赖氨酸巴豆酰化修饰在疾病中的作用机制研究进展

doi:10.3969/j.issn.1674-8115.2026.09.012

上海交通大学学报（医学版） ›› 2026, Vol. 46 ›› Issue (9): 1272-1282.doi: 10.3969/j.issn.1674-8115.2026.09.012

• 综述 • 上一篇

赖氨酸巴豆酰化修饰在疾病中的作用机制研究进展

何祉琳¹, 徐琳¹, 李岩¹, 王林政¹, 陈伟²(), 李衍滨³()

^1.山东中医药大学第一临床医学院，济南 250013
^2.上海交通大学医学院附属第六人民医院消化内科，上海 200233
^3.山东第一医科大学第一附属医院（山东省千佛山医院）神经内科，济南 250014

收稿日期:2026-01-09 接受日期:2026-05-11 出版日期:2026-09-28 发布日期:2026-09-28
通讯作者: 李衍滨，主任医师，博士；电子信箱：13864006933@163.com。
陈　伟，主治医师，博士；电子信箱：weichen_outlook@163.com。
作者简介:第一联系人：为共同通信作者。
基金资助:
国家自然科学基金(82204835);国家自然科学基金(82574764);山东省自然科学基金(ZR2023MH127);上海市卫生健康委员会中医药科研项目(2024QN042);山东第一医科大学学术提升计划(2019QL013)

Research progress in the roles and mechanisms of lysine crotonylation in diseases

He Zhilin¹, Xu Lin¹, Li Yan¹, Wang Linzheng¹, Chen Wei²(), Li Yanbin³()

^1.First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan 250013, China
^2.Department of Gastroenterology, Shanghai Sixth People′s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
^3.Department of Neurology, The First Affiliated Hospital of Shandong First Medical University (Shandong Provincial Qianfoshan Hospital), Jinan 250014, China

Received:2026-01-09 Accepted:2026-05-11 Online:2026-09-28 Published:2026-09-28
Contact: Li Yanbin, E-mail: 13864006933@163.com.
Chen Wei, E-mail: weichen_outlook@163.com.
Supported by:
National Natural Science Foundation of China(82204835);Shandong Province Natural Science Foundation(ZR2023MH127);Traditional Chinese Medicine Research Project of Shanghai Municipal Health Commission(2024QN042);Academic Advancement Program of Shandong First Medical University(2019QL013)

摘要/Abstract

摘要：

赖氨酸巴豆酰化（lysine crotonylation，Kcr）修饰是一种新型的蛋白质翻译后修饰，在多种疾病发生发展中发挥着关键调控作用，近年来已成为疾病机制领域重要的研究热点之一。该文总结了近年Kcr在神经系统、心血管系统、消化系统、泌尿系统、呼吸系统疾病，以及代谢性疾病和自身免疫性疾病中的最新研究进展，全面呈现Kcr修饰的病理生理作用范围。重点阐述其通过“writer-eraser-reader”酶系统动态调控基因转录与细胞代谢的分子机制——三者协同作用动态调控基因转录效率与细胞代谢稳态，系统阐明Kcr通过影响染色质状态、代谢重编程及信号通路参与疾病进程的作用机制。该文旨在综述现有研究成果与未解决的关键问题，为相关疾病的预防、诊断及治疗提供理论依据，并为Kcr作为潜在药物靶点的临床转化研究提供思路。

关键词: 赖氨酸巴豆酰化, 蛋白质翻译后修饰, 疾病机制

Abstract:

