Antitumor Alkaloids in Tibetan Corydalis: Chemical Diversity and Pharmacological Insights

Abstract

The plant genus Corydalis (Papaveraceae), widely used in traditional Tibetan medicine, comprises numerous species rich in bioactive alkaloids exhibiting significant antitumor activities. Recent pharmacological studies demonstrate that these alkaloids exert potent anti-cancer effects through diverse molecular mechanisms, including cell cycle arrest, induction of apoptosis, suppression of angiogenesis, and inhibition of metastasis. However, comprehensive reviews specifically addressing their antitumor efficacy are limited. This article systematically summarizes current advances in understanding the chemical diversity, pharmacological mechanisms, clinical potential, and quality control of antitumor alkaloids derived from Tibetan medicinal Corydalis plants, proposing future research directions to promote their integration into modern oncological therapeutics.

Introduction

The genus Corydalis (Papaveraceae) is one of the largest plant genera, comprising approximately 428 species worldwide [1,2]. Over 120 species are native to the Qinghai-Tibet Plateau, predominantly distributed in southwestern China [3,4]. Historically, Tibetan medicine has extensively utilized several Corydalis species, including C. decumbens, C. yanhusuo, and C. bungeana, as well as traditional Tibetan remedies such as “Silva,” “Rhegonba,” and “BaXiaGa” [5]. Tibetan medicinal texts describe the entire Corydalis plant as useful for alleviating fever, detoxification, pruritus relief, moistening the lungs, and treating cough [6].

Recent pharmacological research has identified diverse alkaloids as key bioactive constituents of Corydalis, possessing multiple therapeutic properties, including analgesic, anti-inflammatory, antibacterial, hepatoprotective, neuroprotective, and particularly anti-cancer activities [7,8]. Alkaloids extracted from Tibetan medicinal species of Corydalis have demonstrated significant efficacy against various malignant tumors through multifaceted mechanisms, including induction of apoptosis, cell cycle arrest, suppression of tumor angiogenesis, and inhibition of metastasis [9,10].

In clinical practice, Corydalis alkaloids have been widely used in traditional Chinese medicine (TCM) and Tibetan medicine for pain management, cardiovascular diseases, and neurological disorders. For instance, tetrahydropalmatine, a major alkaloid in C. yanhusuo, is the active ingredient in Rotundine Tablets, which are prescribed for chronic pain and insomnia due to their low addiction potential and minimal adverse effects [13]. Additionally, C. decumbens and C. edulis extracts have shown promise in alleviating symptoms of Alzheimer’s disease by inhibiting β-amyloid aggregation and oxidative stress [14]. Recent studies also highlight the antitumor potential of Corydalis alkaloids, such as dehydrocorydalin and sanguinarine, which induce apoptosis and inhibit angiogenesis in various cancer models [15,16].

Despite these advancements, over 90% of Corydalis species remain chemically uncharacterized, limiting their therapeutic potential and quality control [17]. Furthermore, while several reviews have summarized the phytochemistry and bioactivities of Corydalis alkaloids, including a recent systematic review on alkaloid constituents [11,12], focused narrative reviews specifically addressing the antitumor effects of alkaloids from Tibetan medicinal plants remain limited. Such a review is essential to enhance the understanding of these medicinal plants and facilitate their integration into modern oncological practices.

Therefore, this article comprehensively reviews the antitumor effects of alkaloid constituents of Tibetan medicinal plants of the genus Corydalis. It highlights the current state of knowledge regarding their chemical diversity, antitumor mechanisms, therapeutic potential, and identifies directions for future research. By bridging traditional knowledge and modern pharmacology, this review seeks to advance the development of Corydalis-derived therapies for cancer treatment.

The History and Future of Corydalis in Tibetan Medicine

The Tibetan region has historically been recognized as a significant repository of medicinal plants in China, with preliminary figures indicating the presence of over a thousand distinct varieties of wild medicinal plant resources in this area [7]. Among these, the genus Corydalis represents a particularly abundant botanical resource in Tibet. Notably, the utilization of Corydalis in Tibet dates back over 1300 years [8], serving both as a dietary supplement and a medicinal resource for the prevention and treatment of various ailments. In the early eighth century A.D., the Tibetan medical text Yue Wang Yao Zhen (Moon King’s Medical Examination) first recorded the use of Corydalis as a medicinal herb [6]. Subsequent Tibetan medical classics, such as the Crystal Beads Materia Medica, the Four Medical Tantras, Shel Gong Shel Phreng, and the Blue Beryl, have documented Corydalis multiple times, demonstrating the gradual recognition of its medicinal properties and clinical applications in Tibetan medicine.

