黄河----中国科学院上海药物研究所

药学

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黄河

姓名	黄河	性别	男	职称	研究员
学历	博士	电话	86-21-68077840	传真
电子邮件	hhuang@simm.ac.cn	个人主页	主页链接	专家类别	研究员
职务	生命过程小分子调控全国重点实验室副主任、课题组长，博导
通讯地址	上海市浦东张江祖冲之路555号

姓名	黄河	性别	男
职称	研究员	学历	博士
电话	86-21-68077840	传真
电子邮件	hhuang@simm.ac.cn
个人主页	主页链接	专家类别	研究员
职务	生命过程小分子调控全国重点实验室副主任、课题组长，博导
通讯地址	上海市浦东张江祖冲之路555号

个人简介

黄河，研究员，博士生导师，课题组长。工作聚焦于蛋白质新型翻译后修饰研究，一方面发现蛋白新型翻译后修饰及其关键调控因子，并结合临床资源和数据揭示其在疾病演进过程中的作用机制；另一方面，鉴定代谢调节活性天然产物分子的作用靶标，阐释其通过翻译后修饰介导表型的新机制。

代表性研究成果：（1）发现蛋白新型修饰：发现了一种全新动态修饰——赖氨酸乙酰乙酰化及其调控酶HBO1，为基于表观遗传靶标的创新药物研究带来了新方向（Adv Sci, 2023）；（2）揭示蛋白新型修饰调控机制：揭示了乳酰化、β-羟基丁酰化、苯甲酰化和琥珀酰化修饰的关键调控酶，拓展了其修饰底物谱，阐释了上述新型修饰耦合乳酸、酮体等代谢物与多种细胞进程的新机制（Cell Metab, 2025；iScience, 2024；Cell Discov, 2023；Sci Adv, 2021）；（3）探索蛋白新型修饰临床转化：将新型修饰组学引入到临床研究中，系统绘制了肝癌组织乳酰化修饰全景图谱，揭示了乳酰化对肝癌细胞代谢的关键调节作用，发现了腺苷酸激酶2（AK2）可以作为潜在的治疗靶标，为肝细胞癌靶向治疗提供了新思路（Nat Metab, 2023）；（4）阐明药物作用新靶标、新机制：发现了高血脂治疗潜在新靶标HNF-1α，揭示了小檗碱类天然产物降脂药物DC371739介导转录因子和组蛋白修饰的独特表观遗传调控机制，鉴定了该药物的临床疗效监控生物标志物PCSK9和ANGPTL3（Cell Metab, 2022）。

共发表SCI论文91篇，获得美国授权专利5项。其中以第一或通讯作者（含共同）在Cell、Cell Metab、Nat Metab、Mol Cell、Sci Adv、Nat Comm、J Am Chem Soc等杂志上发表论文47篇。论文总影响因子865.7，被引用10600余次。

教育经历：

2004.9–2010.7 中国科学院上海药物研究所，博士

2000.9–2004.7 同济大学化学系，学士

工作经历

研究方向

基于蛋白质动态修饰通路的新靶点鉴定及创新药物研究

科研项目

科研成果

1. 新型蛋白质翻译后修饰的关键调控因子研究

细胞代谢为生命过程提供能量，同时代谢物可与蛋白质发生共价结合来发挥信号传导功能。前期研究表明， -羟基丁酸和苯甲酸可转化为新型组蛋白翻译后修饰 -羟基丁酰化和苯甲酰化，并介导转录调控等功能，但其关键的调控酶及底物谱尚不明确。课题组针对上述修饰开展了系列研究。首先，成功鉴定出哺乳动物细胞中的p300和HDAC1/2分别是 -羟基丁酰化修饰的“书写器”和“擦除器”。通过深入的 -羟基丁酰化蛋白质组学分析，该研究在1397个蛋白质中成功鉴定到了3248个独特的 -羟基丁酰化修饰位点。对 -羟基丁酰化修饰底物的分析表明该修饰可能参与了多种细胞功能，例如染色质重塑，转录调控和DNA修复。细胞中 -羟基丁酰化修饰对环境中酮体水平变化的响应方式与乙酰化修饰有非常大的差异，提示酰化转移酶和去酰化酶在不同微环境中对不同修饰的底物存在一定偏好，从而差异性地调控下游生物学进程。其次，我们发现HBO1是苯甲酰化修饰的主要转移酶。通过定量修饰组学分析，我们在哺乳动物细胞中鉴定到1747个苯甲酰化修饰位点，其中77个受到HBO1靶向调控。功能分析表明，HBO1靶向的苯甲酰化位点与染色质重塑、转录调控、免疫调控和肿瘤生长等多个生物学进程密切相关。