Lysine crotonylation (Kcr) is a novel post-translational modification of proteins that plays a critical regulatory role in the occurrence and development of various diseases, and has become a significant research hotspot in the field of disease mechanisms in recent years. This review summarizes the latest research progress in Kcr in diseases of the nervous, cardiovascular, digestive, urinary, and respiratory systems, as well as metabolic and autoimmune diseases, comprehensively presenting the range of pathophysiological roles of Kcr modification. It focuses on summarizing the molecular mechanisms by which Kcr dynamically regulates gene transcription and cellular metabolism through the "writer-eraser-reader" enzyme system. The three components act synergistically to dynamically regulate gene transcription efficiency and cellular metabolic homeostasis. Additionally, this article systematically clarifies the mechanisms by which Kcr participates in disease progression by affecting chromatin status, metabolic reprogramming, and signaling pathways. This review aims to summarize existing findings and unresolved issues, provide a theoretical basis for the prevention, diagnosis, and treatment of related diseases, and offer insights into the clinical translation of Kcr as a potential drug target.

Key words: lysine crotonylation (Kcr), protein post-translational modification, disease mechanism

中图分类号:

R363

何祉琳, 徐琳, 李岩, 王林政, 陈伟, 李衍滨. 赖氨酸巴豆酰化修饰在疾病中的作用机制研究进展[J]. 上海交通大学学报（医学版）, 2026, 46(9): 1272-1282.

He Zhilin, Xu Lin, Li Yan, Wang Linzheng, Chen Wei, Li Yanbin. Research progress in the roles and mechanisms of lysine crotonylation in diseases[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2026,(9): 1272-1282.

