中草药

天然产物靶点发现策略研究进展及应用

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高艳杰 ¹,,², , 李杨小涵 ¹,,², , 方朵 ¹,,², , 高改 ¹,,², , 谢治深 ¹,,², , 张振强 ¹,,², , 徐江雁 ¹,,², , 张效威 ¹,,²,

中草药 | 综述 2026,57(16): 6566-6577

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中草药 |综述 2026 , 57 (16) : 6566 -6577

天然产物靶点发现策略研究进展及应用

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高艳杰¹,,²,, 李杨小涵¹,,²,, 方朵¹,,²,, 高改¹,,²,, 谢治深¹,,²,, 张振强¹,,²,, 徐江雁¹,,²,, 张效威¹,,²,

作者信息

^1.河南中医药大学中医药科学院, 河南郑州 450046

^2.中西医防治重大疾病河南省协同创新中心, 河南郑州 450046

^3.河南中医药大学中医药科学院, 河南郑州 450046

^4.中西医防治重大疾病河南省协同创新中心, 河南郑州 450046

通讯作者:

张效威

作者简介:

高艳杰: 高艳杰,硕士研究生,研究方向为中药活性成分靶点发现及机制。E-mail:15890389358@163.com

Research progress and applications of target discovery strategies for natural products

Affiliations

出版时间: 2026-08-28 doi: 10.7501/j.issn.0253-2670.2026.16.028

文章导航

摘要

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天然产物具有结构多样、生物活性广泛等特点，已经成为新药开发及先导化合物发现的主要来源。靶点不明确严重阻碍了许多天然产物的研究和开发进程，靶点解析也因此成为天然产物研究领域亟待突破的瓶颈问题和当前的热点问题。近年来，围绕天然产物靶点发现开展了大量研究，并逐步建立起较为系统的方法体系。天然产物靶点发现策略通常可根据是否需要对研究对象进行化学修饰，分为标记策略和非标记策略2大类。系统梳理上述2类策略框架下的主要靶点发现技术，重点总结各类方法的作用原理、技术优势、局限性、适用场景及其代表性应用案例，为天然产物作用机制研究以及靶点发现提供参考与思路。

关键词

天然产物 / 靶点发现 / 活性探针 / 点击化学 / 标记策略 / 非标记策略

Abstract

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Natural products, characterized by structural diversity and broad biological activities, have become a major source for drug discovery and lead compound identification. However, unclear targets have seriously hindered the research and development of many natural products, making target identification a critical bottleneck and a major focus in this field. In recent years, extensive efforts have been devoted to the discovery of natural product targets, and a relatively systematic methodological framework has gradually been established. According to whether chemical modification is required, current target identification strategies for natural products can be broadly classified into two categories:labeled and label-free approaches. This review systematically summarizes the major target identification techniques within these two strategic frameworks, with particular emphasis on their underlying principles, technical advantages, limitations, applicable scenarios, and representative applications, in order to provide references and insights for mechanistic studies and target discovery of natural products.

Key words

natural products / target discovery / activity probes / click chemistry / labeling-based strategies / label-free approaches

引用本文

高艳杰, 李杨小涵, 方朵, 高改, 谢治深, 张振强, 徐江雁, 张效威. 天然产物靶点发现策略研究进展及应用. 中草药, 2026 , 57 (16) : 6566 -6577 . DOI: 10.7501/j.issn.0253-2670.2026.16.028

GAO Yanjie, LI Yangxiaohan, FANG Duo, GAO Gai, XIE Zhishen, ZHANG Zhenqiang, XU Jiangyan, ZHANG Xiaowei. Research progress and applications of target discovery strategies for natural products[J]. Chinese Traditional and Herbal Drugs, 2026 , 57 (16) : 6566 -6577 . DOI: 10.7501/j.issn.0253-2670.2026.16.028

基金

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国家自然科学基金资助项目
国家重点研发计划项目
河南省高校科技创新人才支持计划
河南省省级科技研发计划联合基金（学科类）项目

参考文献

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文献

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参考文献引证文献

排序方式：

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Chang J, Kim Y, Kwon H J. Advances in identification and validation of protein targets of natural products without chemical modification [J]. Nat Prod Rep, 2016, 33(5): 719-730.

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Wright M H, Sieber S A. Chemical proteomics approaches for identifying the cellular targets of natural products [J]. Nat Prod Rep, 2016, 33(5): 681-708.

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Chen S Q, Bi K J, Liang H X, et al. PROTAC derivatization of natural products for target identification and drug discovery: Design of evodiamine-based PROTACs as novel REXO4 degraders [J]. J Adv Res, 2024, 63: 219-230.