2. 蛋白质新型修饰调控机制阐释与临床应用

为探索乳酰化在肝细胞癌中的调控机制，课题组与临床研究团队合作开展了肝癌乳酰化修饰组学研究，绘制了肝癌组织乳酰化修饰图谱，并开展了肝癌乳酰化功能研究。该研究共收集52位乙型肝炎病毒（HBV）相关HCC患者的癌与癌旁组织，开展了深入的乳酰化修饰组分析，鉴定到了9275个乳酰化位点，极大拓展了乳酰化修饰底物谱。其中，9256个乳酰化修饰位点位于非组蛋白上，表明该修饰除了转录调控，可能涉及更广泛的生物学功能。对乳酰化修饰底物的分析结果表明，该修饰影响多个重要代谢途径，包括糖代谢、三羧酸（TCA）循环、氨基酸代谢、脂肪酸代谢和核苷酸代谢，揭示该修饰与细胞代谢和能量稳态等生物学功能密切相关。此外，上述代谢途径中蛋白质上较高的乳酰化水平与HCC的侵袭性临床特征和驱动突变密切相关，提示乳酰化修饰在异常肝癌代谢微环境中具有关键性作用。

该研究探索性地将新型修饰组学引入到临床研究中，首次系统全面绘制了肝癌组织乳酰化修饰全景图谱，揭示了乳酰化对肝癌细胞代谢具有广泛和关键的调节作用，并通过实验验证了乳酰化调控代谢相关蛋白功能，表明乳酰化修饰可能是联系乳酸、肿瘤代谢和患者预后的重要枢纽，为HCC的病程进展和治疗干预提供了新见解。同时，发现了非组蛋白AK2可以作为潜在的治疗靶标，为肝细胞癌转移靶向治疗提供了新的思路。

3. 活性小分子作用机制阐释和靶点鉴定

为阐明小檗碱衍生物DC739的作用靶标和作用机制，课题组与本研究所开发DC739的药物化学研究团队合作，利用定量蛋白质组学和修饰组学等手段，在分子层面探索了该候选药物的作用机制和作用靶标。蛋白质组研究结果表明，该候选药物能显著下调重要降脂蛋白PCSK9的表达水平，但其与小檗碱、单克隆抗体类PCSK9抑制剂的作用机制截然不同，并不直接作用于PCSK9，对LDLR的mRNA也无影响。进一步研究揭示DC371739通过与HNF-1 结合抑制其转录功能，降低PCSK9和ANGPTL3的转录水平，下调了PCSK9蛋白和ANGPTL3蛋白表达，进而增加了LDLR蛋白表达和LPL活性，促进循环中LDL-C和TG的清除，从而发挥降脂作用。

该研究揭示了小檗碱类降脂候选药物DC371739通过介导转录因子和特定新型翻译后修饰发挥的独特表观遗传调控机制，首次发现高血脂治疗潜在新靶标HNF-1 ，为活性天然产物靶标鉴定和机制探索提供了较好的案例。

荣誉获奖

2022, 中国科学院上海分院第八届杰出青年科技创新人才

代表论著

1. Liu R, Ren X, Park YE, Feng H, Sheng X, Song X, AminiTabrizi R, Shah H, Li L, Zhang Y, Abdullah KG, Dubois-Coyne S, Lin H, Cole PA, DeBerardinis RJ, McBrayer SK, Huang H*, Zhao Y*. Nuclear GTPSCS functions as a lactyl-CoA synthetase to promote histone lactylation and gliomagenesis. Cell Metab, 2025, 37, 377.

2. Song X#, Ren X#, Mei Qi, Liu H*, Huang H*. Advancing In-Depth N-Terminomics Detection with a Cleavable 2-Pyridinecarboxyaldehyde Probe. J Am Chem Soc, 2024, 146, 6487.

3. Lin Z#, Liu B#,*, Lu M, Wang Y, Ren X, Liu Z, Luo C, Shi W, Zou X, Song X, Tang F, Huang H*, Huang W*. Controlled Reversible N-Terminal Modification of Peptides and Proteins. J Am Chem Soc, 2024, 146, 23752.

4. Peng P, Lu Y, Ren X, Yan C, Guo X, Liu R, Song X, Huang H*. SIRT3 differentially regulates lysine benzoylation from SIRT2 in mammalian cells. iScience, 2024, 27, 111176.