图/表 2

参考文献 57

[1]	Sabari B R, Tang Z Y, Huang H, et al. Intracellular crotonyl-CoA stimulates transcription through p300-catalyzed histone crotonylation[J]. Mol Cell, 2015, 58(2): 203-215.
[2]	Hou J Y, Zhou L, Li J L, et al. Emerging roles of non-histone protein crotonylation in biomedicine[J]. Cell Biosci, 2021, 11(1): 101.
[3]	Jenuwein T, Allis C D. Translating the histone code[J]. Science, 2001, 293(5532): 1074-1080.
[4]	Wei W, Mao A Q, Tang B, et al. Large-scale identification of protein crotonylation reveals its role in multiple cellular functions[J]. J Proteome Res, 2017, 16(4): 1743-1752.
[5]	Tan M J, Luo H, Lee S, et al. Identification of 67 histone marks and histone lysine crotonylation as a new type of histone modification[J]. Cell, 2011, 146(6): 1016-1028.
[6]	Wang Y F, Wan Y T, Qi Q R, et al. Echs1-mediated histone crotonylation facilitates zygotic genome activation and expression of repetitive elements in early mammalian embryos[J]. Nat Commun, 2025, 16(1): 5630.
[7]	Xu W Z, Wan J H, Zhan J, et al. Global profiling of crotonylation on non-histone proteins[J]. Cell Res, 2017, 27(7): 946-949.
[8]	Yang P, Qin Y Y, Zeng L S, et al. Crotonylation and disease: current progress and future perspectives[J]. Biomed Pharmacother, 2023, 165: 115108.
[9]	Chen Q J, Yang B H, Liu X C, et al. Histone acetyltransferases CBP/p300 in tumorigenesis and CBP/p300 inhibitors as promising novel anticancer agents[J]. Theranostics, 2022, 12(11): 4935-4948.
[10]	Huang H, Wang D L, Zhao Y M. Quantitative crotonylome analysis expands the roles of p300 in the regulation of lysine crotonylation pathway[J]. Proteomics, 2018, 18(15): e1700230.
[11]	Sheng C, Li T, Lin H, et al. Hepatic CBP/p300 orchestrate amino acid-driven gluconeogenesis through histone crotonylation[J]. Adv Sci (Weinh), 2025, 12(41): e07635.
[12]	Liu X G, Wei W, Liu Y T, et al. MOF as an evolutionarily conserved histone crotonyltransferase and transcriptional activation by histone acetyltransferase-deficient and crotonyltransferase-competent CBP/p300[J]. Cell Discov, 2017, 3: 17016.
[13]	Xiao Y H, Li W J, Yang H, et al. HBO1 is a versatile histone acyltransferase critical for promoter histone acylations[J]. Nucleic Acids Res, 2021, 49(14): 8037-8059.
[14]	Kollenstart L, de Groot A J L, Janssen G M C, et al. Gcn5 and Esa1 function as histone crotonyltransferases to regulate crotonylation-dependent transcription[J]. J Biol Chem, 2019, 294(52): 20122-20134.
[15]	Wei W, Liu X G, Chen J W, et al. Class Ⅰ histone deacetylases are major histone decrotonylases: evidence for critical and broad function of histone crotonylation in transcription[J]. Cell Res, 2017, 27(7): 898-915.
[16]	Madsen A S, Olsen C A. Profiling of substrates for zinc-dependent lysine deacylase enzymes: HDAC3 exhibits decrotonylase activity in vitro[J]. Angew Chem Int Ed, 2012, 51(36): 9083-9087.
[17]	Bao X C, Wang Y, Li X, et al. Identification of ‘erasers’ for lysine crotonylated histone marks using a chemical proteomics approach[J]. eLife, 2014, 3: e02999.
[18]	Yang J, He Z M, Chen C J, et al. Toxoplasma gondii infection inhibits histone crotonylation to regulate immune response of porcine alveolar macrophages[J]. Front Immunol, 2021, 12: 696061.
[19]	Zhang N, Song L M, Xu Y, et al. The decrotonylase FoSir5 facilitates mitochondrial metabolic state switching in conidial germination of Fusarium oxysporum[J]. eLife, 2021, 10: e75583.
[20]	Li Y Y, Sabari B R, Panchenko T, et al. Molecular coupling of histone crotonylation and active transcription by AF9 YEATS domain[J]. Mol Cell, 2016, 62(2): 181-193.
[21]	Zhao D, Guan H P, Zhao S, et al. YEATS2 is a selective histone crotonylation reader[J]. Cell Res, 2016, 26(5): 629-632.
[22]	Andrews F H, Shinsky S A, Shanle E K, et al. The Taf14 YEATS domain is a reader of histone crotonylation[J]. Nat Chem Biol, 2016, 12(6): 396-398.
[23]	Liu N, Konuma T, Sharma R, et al. Histone H3 lysine 27 crotonylation mediates gene transcriptional repression in chromatin[J]. Mol Cell, 2023, 83(13): 2206-2221.e11.
[24]	Flynn E M, Huang O W, Poy F, et al. A subset of human bromodomains recognizes butyryllysine and crotonyllysine histone peptide modifications[J]. Structure, 2015, 23(10): 1801-1814.
[25]	Xiong X Z, Panchenko T, Yang S, et al. Selective recognition of histone crotonylation by double PHD fingers of MOZ and DPF2[J]. Nat Chem Biol, 2016, 12(12): 1111-1118.
[26]	Dai S K, Liu P P, Li X, et al. Dynamic profiling and functional interpretation of histone lysine crotonylation and lactylation during neural development[J]. Development, 2022, 149(14): dev200049.
[27]	Zou Y, Bai X H, Kong L C, et al. Involvement of histone lysine crotonylation in the regulation of nerve-injury-induced neuropathic pain[J]. Front Immunol, 2022, 13: 885685.
[28]	Li H C, Liu H X, Chen R, et al. Pyruvate dehydrogenase complex E1 subunit α crotonylation modulates cocaine-associated memory through hippocampal neuron activation[J]. Cell Rep, 2024, 43(8): 114529.
[29]	Weng Y, He T, Li M, et al. Microglial histone H3K18 crotonylation promotes STAT1 expression and induces cognitive deficit in Alzheimer disease[J]. Front Immunol, 2026, 17: 1744375.
[30]	Cai W Q, Xu D C, Zeng C, et al. Modulating lysine crotonylation in cardiomyocytes improves myocardial outcomes[J]. Circ Res, 2022, 131(5): 456-472.