Ni Z H, Shi Y, Liu Q L, et al. Degradation-based protein profiling: A case study of celastrol [J]. Adv Sci, 2024, 11(25): 2308186.

Sun Y, Liu S, Chen L, et al. AI-driven discovery of dual antiaging and anti-AD therapeutics via PROTAC target deconvolution of a super-enhancer-regulated axis [J]. Sci Adv, 2025, 11(47): eadz9283.

Kannt A, Đikić I. Expanding the arsenal of E3 ubiquitin ligases for proximity-induced protein degradation [J]. Cell Chem Biol, 2021, 28(7): 1014-1031.

Ye S J, Luo W, Khan Z A, et al. Celastrol attenuates angiotensin II-induced cardiac remodeling by targeting STAT3[J]. Circ Res, 2020, 126(8): 1007-1023.

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Zhang Z D, Chen M J, Xu Y T, et al. A natural small molecule isoginkgetin alleviates hypercholesterolemia and atherosclerosis by targeting ACLY [J]. Theranostics, 2025, 15(10):4325-4344.

Lai H Q, Fan P L, Zhang P X, et al. Targeting complement C3 with Tanshinone I decreases microglia-mediated synaptic engulfment to exert antidepressant effects [J]. Theranostics, 2025, 15(16): 8150-8175.

Li Y Y, Wu Y Q, Liang J, et al. Ligustilide suppresses macrophage-mediated intestinal inflammation and restores gut barrier via EGR1-ADAM17-TNF-α pathway in colitis mice [J]. Research, 2025, 8: 864.

Li F F, Zhang Z X, Shi Q Y, et al. Thermal proteome profiling (TPP) reveals NAMPT as the anti-glioma target of phenanthroindolizidine alkaloid PF403[J]. Acta Pharm Sin B, 2025, 15(4): 2008-2023.

Dong R C, Wei J, Tian S, et al. Asperosaponin VI promotes osteoporotic fracture healing by targeting Piezo1 to enhance the coupling of LEPR⁺ BMSCs and PODXL⁺ ECs [J]. Phytother Res, 2025, 39(7): 3148-3166.

Yuan J F, Tao Y L, Wang M X, et al. Astragaloside II, a natural saponin, facilitates remyelination in demyelination neurological diseases via p75NTR receptor mediated β-catenin/Id2/MBP signaling axis in oligodendrocyte precursor cells [J]. J Adv Res, 2026, 80:577-591.

Lomenick B, Hao R, Jonai N, et al. Target identification using drug affinity responsive target stability (DARTS) [J]. Proc Natl Acad Sci USA, 2009, 106(51): 21984-21989.

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Chen S Z, Liu X X, Peng C, et al. The phytochemical hyperforin triggers thermogenesis in adipose tissue via a Dlat-AMPK signaling axis to curb obesity [J]. Cell Metab, 2021, 33(3):565-580.e7.

Wang K Y, Li Y N, Ma Y N, et al. Probing ligand-induced local stability shifts: A sensitive approach to identify target proteins and binding sites at the proteomic scale [J]. Curr Opin Chem Biol, 2025, 87: 102602.

Li K J, Chen S J, Wang K Y, et al. A peptide-centric local stability assay enables proteome-scale identification of the protein targets and binding regions of diverse ligands [J]. Nat Meth, 2025, 22(2): 278-282.