5. Du R#, Gao Y, Yan C, Ren X, Qi S, Liu G, Guo X, Song X, Wang H, Rao J, Zang Y, Zheng M, Li J, Huang H*. SIRT1/SIRT3 are robust lysine delactylases and SIRT1-mediated delactylation regulates glycolysis. iScience, 2024, 27, 110911.

6. Jiang Y#, Ren X#, Zhao J, Liu G, Liu F, Guo X, Hao M, Liu H, Liu K*, Huang H*. Exploring the Molecular Therapeutic Mechanisms of Gemcitabine through Quantitative Proteomics. J Proteome Res, 2024, 23, 2343.

7. Lou J#, Zhou Q#, Lyu X#, Cen X, Liu C, Yan Z, Li Y, Tang H, Liu Q, Ding J, Lu Y, Huang H*, Xie H*, Zhao Y*. Discovery of a Covalent Inhibitor That Overcame Resistance to Venetoclax in AML Cells Overexpressing BFL-1. J Med Chem, 2024, 67, 10795.

8. Yang Z#, Yan C#, Ma J#, Peng P#, Ren X, Cai S, Shen X, Wu Y, Zhang S, Wang X, Qiu S, Zhou J, Fan J, Huang H*, Gao Q*. Lactylome suggests novel mechanisms of metabolic adaptation in hepatocellular carcinoma. Nat Metab, 2023, 5, 61.

9. Gao Y#, Sheng X#, Tan D#, Kim S#, Choi S, Paudel S, Lee T, Yan C, Tan M, Kim KM, Cho SS, Ki SH, Huang H*, Zhao Y*, Lee SK*. Identification of Histone Lysine Acetoacetylation as a Dynamic Post‐Translational Modification Regulated by HBO1. Adv Sci, 2023, 2300032.

10. Li J#, Lu L#, Liu L#, Ren X, Chen J, Yin X, Xiao Y, Li J, Wei G, Huang H*, Wei W*, Wong J*. HDAC1/2/3 Are Major Histone Desuccinylase Critical for Promoter Desuccinylation. Cell Discov, 2023, 9, 85.

11. Yang Z#, Yan C#, Ma J#, Peng P#, Ren X, Cai S, Shen X, Wu Y, Zhang S, Wang X, Qiu S, Zhou J, Fan J, Huang H*, Gao Q*. Lactylome suggests novel mechanisms of metabolic adaptation in hepatocellular carcinoma. Nat Metab., 2023, 5, 61.

12. Tan D, Wei W, Han Z, Ren X, Yan C, Qi S, Song X, Zheng YG, Wong J, Huang H*. HBO1 Catalyzes Lysine Benzoylation in Mammalian Cells. iSCIENCE, 2022, 25, 105443.

13. Wang J#, Zhao J#, Yan C#, Xi C#, Wu C, Zhao J, Li F, Ding Y, Zhang R, Qi S, Li X, Liu C, Hou W, Chen H, Wang Y, Wu D, Chen K, Jiang H, Huang H*, Liu H*. Identification and evaluation of a lipid-lowering small compound in preclinical models and in a Phase I trial. Cell Metab., 2022, 667.

14. Zeng Y, Shi W, Dong Q, Li W, Zhang J, Ren X, Tang C, Liu B, Song Y, Wu Y, Diao X, Zhou H, Huang H, Tang F, Huang W*. A Traceless Site-Specific Conjugation on Native Antibodies Enables Efficient One-Step Payload Assembly. Angew. Chem. Int. Ed., 2022, 61, e202204132.

15. Huang H#,*, Zhang D #, Weng Y, Delaney K, Tang Z, Yan C, Qi S, Peng C, Cole PA, Roeder RG, Zhao Y*. The regulatory enzymes and protein substrates for the lysine β-hydroxybutyrylation pathway. Sci. Adv., 2021, 7, eabe2771.

16. Koronowski K#,*, Greco C#,*, Huang H, Kim J, Fribourgh J, Crosby P, Mathur L, Ren X, Partch C, Jang C, Qiao F, Zhao Y, Sassone-Corsi P. Ketogenesis impact on liver metabolism revealed by proteomics of lysine β-hydroxybutyrylation. Cell Rep., 2021, 36, 109487.

17. Shi W#, Tang F#, Ao J, Yu Q, Liu J, Tang Y, Jiang B, Ren X, Huang H, Yang W*, Huang W*. Manipulating the Click Reactivity of Dibenzoazacyclooctynes: From Azide Click Component to Caged Acylation Reagent by Silver Catalysis. Angew. Chem. Int. Ed., 2020, 59, 19940.