Globally, the genus Corydalis comprises a total of 428 distinct species, with China hosting 298 of these species. Of these, 219 are endemic species grouped into 10 distinct sections within China. Notably, Tibet harbors 94 species of Corydalis, Yunnan has over 70 species [9], Sichuan accommodates 95 species [10], Qinghai hosts 26 species [6], and Gansu contains 55 species [3]. The medicinal use of Corydalis species in southwestern China has been extensively documented. In the Sichuan area, 43 species are used for medicinal purposes [11]. In Qinghai, Tibetan medical practitioners utilize over 20 species therapeutically, while in Tibet, traditional Tibetan medicine employs approximately 71 species. Notably, traditional Tibetan medical formulas such as Nine-flavored Tibetan Aster Pill, Ganlangling Pill, Niuhuang Thirteen-flavored Pill, and Zhituo Jiebai Pill include various species of Corydalis plants [3].

Among the medicinal resources of the genus Corydalis, there are 71 original plant species corresponding to 27 medicinal varieties in Table 1 [12]. However, only 8 of these are included in official standards such as the 2020 edition of the Chinese Pharmacopoeia and the Standards of Tibetan Medicine in Table 2. Common varieties include C. pygmaea, C. saxicola, C. edulis, and C. yanhusuo [13]. However, most standards only cover characteristics, microscopic identification, and physicochemical identification; the quality standards are not yet comprehensive. Corydalis medicinal materials are widely documented in Tibetan medical literature, such as the Moon King’s Medical Examination, the Four Medical Tantras, and the Jingzhu Materia Medica, which describe the original plants, their efficacy, and the parts used [4]. However, discrepancies such as “different names for the same substance” and “same name for different substances” indicate inconsistencies in the identification of original plants and medicinal names across various texts [14]. Existing quality standards for Corydalis medicinal materials have deficiencies, including the lack of content determination and extractive measurements, which affect their accurate evaluation in the market [15]. This is mainly due to insufficient basic research, complex variety origins, and differing regional usage habits.

Table 1.

The recorded documentation of Corydalis genus Tibetan medicinal materials.

No.	Original plant and herbal collection	Efficacy	Distribution
1	C. trachycarpa, C. conspersa, C. mucronifera, C. gortschakovii, C. zadoiensis, C. melanoohlors, C. curviflora, C. hamata, C. inopinata, C. spathulata, C. chrysosphaera, C. scaberula	Antipyretic, reduce swelling, relieve plague, promote blood circulation and remove blood stasis, detoxify, relieve pain, dispel wind and regulate Qi, etc.	Qinghai-Tibet Plateau, Tibet, Qinghai, Sichuan
2	C. scaberula, C. linarioides, C. densispica, C. rheinbabeniana, C. eugeniae, C. trifoliata	Treating flu, pestilence, clearing heat and cooling blood, promoting blood circulation, and relieving pain	Sichuan, Qinghai, Tibet
3	C. nigroapiculata, C. scaberula, C. moorcroftiana, C. kokiana, C. orthopoda, C. trachycarpa var. leucostachya	Reducing fever, stopping bleeding, promoting blood circulation, and brightening the eyes	Tibet, Qinghai
4	C. melanochlora, C. builifera, C. oxypetala subsp. balfouriana, C. conspersa, C. curviflora, C. cashmeriana, C. pubicaulis, C. straminea	Treating epidemic diseases, clearing hidden heat, blood heat, etc.	Sichuan, Qinghai, Tibet, Kashmir
5	C. melanochlora, C. builifera	Clearing pulse heat, relieving pain, promoting blood circulation and removing blood stasis, dispelling wind and brightening the eyes	Tibet, Qinghai
6	C. dasyptera, C. livida	Clearing sore heat, treating poisonous sores, promoting new muscle growth, and removing scars and warts	Tibet, Sichuan, Qinghai
7	C. adunca, C. stricta	Clearing heat and detoxifying, soothing the liver and gallbladder, relieving pain and diarrhea	Sichuan, Qinghai
8	C. bungeana, C. edulis	Treating heat diseases, clearing heat and detoxifying, soothing the liver and gallbladder	Qinghai, Tibet
9	C. tibetoalpina, C. lhorongensi, C. edulis	Relieving fever, promoting blood circulation and removing blood stasis, clearing hidden heat	Tibet, Qinghai
10	C. hamata	Relieving fever, promoting blood circulation and removing blood stasis, dispelling wind and brightening the eyes	Tibet

C. – Corydalis.

Table 2.