[31]	Ju J, Wang K, Liu F, et al. Crotonylation of NAE1 modulates cardiac hypertrophy via gelsolin neddylation[J]. Circ Res, 2024, 135(8): 806-821.
[32]	Chen H X, Wang X C, Hou H T, et al. Lysine crotonylation of SERCA2a correlates to cardiac dysfunction and arrhythmia in Sirt1 cardiac-specific knockout mice[J]. Int J Biol Macromol, 2023, 242(Pt 4): 125151.
[33]	Liu S, Li H F, Li R, et al. Prevotella copri promotes white adipose browning and ameliorates adiposity[J]. Nat Commun, 2025, 17(1): 680.
[34]	Liu Y X, Liang J T, Liu Z H, et al. Dihydrolipoyl dehydrogenase promotes white adipocytes browning by activating the RAS/ERK pathway and undergoing crotonylation modification[J]. Int J Biol Macromol, 2024, 265(Pt 1): 130816.
[35]	Li F J, Ye H W, Li L L, et al. Histone lysine crotonylation accelerates ACSL4-mediated ferroptosis of keratinocytes via modulating autophagy in diabetic wound healing[J]. Pharmacol Res, 2025, 213: 107632.
[36]	He Y Q, Xie Y M, Zhou T T, et al. Sodium crotonate alleviates diabetic kidney disease partially via the histone crotonylation pathway[J]. Inflammation, 2025, 48(1): 254-275.
[37]	Hou J Y, Wang X L, Chang H J, et al. PTBP1 crotonylation promotes colorectal cancer progression through alternative splicing-mediated upregulation of the PKM2 gene[J]. J Transl Med, 2024, 22(1): 995.
[38]	Hou J Y, Cao J, Gao L J, et al. Upregulation of α enolase (ENO1) crotonylation in colorectal cancer and its promoting effect on cancer cell metastasis[J]. Biochem Biophys Res Commun, 2021, 578: 77-83.
[39]	Liao M J, Sun X L, Zheng W D, et al. LINC00922 decoys SIRT3 to facilitate the metastasis of colorectal cancer through up-regulation the H3K27 crotonylation of ETS1 promoter[J]. Mol Cancer, 2023, 22(1): 163.
[40]	Zhang D, Tang J, Xu Y H, et al. Global crotonylome reveals hypoxia-mediated lamin A crotonylation regulated by HDAC6 in liver cancer[J]. Cell Death Dis, 2022, 13(8): 717.
[41]	Zhang Y, Chen Y L, Zhang Z, et al. Acox2 is a regulator of lysine crotonylation that mediates hepatic metabolic homeostasis in mice[J]. Cell Death Dis, 2022, 13(3): 279.
[42]	Lao Y X, Cui X H, Xu Z, et al. Glutaryl-CoA dehydrogenase suppresses tumor progression and shapes an anti-tumor microenvironment in hepatocellular carcinoma[J]. J Hepatol, 2024, 81(5): 847-861.
[43]	Zhang X Y, Liu Z X, Zhang Y F, et al. SEPT2 crotonylation promotes metastasis and recurrence in hepatocellular carcinoma and is associated with poor survival[J]. Cell Biosci, 2023, 13(1): 63.
[44]	Yuan M, Chen S P, Lin Z S, et al. ACSS2-mediated histone H4 lysine 12 crotonylation (H4K12cr) alleviates colitis via enhancing transcription of CLDN7[J]. Adv Sci (Weinh), 2025, 12(30): e00461.
[45]	Chen X F, Ji S X. Sorafenib attenuates fibrotic hepatic injury through mediating lysine crotonylation[J]. Drug Des Devel Ther, 2022, 16: 2133-2144.
[46]	Liu S S, Ji Y, Wei L Y, et al. Crotonylation of IDH1 alleviates MASLD progression by enhancing the TCA cycle[J]. Nat Commun, 2025, 16(1): 7961.
[47]	Wang X L, He J H, Xie P, et al. Augmenter of liver regeneration crotonylation assists in mitochondria-ER contact to alleviate hepatic steatosis[J]. Cell Mol Gastroenterol Hepatol, 2025, 19(3): 101436.
[48]	Zheng Y, Zhu L, Qin Z Y, et al. Modulation of cellular metabolism by protein crotonylation regulates pancreatic cancer progression[J]. Cell Rep, 2023, 42(7): 112666.
[49]	Li H X, Li C, Ren M H, et al. Fasting-mimicking diet prevents pancreatic carcinogenesis via gut microbiota and metabolites[J]. J Agric Food Chem, 2024, 72(46): 25638-25647.
[50]	Li Y Z, Wang Z, Xu H Z, et al. Targeting the transmembrane cytokine co-receptor neuropilin-1 in distal tubules improves renal injury and fibrosis[J]. Nat Commun, 2024, 15(1): 5731.
[51]	Li L Z, Xiang T, Guo J J, et al. Inhibition of ACSS2-mediated histone crotonylation alleviates kidney fibrosis via IL-1β-dependent macrophage activation and tubular cell senescence[J]. Nat Commun, 2024, 15(1): 3200.
[52]	Zheng J W, Wang Q, Xu K J, et al. Fluoride induces immune-inflammatory disorder in the kidneys via histone lysine crotonylation in vivo[J]. Ecotoxicol Environ Saf, 2024, 288: 117385.
[53]	Dang L, Cao X Y, Zhang T Y, et al. Nuclear condensation of CDYL links histone crotonylation and cystogenesis in autosomal dominant polycystic kidney disease[J]. J Am Soc Nephrol, 2022, 33(9): 1708-1725.
[54]	He J, Lai T M, Zhou Z Y, et al. Multiomics profiling reveals the involvement of protein lactylation in nonhomologous end joining pathway conferring radioresistance in lung adenocarcinoma cell[J]. Sci Rep, 2025, 15(1): 24651.
[55]	Gan Q, Tang D E, Yan Q, et al. Differential expression study of lysine crotonylation and proteome for chronic obstructive pulmonary disease combined with type Ⅱ respiratory failure[J]. Can Respir J, 2021, 2021: 6652297.
[56]	Zeng H Y, Li D D, Dong J J, et al. Qualitative proteome-wide lysine crotonylation profiling reveals protein modification alteration in the leukocyte extravasation pathway in systemic lupus erythematosus[J]. ACS Omega, 2023, 8(47): 44905-44919.
[57]	Liang H F, Wang Y, Li J Q, et al. Crotonylation deficiency of S100A7 K49 promotes psoriatic keratinocyte proliferation through enhanced interaction with RAGE[J]. Sci Rep, 2025, 15(1): 14678.