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Curtis M J. New drug discovery and development from natural products [J]. Pharmacol Ther, 2024, 263:108733.
Newman D J, Cragg G M. Natural products as sources of new drugs over the nearly four decades from 01/1981 to 09/2019[J]. J Nat Prod, 2020, 83(3): 770-803.
代国年, 孙凯瑞, 周雅馨, 等. 基于铁死亡的青蒿素衍生物多病靶向治疗研究进展[J]. 中草药, 2025, 56(17): 6389-6403.
Li C X, Wood J C, Vu A H, et al. Single-cell multi-omics in the medicinal plant Catharanthus roseus [J]. Nat Chem Biol, 2023, 19(8): 1031-1041.
Wang S Y, Zhang Y, Yu R Z, et al. Labeled and label-free target identifications of natural products [J]. J Med Chem, 2024, 67(20): 17980-17996.
Chang J, Kim Y, Kwon H J. Advances in identification and validation of protein targets of natural products without chemical modification [J]. Nat Prod Rep, 2016, 33(5): 719-730.
Heal W P, Tam Dang T H, Tate E W. Activity-based probes: Discovering new biology and new drug targets [J]. Chem Soc Rev, 2011, 40(1): 246-257.
Wright M H, Sieber S A. Chemical proteomics approaches for identifying the cellular targets of natural products [J]. Nat Prod Rep, 2016, 33(5): 681-708.
Zhang H W, Xu Q X, Jiang Z R, et al. Targeting senescence with apigenin improves chemotherapeutic efficacy and ameliorates age-related conditions in mice [J]. Adv Sci, 2025, 12(20):2412950.
Cheng Y F, Wang G Q, Yang X X, et al. Artesunate alleviates Parkinson’s disease by targeting astrocyte MT2A to attenuate dopamine neuronal cuproptosis [J]. Pharmacol Res, 2025, 219:107895.
Moses J E, Moorhouse A D. The growing applications of click chemistry [J]. Chem Inform, 2007, 38(44):200744237.
Huang L, Li G J, Zhang Y, et al. Small-molecule targeting BCAT1-mediated BCAA metabolism inhibits the activation of SHOC2-RAS-ERK to induce apoptosis of Triple-negative breast cancer cells [J]. J Adv Res, 2025, 75: 723-738.
He H K, Hao M J, Luo P, et al. Inhibition peroxiredoxin-2 by capsaicin ameliorates rheumatoid arthritis via ROS-mediated apoptosis in fibroblast-like synoviocytes [J]. MedComm, 2025, 6(6):e70209.
Luo P, Zhang Q, Shen S, et al. Mechanistic engineering of celastrol liposomes induces ferroptosis and apoptosis by directly targeting VDAC2 in hepatocellular carcinoma [J]. Asian J Pharm Sci, 2023, 18(6): 100874.
Li G J, Li H Y, Wang P L, et al. Chemo-proteomics reveals dihydrocaffeic acid exhibits anti-inflammation effects via transaldolase 1 mediated PERK-NF-κB pathway [J]. Cell Commun Signal, 2025, 23(1): 65.
Chen X, Wang Y T, Ma N, et al. Target identification of natural medicine with chemical proteomics approach: Probe synthesis, target fishing and protein identification [J]. Signal Transduct Target Ther, 2020, 5: 72.
Chan W C, Zhao Q, Wong K H, et al. Tetrandrine regulates NAADP-mediated calcium signaling through a LIMP-2-dependent and sphingosine-mediated mechanism [J]. Nat Commun, 2025, 16: 6308.
Li T, Wang A H, Zhang Y L, et al. Chemoproteomic profiling of signaling metabolite fructose-1,6-bisphosphate interacting proteins in living cells [J]. J Am Chem Soc, 2024, 146(22):15155-15166.
Chiu D C, Cho Y T, Lin H N, et al. Photoaffinity labeling reveals a role for the unusual triply acylated phospholipid N-acylphosphatidylethanolamine in lactate homeostasis [J]. J Am Chem Soc, 2025, 147(37): 33386-33394.
Jiang H W, Chen H, Zheng Y X, et al. Specific pupylation as IDEntity reporter (SPIDER) for the identification of protein-biomolecule interactions [J]. Sci China Life Sci, 2023, 66(8):1869-1887.
Gu S S, Cui D R, Chen X Y, et al. PROTACs: An emerging targeting technique for protein degradation in drug discovery [J]. BioEssays, 2018, 40(4): 1700247.
Hughes G R, Dudey A P, Hemmings A M, et al. Frontiers in PROTACs [J]. Drug Discov Today, 2021, 26(10): 2377-2383.
Chen S Q, Bi K J, Liang H X, et al. PROTAC derivatization of natural products for target identification and drug discovery: Design of evodiamine-based PROTACs as novel REXO4 degraders [J]. J Adv Res, 2024, 63: 219-230.
Ni Z H, Shi Y, Liu Q L, et al. Degradation-based protein profiling: A case study of celastrol [J]. Adv Sci, 2024, 11(25): 2308186.
Sun Y, Liu S, Chen L, et al. AI-driven discovery of dual antiaging and anti-AD therapeutics via PROTAC target deconvolution of a super-enhancer-regulated axis [J]. Sci Adv, 2025, 11(47): eadz9283.