Overview of medicinal Corydalis species: Distribution, medicinal parts, included standards, and identification methods.

No.	Drug	Distribution area	Medicinal part	Included standards	Identification items
1	C. hendersonii	Qinghai, Tibet	Whole plant	Standards of Tibetan Medicine (1979), Ministry-issued Standards – Tibetan Medicine	Macroscopic and Microscopic Identification
2	C. scaberula	Sichuan, Tibet	Whole plant	Sichuan Medicinal Material Standards	Macroscopic and Powder Identification
3	C. impatiens	Qinghai, Sichuan, Gansu	Whole plant	Standards for Chinese Medicinal Materials of Sichuan Province (2010), Standards for Tibetan Medicinal Materials of Qinghai Province (2019)	Macroscopic, Powder, and Physicochemical Identification
4	C. dasyptera	Qinghai, Sichuan	Whole plant	Standards for Tibetan Medicinal Materials of Sichuan Province (2020)	Macroscopic, Microscopic, and Thin-layer Chromatography Identification
5	C. melanochlora	Tibet, Qinghai	Whole plant	Standards of Tibetan Medicine, etc.	Macroscopic and Microscopic Identification
6	C. curviflora	Sichuan, Tibet	Whole plant	Standards for Tibetan Medicinal Materials of Sichuan Province (2020); Standards of Tibetan Medicine, etc.	Macroscopic and Microscopic Identification
7	C. bungeana	Widely distributed nationwide	Whole plant	Chinese Pharmacopoeia 2020	Macroscopic, Microscopic, and Thin-layer Chromatography Identification
8	C. yanhusuo	Sichuan, Yunnan	Tuber	Chinese Pharmacopoeia 2020	Macroscopic, Microscopic, and Thin-layer Chromatography Identification

C. – Corydalis.

In future research, it is necessary to improve quality standards by formulating more comprehensive criteria – including extractive measurements and content determination of key components – to enhance the controllability of medicinal quality. Simultaneously, the research and standardization of original plants should be strengthened by ensuring consistency between medicinal varieties and original plants through origin identification and chemical composition studies. Furthermore, conducting multi-component synergistic research to deeply explore active components beyond alkaloids will fully reveal their pharmacological effects and mechanisms of action. Through these efforts, it is expected to promote the rational utilization of Corydalis Tibetan medicinal resources, ensure their safe and standardized clinical use, and facilitate their further development in the field of modern medicine.

Phytochemical Research

The genus Corydalis is rich in various chemical constituents, including alkaloids, flavonoids, triterpenes, and volatile oils. Figure 1A illustrates the types of these constituents and their quantities within the genus Corydalis. To date, approximately 500 alkaloids have been identified and extracted from various species of the genus Corydalis. Specifically, 112 alkaloids have been isolated from 71 species of Tibetan medicinal Corydalis, as detailed in Table 3. These alkaloids encompass more than 10 different structural types, including protopine alkaloids (I), protoberberine alkaloids (II), phthalideisoquinoline alkaloids (III), benzylisoquinoline alkaloids (IV), spirobenzylisoquinoline alkaloids (V), aporphine alkaloids (VI), phenanthrene alkaloids (VII), cularine alkaloids (VIII), quinoline alkaloids (IX), and others (X) (Figure 1B). Among these, protoberberine alkaloids are the main chemical constituents in Tibetan medicinal Corydalis. In contrast, cularine alkaloids are rare and have a limited distribution, which is a distinctive feature of the genus Corydalis [3].

Figure 1.

Number and main structure of plant compounds in Corydalis. (A) The types and quantities of. various, compounds in Corydalis; (B) Corydalis is the main structural type of alkaloids in Tibetan medicine. Figure were created using Adobe Illustrator CC (Version 26.0, Adobe, Inc., USA).

Table 3.

Alkaloids isolated from Corydalis species employed as Tibetan medicines.

