC%8ECurrent%E2%80%83%0AMedicinal%E2%80%83Chemistry%EF%BC%8C2019%EF%BC%8C26%EF%BC%8818%EF%BC%89%EF%BC%9A3242-3252%EF%BC%8E

61、LE%E2%80%83A%EF%BC%8CCOOPER%E2%80%83C%E2%80%83R%EF%BC%8CGOUW%E2%80%83A%E2%80%83M%EF%BC%8Cet%E2%80%83al%EF%BC%8EInhibition%E2%80%83%0Aof%E2%80%83lactate%E2%80%83dehydrogenase%E2%80%83a%E2%80%83induces%E2%80%83oxidative%E2%80%83stress%E2%80%83and%E2%80%83%0Ainhibits%E2%80%83tumor%E2%80%83progression%EF%BC%BBJ%EF%BC%BD%EF%BC%8EProceedings%E2%80%83of%E2%80%83the%E2%80%83%0ANational%E2%80%83Academy%E2%80%83of%E2%80%83Sciences%E2%80%83of%E2%80%83the%E2%80%83United%E2%80%83States%E2%80%83of%E2%80%83%0AAmerica%EF%BC%8C2010%EF%BC%8C107%EF%BC%885%EF%BC%89%EF%BC%9A2037-2042%EF%BC%8E

62、ELIA%E2%80%83I%EF%BC%8CROSSI%E2%80%83M%EF%BC%8CSTEGEN%E2%80%83S%EF%BC%8Cet%E2%80%83al%EF%BC%8EBreast%E2%80%83%0Acancer%E2%80%83cells%E2%80%83%20rely%E2%80%83on%E2%80%83environmental%E2%80%83pyruvate%E2%80%83to%E2%80%83%20shape%E2%80%83%0Athe%E2%80%83metastatic%E2%80%83niche%EF%BC%BBJ%EF%BC%BD%EF%BC%8ENature%EF%BC%8C2019%EF%BC%8C568%0A%EF%BC%887750%EF%BC%89%EF%BC%9A117-121.

63、WENG%E2%80%83Y%E2%80%83S%EF%BC%8CTSENG%E2%80%83H%E2%80%83Y%EF%BC%8CCHEN%E2%80%83Y%E2%80%83A%EF%BC%8Cet%E2%80%83al%EF%BC%8EMCT-%0A1%2FmiR-34a%2FIL-6%2FIL-6R%E2%80%83signaling%E2%80%83axis%E2%80%83promotes%E2%80%83EMT%E2%80%83%0Aprogression%EF%BC%8Ccancer%E2%80%83%20stemness%E2%80%83%20and%E2%80%83M2%E2%80%83macrophage%E2%80%83%0Apolarization%E2%80%83in%E2%80%83triple-negative%E2%80%83breast%E2%80%83cancer%EF%BC%BBJ%EF%BC%BD%EF%BC%8E%0AMol%E2%80%83Cancer%EF%BC%8C2019%EF%BC%8C18%EF%BC%881%EF%BC%89%EF%BC%9A42.

64、WADDELL%E2%80%83A%E2%80%83R%EF%BC%8CHUANG%E2%80%83H%EF%BC%8CLIAO%E2%80%83D%EF%BC%8ECBP%2Fp300%EF%BC%9A%0ACritical%E2%80%83%20co-activators%E2%80%83for%E2%80%83%20nuclear%E2%80%83%20steroid%E2%80%83%20hormone%E2%80%83%0Areceptors%E2%80%83and%E2%80%83emerging%E2%80%83therapeutic%E2%80%83targets%E2%80%83in%E2%80%83prostate%E2%80%83%0Aand%E2%80%83breast%E2%80%83cancers%EF%BC%BBJ%EF%BC%BD%EF%BC%8ECancers%EF%BC%88Basel%EF%BC%89%EF%BC%8C2021%EF%BC%8C%0A13%EF%BC%8812%EF%BC%89%EF%BC%9A2872%EF%BC%8E

65、HE%E2%80%83Z%E2%80%83X%EF%BC%8CWEI%E2%80%83B%E2%80%83F%EF%BC%8CZHANG%E2%80%83X%EF%BC%8Cet%E2%80%83al%EF%BC%8ECurrent%E2%80%83%0Adevelopment%E2%80%83of%E2%80%83CBP%2Fp300%E2%80%83inhibitors%E2%80%83in%E2%80%83the%E2%80%83last%E2%80%83decade%0A%EF%BC%BBJ%EF%BC%BD%EF%BC%8EEuropean%E2%80%83Journal%E2%80%83of%E2%80%83Medicinal%E2%80%83Chemistry%EF%BC%8C%0A2021%EF%BC%8C209%EF%BC%9A112861%EF%BC%8E

66、YU%E2%80%83Y%EF%BC%8CHUANG%E2%80%83X%EF%BC%8CLIANG%E2%80%83C%EF%BC%8Cet%E2%80%83al%EF%BC%8EEvodiamine%E2%80%83%0Aimpairs%E2%80%83HIF1A%E2%80%83histone%E2%80%83lactylation%E2%80%83to%E2%80%83inhibit%E2%80%83Sema3A%02mediated%E2%80%83%20angiogenesis%E2%80%83%20and%E2%80%83%20PD-L1%E2%80%83%20by%E2%80%83%20inducing%E2%80%83%0Aferroptosis%E2%80%83in%E2%80%83prostate%E2%80%83cancer%EF%BC%BBJ%EF%BC%BD%EF%BC%8EEuropean%E2%80%83Journal%E2%80%83%0Aof%E2%80%83Pharmacology%EF%BC%8C2023%EF%BC%88957%EF%BC%89%EF%BC%9A176007%EF%BC%8E

1、傅梦蝶.HDAC1乳酸化修饰对血管内皮细胞增殖的影响[D].赣南医科大学,2025.DOI:10.27959/d.cnki.ggnyx.2025.000063.

2、杨晓玉,宁子昕,高坤,等.乳酸化修饰在肿瘤中的作用及中医药调控相关研究[J/OL].中国中医基础医学杂志,1-18[2026-01-15].https://doi.org/10.19945/j.cnki.issn.1006-3250.20250923.002.

1、2019 年国家自然科学基金（K10120033）()