Kannt A, Đikić I. Expanding the arsenal of E3 ubiquitin ligases for proximity-induced protein degradation [J]. Cell Chem Biol, 2021, 28(7): 1014-1031.
Ye S J, Luo W, Khan Z A, et al. Celastrol attenuates angiotensin II-induced cardiac remodeling by targeting STAT3[J]. Circ Res, 2020, 126(8): 1007-1023.
Zhao B X, Liang Z H, Zhang L S, et al. Ponicidin promotes hepatocellular carcinoma mitochondrial apoptosis by stabilizing Keap1-PGAM5 complex [J]. Adv Sci, 2024, 11(38): e2406080.
Zhang Z D, Chen M J, Xu Y T, et al. A natural small molecule isoginkgetin alleviates hypercholesterolemia and atherosclerosis by targeting ACLY [J]. Theranostics, 2025, 15(10):4325-4344.
Lai H Q, Fan P L, Zhang P X, et al. Targeting complement C3 with Tanshinone I decreases microglia-mediated synaptic engulfment to exert antidepressant effects [J]. Theranostics, 2025, 15(16): 8150-8175.
Li Y Y, Wu Y Q, Liang J, et al. Ligustilide suppresses macrophage-mediated intestinal inflammation and restores gut barrier via EGR1-ADAM17-TNF-α pathway in colitis mice [J]. Research, 2025, 8: 864.
Li F F, Zhang Z X, Shi Q Y, et al. Thermal proteome profiling (TPP) reveals NAMPT as the anti-glioma target of phenanthroindolizidine alkaloid PF403[J]. Acta Pharm Sin B, 2025, 15(4): 2008-2023.
Dong R C, Wei J, Tian S, et al. Asperosaponin VI promotes osteoporotic fracture healing by targeting Piezo1 to enhance the coupling of LEPR⁺ BMSCs and PODXL⁺ ECs [J]. Phytother Res, 2025, 39(7): 3148-3166.
Yuan J F, Tao Y L, Wang M X, et al. Astragaloside II, a natural saponin, facilitates remyelination in demyelination neurological diseases via p75NTR receptor mediated β-catenin/Id2/MBP signaling axis in oligodendrocyte precursor cells [J]. J Adv Res, 2026, 80:577-591.
Lomenick B, Hao R, Jonai N, et al. Target identification using drug affinity responsive target stability (DARTS) [J]. Proc Natl Acad Sci USA, 2009, 106(51): 21984-21989.
Hu S R, Liang X F, Qin Y M, et al. Alnustone ameliorates metabolic dysfunction-associated steatotic liver disease by facilitating mitochondrial fatty acid β-oxidation via targeting calmodulin [J]. Adv Sci, 2025, 12(31): e11984.
Chen S Z, Liu X X, Peng C, et al. The phytochemical hyperforin triggers thermogenesis in adipose tissue via a Dlat-AMPK signaling axis to curb obesity [J]. Cell Metab, 2021, 33(3):565-580.e7.
Wang K Y, Li Y N, Ma Y N, et al. Probing ligand-induced local stability shifts: A sensitive approach to identify target proteins and binding sites at the proteomic scale [J]. Curr Opin Chem Biol, 2025, 87: 102602.
Li K J, Chen S J, Wang K Y, et al. A peptide-centric local stability assay enables proteome-scale identification of the protein targets and binding regions of diverse ligands [J]. Nat Meth, 2025, 22(2): 278-282.
Zhao J, Ma Y B, Xia R H, et al. Skullcapflavone II inhibits SLC1A4-mediated L-serine uptake and promotes mitochondrial damage in gastric cancer [J]. Adv Sci, 2025, 12(45):e17225.
West G M, Tang L J, Fitzgerald M C. Thermodynamic analysis of protein stability and ligand binding using a chemical modification- and mass spectrometry-based strategy [J]. Anal Chem, 2008, 80(11): 4175-4185.
West G M, Tucker C L, Xu T, et al. Quantitative proteomics approach for identifying protein-drug interactions in complex mixtures using protein stability measurements [J]. Proc Natl Acad Sci USA, 2010, 107(20): 9078-9082.
Liu F, Meng H, Fitzgerald M C. Large-scale analysis of breast cancer-related conformational changes in proteins using SILAC-SPROX [J]. J Proteome Res, 2017, 16(9): 3277-3286.
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2026年第57卷第16期

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doi: 10.7501/j.issn.0253-2670.2026.16.028

接收时间：2026-04-14
首发时间：2026-10-22
出版时间：2026-08-28

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收稿日期：2026-04-14

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国家自然科学基金资助项目

国家重点研发计划项目

河南省高校科技创新人才支持计划

河南省省级科技研发计划联合基金（学科类）项目

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^1.河南中医药大学中医药科学院, 河南郑州 450046

^2.中西医防治重大疾病河南省协同创新中心, 河南郑州 450046

^3.河南中医药大学中医药科学院, 河南郑州 450046

^4.中西医防治重大疾病河南省协同创新中心, 河南郑州 450046

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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