System	Disease	Enzyme	Regulation	Reference
Nervous system	Neural development	HDAC1‒3	Downregulation	[26]
	Neuropathic pain	p300	Upregulation	[27]
	Memory impairment	p300	Upregulation	[28]
Cardiovascular system	Arrhythmia	SIRT1	Downregulation	[32]
Metabolic disease	Browning of white adipocytes	Cr-CoA	Upregulation	[34]
	Browning of white adipocytes	SIRT3	Downregulation	[34]
	Diabetic ulcer	GCN5	Upregulation	[35]
	Diabetic kidney disease	ACSS2	Downregulation	[36]
		p300	Downregulation	[36]
		Cr-CoA	Downregulation	[36]
Digestive system	Colorectal cancer	KAT2B	Upregulation	[37]
		CBP	Upregulation	[38]
		SIRT2	Downregulation	[38]
	Metastatic colorectal cancer	SIRT3	Downregulation	[39]
	Hepatocellular carcinoma	HDAC6	Downregulation	[40]
		ACOX2	Downregulation	[41]
		Cr-CoA	Downregulation	[42]
		SIRT2	Downregulation	[43]
	Colitis	ACSS2	Downregulation	[44]
	Colitis	Cr-CoA	Downregulation	[44]
	Hepatic fibrosis	HDAC1, 3	Upregulation	[45]
	Hepatic fibrosis	CDYL	Upregulation	[45]
	Metabolic dysfunction-associated fatty liver disease	SIRT7	Upregulation	[46]
		PCAF	Downregulation	[46]
		HDAC1, 2	Upregulation	[47]
		KAT8	Downregulation	[47]
	Pancreatic cancer	CBP/p300	Downregulation	[48]
		HDAC1, 3 ACOX1	Upregulation Downregulation	[48] [49]
		Cr-CoA	Upregulation	[49]
Urinary system	Renal fibrosis	Cr-CoA	Downregulation	[50]
	Renal fibrosis	ACSS2	Upregulation	[51]
	Fluoride-induced renal injury	p300	Downregulation	[52]
		SIRT1	Downregulation	[52]
		HDAC2, 3	Downregulation	[52]
	Polycystic kidney disease	CDYL	Downregulation	[53]
	Polycystic kidney disease	Cr-CoA	Downregulation	[53]
Autoimmune disease	Psoriasis	CBP	Downregulation	[57]
Autoimmune disease		HDAC2	Upregulation	[57]