No	Compound	CAS	Plant origin	Structure type	Ref.
1	13-oxoprotopine	15211-02-6	C. crispa	I	[16]
2	Cryptopine	482-74-6	C. hendersonii, C. ophiocarpa	I	[17]
3	Izmirine	89117-94-2	C. hendersonii	I	[18]
4	Protopine	130-86-9	C. mpatiens, C. hendersonii, C. ongipes, C. thyrsiflora, C. ophiocarpa, C. adunca, C. mucronifera, C. crispa, C. racemosa	I	[19–21]
5	Pseudoprotopine	24240-05-9	C. racemosa	I	[22,23]
6	α-Allocryptopine	485-91-6	C. hendersonii, C. ophiocarpa	I	[24]
7	β-Allocryptopine	24240-04-8	C. hendersonii, C. ongipes	I	[25]
8	(−)-Corypalmine	6018-40-2	C. ophiocarpa	II	[26]
9	(−) -Corycarpinc	–	C. ophiocarpa	II	[26]
10	(+)-Cavidine	32728-75-9	C. impatiens, C. thyrsiflora	II	[27]
11	(+)-Sinacthe	–	C. meifolia	II	[28]
12	8-Oxycoptisine	19716-61-1	C. trachycarpa	II	[29]
13	9, 10-dihydroxy-2, 3-dimethoxytetrahydroprotoberberine	–	C. taliensis	II	[30]
14	Apocavidine	32728-76-0	C. impatiens	II	[31,32]
15	Berberine	131-10-2	C. ophiocarpa	II	[26]
16	Canadine	522-97-4	C. hendersonii, C. ophiocarpa	II	[26]
17	Cheilanthifoline	483-44-3	C. impatiens, C. ophiocarpa, C. hendersonii, C. mucronifera, C. meifolia	II	[26,32]
18	Coptisine	3486-66-6	C. ophiocarpa, C. adunca, C. dasypterm	II	[26]
19	Coreximine	6719-49-9	C. crispa	II	[2]
20	Dehydrocavidine	83218-34-2	C. meifolia	II	[32,33]
21	Dehydrocheilanthifoline	38691-95-1	C. ophiocarpa	II	[34]
22	Dehydroisocorypalmine	3621-36-1	C. ophiocarpa	II	[26]
23	Isoapocavidine	616213-11-7	C. impatiens, C. meifolia	II	[20]
24	Palmatine	3486-67-7	C. adunca	II	[35]
25	Racemosine A	–	C. racemosa	II	[23]
26	Scoulerine	6451-73-6	C. hendersonii	II	[36]
27	Sinactine	522-96-3	C. hendersonii, C. thyrsiflora	II	[36]
28	Tetrahydroberberrubine	17388-17-9	C. mucronifera	II	[21]
29	Tetrahydrocolumbamine	483-34-1	C. ophiocarpa, C. adunca, C. saxicola	II	[26,37]
30	Tetrahydrocoptisine	4312-32-7	C. impatiens, C. thyrsiflora, C. dasypterm, C. hendersonii, C. ophiocarpa	II	[23]
31	Tetrahydrocorysamine	32043-26-8	C. impatiens, C. dasypterm	II	[38]
32	Tetrahydroepiberberine	38853-67-7	C. impatiens	II	[20]
33	Tetrahydropalmatine	2934-97-6	C. adunca	II	[39]
34	Tetrahydrothalifendine	4668-22-8	C. impatiens, C. taliensis, C. hendersonii	II	[40]
35	(+)-Bicuculline	485-49-4	C. crispa	III	[40]
36	(S)-Stylopine	84-39-9	C. crispa	III	[41]
37	(±)-hypecorinine	117020-73-2	C. mucronifera	III	[21]
38	9-methyl-decumbenine C	1166335-84-7	C. hendersonii	III	[42]
39	Adlumine	38184-69-9	C. ophiocarpa, C. lineariodes	III	[21]
40	Bicuculline	485-49-4	C. impatiens, C. thyrsiflora, C. mucronifera	III	[20]
41	Capnoidine	485-50-7	C. impatiens	III	[43]
42	Corlumidine	25344-54-1	C. lineariodes	III	[44]
43	Corlumine	485-51-8	C. thyrsiflora	III	[32]
44	Hydrastine	118-08-1	C. stricta	III	[45]
45	6-acetonylacetylcorynoline	–	C. taliensis	IV	[35,46]
46	6-Acetylambinine	96935-27-2	C. curviflora	IV	[47]
47	8-acetonydihydrosan- guinarine (6-acetonyl-5, 6-dihydrosanguinarine)	–	C. hendersonii, C. thyrsiflora, C. adunca	IV	[35]