18. Di Zhang#, Zhanyun Tang#, He Huang, Guolin Zhou, Chang Cui, Yejing Weng, Wenchao Liu, Sunjoo Kim, Sangkyu Lee, Mathew Perez-Neut, Jun Ding, Daniel Czyz, Rong Hu, Zhen Ye, Maomao He, Y George Zheng, Howard A Shuman, Lunzhi Dai, Bing Ren, Robert G Roeder, Lev Becker*, Yingming Zhao*. Metabolic regulation of gene expression by histone lactylation. Nature 2019, 574, 575.

19. He Huang#, Di Zhang, Yi Wang, Mathew Perez-Neut, Zhen Han, Y. George Zheng, Quan Hao, Yingming Zhao*. Lysine benzoylation is a histone mark regulated by SIRT2. Nat. Commun. 2018, 9, 3374.

20. He Huang#, Shuang Tang#, Ming Ji#, Zhanyun Tang, Miho Shimada, Xiaojing Liu, Shankang Qi, Jason W Locasale, Robert G Roeder, Yingming Zhao*, Xiaoling Li*. EP300-Mediated Lysine 2-Hydroxyisobutyrylation Regulates Glycolysis. Mol. Cell 2018, 70, 663-678.

21. He Huang#, Zhouqing Luo#, Shankang Qi#, Jing Huang#, Peng Xu, Xiuxuan Wang, Li Gao, Fangyi Li, Jian Wang, Wenhui Zhao, Wei Gu, Zhucheng Chen, Lunzhi Dai*, Junbiao Dai*, Yingming Zhao*. Landscape of the regulatory elements for lysine 2-hydroxyisobutyrylation pathway. Cell Res. 2018, 28, 111-125.

22. Jing Huang#, Zhouqing Luo#, Wantao Ying#, Qichen Cao, He Huang, Junkai Dong, Qingyu Wu, Yingming Zhao, Xiaohong Qian*, Junbiao Dai*. 2-Hydroxyisobutyrylation on histone H4K8 is regulated by glucose homeostasis in Saccharomyces cerevisiae. Proc. Natl. Acad. Sci. U. S. A. 2017, 114, 8782-8787.

23. Zuzanna Kaczmarska#, Esther Ortega, Afsaneh Goudarzi, He Huang, Sunjoo Kim, José A Márquez, Yingming Zhao, Saadi Khochbin, Daniel Panne*. Structure of p300 in complex with acyl-CoA variants. Nat. Chem. Biol. 2017, 13, 21-25.

24. Zhongyu Xie#, Di Zhang#, Dongjun Chung#, Zhanyun Tang, He Huang, Lunzhi Dai, Shankang Qi, Jingya Li, Gozde Colak, Yue Chen, Chunmei Xia, Chao Peng, Haibin Ruan, Matt Kirkey, Danli Wang, Lindy M. Jensen, Oh Kwang Kwon, Sangkyu Lee, Scott D Pletcher, Minjia Tan, David B Lombard, Kevin P White, Hongyu Zhao, Jia Li, Robert G Roeder, Xiaoyong Yang*, Yingming Zhao*. Metabolic regulation of gene expression by histone lysine β-hydroxybutyrylation. Mol. Cell 2016, 62, 194-206.

25. Yuanyuan Li#, Benjamin R Sabari#, Tatyana Panchenko#, Hong Wen, Dan Zhao, Haipeng Guan, Liling Wan, He Huang, Zhanyun Tang, Yingming Zhao, Robert G Roeder, Xiaobing Shi, C. David Allis*, Haitao Li*. Molecular coupling of histone crotonylation and active transcription by AF9 YEATS domain. Mol. Cell 2016, 62, 181-193.

26. Afsaneh Goudarzi#, Di Zhang#, He Huang, Sophie Barral, Oh Kwang Kwon, Shankang Qi, Zhanyun Tang, Thierry Buchou, Anne-Laure Vitte, Tieming He, Zhongyi Cheng, Emilie Montellier, Jonathan Gaucher, Sandrine Curtet, Alexandra Debernardi, Guillaume Charbonnier, Denis Puthier, Carlo Petosa, Daniel Panne, Sophie Rousseaux, Robert G Roeder, Yingming Zhao*, Saadi Khochbin*. Dynamic competing histone H4 K5K8 acetylation and butyrylation are hallmarks of highly active gene promoters. Mol. Cell 2016, 62, 169-180.