System	Disease	Enzyme	Regulation	Reference
Nervous system	Neural development	HDAC1‒3	Downregulation	[26]
	Neuropathic pain	p300	Upregulation	[27]
	Memory impairment	p300	Upregulation	[28]
Cardiovascular system	Arrhythmia	SIRT1	Downregulation	[32]
Metabolic disease	Browning of white adipocytes	Cr-CoA	Upregulation	[34]
	Browning of white adipocytes	SIRT3	Downregulation	[34]
	Diabetic ulcer	GCN5	Upregulation	[35]
	Diabetic kidney disease	ACSS2	Downregulation	[36]
		p300	Downregulation	[36]
		Cr-CoA	Downregulation	[36]
Digestive system	Colorectal cancer	KAT2B	Upregulation	[37]
		CBP	Upregulation	[38]
		SIRT2	Downregulation	[38]
	Metastatic colorectal cancer	SIRT3	Downregulation	[39]
	Hepatocellular carcinoma	HDAC6	Downregulation	[40]
		ACOX2	Downregulation	[41]
		Cr-CoA	Downregulation	[42]
		SIRT2	Downregulation	[43]
	Colitis	ACSS2	Downregulation	[44]
	Colitis	Cr-CoA	Downregulation	[44]
	Hepatic fibrosis	HDAC1, 3	Upregulation	[45]
	Hepatic fibrosis	CDYL	Upregulation	[45]
	Metabolic dysfunction-associated fatty liver disease	SIRT7	Upregulation	[46]
		PCAF	Downregulation	[46]
		HDAC1, 2	Upregulation	[47]
		KAT8	Downregulation	[47]
	Pancreatic cancer	CBP/p300	Downregulation	[48]
		HDAC1, 3 ACOX1	Upregulation Downregulation	[48] [49]
		Cr-CoA	Upregulation	[49]
Urinary system	Renal fibrosis	Cr-CoA	Downregulation	[50]
	Renal fibrosis	ACSS2	Upregulation	[51]
	Fluoride-induced renal injury	p300	Downregulation	[52]
		SIRT1	Downregulation	[52]
		HDAC2, 3	Downregulation	[52]
	Polycystic kidney disease	CDYL	Downregulation	[53]
	Polycystic kidney disease	Cr-CoA	Downregulation	[53]
Autoimmune disease	Psoriasis	CBP	Downregulation	[57]
Autoimmune disease		HDAC2	Upregulation	[57]

赖氨酸巴豆酰化修饰在疾病中的作用机制研究进展

Research progress in the roles and mechanisms of lysine crotonylation in diseases

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