27. Inmaculada Martínez-Reyes#, Lauren P Diebold, Hyewon Kong, Michael Schieber, He Huang, Christopher T Hensley, Manan M Mehta, Tianyuan Wang, Janine H Santos, Richard Woychik, Eric Dufour, Johannes N Spelbrink, Samuel E Weinberg, Yingming Zhao, Ralph J De Berardinis, Navdeep S Chandel*. TCA cycle and mitochondrial membrane potential are necessary for diverse biological functions. Mol. Cell 2016, 61, 199-209.

28. Benjamin R Sabari#, Zhanyun Tang, He Huang, Vladimir Yong-Gonzalez, Henrik Molina, Ha Eun Kong, Lunzhi Dai, Miho Shimada, Justin R Cross, Yingming Zhao, Robert G. Roeder, C. David Allis*. Intracellular crotonyl-CoA stimulates transcription through p300-catalyzed histone crotonylation. Mol. Cell 2015, 58, 203-215.

29. He Huang#, Shu Lin, Benjamin A Garcia, Yingming Zhao*. Quantitative proteomic analysis of histone modifications. Chem. Rev. 2015, 115, 2376-2418.

30. Jeffrey K Holden#, Soosung Kang, Scott A Hollingsworth, Huiying Li, Nathan Lim, Steven Chen, He Huang, Fengtian Xue, Wei Tang, Richard B Silverman, Thomas L. Poulos*. Structure-based design of bacterial nitric oxide synthase inhibitors. J. Med. Chem. 2015, 58, 994-1004.

31. He Huang#, Benjamin R Sabari, Benjamin A Garcia, C David Allis, Yingming Zhao*. SnapShot: histone modifications. Cell 2014, 159, 458-458.

32. Minjia Tan#, Chao Peng#, Kristin A Anderson#, Peter Chhoy, Zhongyu Xie, Lunzhi Dai, Jeongsoon Park, Yue Chen, He Huang, Yi Zhang, Jennifer Ro, Gregory R. Wagner, Michelle F. Green, Andreas S. Madsen, Jessica Schmiesing, Brett S. Peterson, Guofeng Xu, Olga R. Ilkayeva, Michael J. Muehlbauer, Thomas Braulke, Chris Mühlhausen, Donald S. Backos, Christian A. Olsen, Peter J. McGuire, Scott D. Pletcher, David B. Lombard, Matthew D. Hirschey*, Yingming Zhao*. Lysine glutarylation is a protein posttranslational modification regulated by SIRT5. Cell Metab. 2014, 19, 605-617.

33. He Huang#, Huiying Li, Sun Yang, Georges Chreifi, Pavel Martásek, Linda J Roman, Frank L Meyskens, Thomas L Poulos*, Richard B Silverman*. Potent and selective double-headed thiophene-2-carboximidamide inhibitors of neuronal nitric oxide synthase for the treatment of melanoma. J. Med. Chem. 2014, 57, 686-700.

34. He Huang#, Huiying Li, Pavel Martásek, Linda J Roman, Thomas L Poulos*, Richard B Silverman*. Structure-guided design of selective inhibitors of neuronal nitric oxide synthase. J. Med. Chem. 2013, 56, 3024-3032.

35. He Huang#, Haitao Ji, Huiying Li, Qing Jing, Kristin Jansen Labby, Pavel Martásek, Linda J Roman, Thomas L Poulos*, Richard B Silverman*. Selective monocationic inhibitors of neuronal nitric oxide synthase. Binding mode insights from molecular dynamics simulations. J. Am. Chem. Soc. 2012, 134, 11559-11572.

36. Qian Ba#, Miao Hao#, He Huang#, Junmei Hou, Shichao Ge, Zhuzhen Zhang, Jun Yin, Ruiai Chu, Hualiang Jiang, Fudi Wang, Kaixian Chen, Hong Liu*, Hui Wang*. Iron deprivation suppresses hepatocellular carcinoma growth in experimental studies. Clin. Cancer Res. 2011, 17, 7625-7633.

37. He Huang#, Qin Chen#, Xin Ku, Linghua Meng*, Liping Lin, Xiang Wang, Caihua Zhu, Yi Wang, Zhi Chen, Ming Li, Hualiang Jiang, Kaixian Chen, Jian Ding, Hong Liu*. A series of α-heterocyclic carboxaldehyde thiosemicarbazones inhibit topoisomerase IIα catalytic activity. J. Med. Chem. 2010, 53, 3048-3064.