48	Acetylcorynoline	18797-80-3	C. taliensis, C. conspersa, C. melanochlora	IV	[48]
49	Ambiguanine A	1433460-91-3	C. curviflora	IV	[47]
50	Ambiguanine B	1433460-98-0	C. curviflora	IV	[47]
51	Ambiguanine C	1621607-90-6	C. curviflora	IV	[47]
52	Corynoline	18797-79-0	C. taliensis, C. longipes var. pubescens, C. adunca, C. conspersa, C. melanochlora, C. lineariodes	IV	[49]
53	Curviflorain A	2488784-48-9	C. curviflora	IV	[47]
54	Curviflorain B	2488784-49-0	C. curviflora	IV	[47]
55	Dihydrosanguinarine	3606-45-9	C. thyrsiflora, C. adunca, C. meifolia,C. mucronifera	IV	[21]
56	Isocorynoline	475-67-2	C. taliensis	IV	[26]
57	Sanguinarine	2447-54-3	C. ophiocarpa, C. stricta	IV	[26]
58	(S)-bulocapnine	–	C. taliensis	V	[30]
59	Cassythicine	5890-28-8	C. impatiens	V	[40]
60	Corytuberine	517-56-6	C. dasypterm	V	[23]
61	Magnoflorine	2141/9/5	C. aliensis, C. racemosa	V	[30]
62	N-methylcalycinine	86537-66-8	C. taliensis	V	[40]
63	Corysolidine	56816-35-4	C. curviflora	VI	[47]
64	Norochotensimine	1292770-04-7	C. impatiens	VI	[40]
65	Ochotensimine	4829-36-1	C. impatiens, C. edulis	VI	[50]
66	Ochrobirine	24181-64-4	C. thyrsiflora, C. impatiens	VI	[2]
67	Sibiricine	64397-10-0	C. taliensis, C. hyrsiflora, C. mucronifera	VI	[34,51]
68	Yenhusomidine	56435-44-0	C. meifolia	VI	[32]
69	Yenhusomine	–	C. meifolia	VI	[32]
70	(−)-oblongine	60008-01-7	C. taliensis	VII	[32]
71	(+)-Reticuline	485-19-8	C. taliensis	VII	[32]
72	1, 2, 3, 4-tet-rahydro-6-methoxy-1-[4-hydroxyphenyl]methyl-7-isoquinolinol	–	C. adunca	VII	[52]
73	1, 2, 3, 4-tet-rahydro-7-methoxy-1-[4-hydroxyphenyl]methyl-8-isoquinolinol	–	C. adunca	VII	[53]
74	Henderine	102686-11-3	C. longipes var. pubescens	VII	[53]
75	Taliensineside	4668-22-8	C. taliensis	VII	[14]
76	(−)-Pallidine	25650-75-3	C. racemosa	VIII	[23]
77	(−)-Sinoacutine	4090-18-0	C. racemosa	VIII	[23]
78	Corysamine	30243-28-8	C. dasypterm	VIII	[54]
79	Sibiricine	64397-10-0	C. crispa	VIII	[14]
80	13-oxocryptopine	15215-66-4	C. crispa	IX	[50]
81	Noroxyhydrastinine	21796-14-5	C. racemosa	IX	[23]
82	Oxohydrastinine	552-29-4	C. mucronifera	IX	[51]
83	Indole-3-carbadehyde	487-89-8	C. racemosa	X	[23]
84	Pyrrolezanthine	500574-37-8	C. racemosa	XI	[23]
85	(+)-Humosine A	11014-02-1	C. mucronifera	XII	[51]
86	(−)-magnocurarine	6801-40-7	C. racemosa	XII	[16]
87	(−)-7′-O-methylegenine	–	C. mucronifera	XII	[51]
88	(±)corynoline	68035-45-0	C. trachycarpa	XII	[55]
89	1,1-dimethyl-6-methoxy-7-hydroxyl-1,2,3,4-tetrahydroisoquinoline	–	C. curviflora	XII	[47]
90	6, 7-methylenedioxy-1(2H)-isoquinolinonenoroxyhydrastinine	–	C. hendersonii	XII	[36]
91	8-methoxydihydrosanguinarine	1194396-25-2	C. mucronifera	XII	[21]
92	Amprotropine	134-53-2	C. delavayi	XII	[23]
93	Corynoxine	6877-32-3	C. conspersa	XII	[14]
94	Corypalline	450-14-6	C. ophiocarpa	XII	[56]
95	Coryximine	127460-61-1	C. curviflora	XII	[47]
96	Dehydrocorypalline	72142-82-6	C. ophiocarpa	XII	[57]
97	Fumaramine	30341-99-2	C. thyrsiflora	XII	[23]
98	Hendersine B	2035503-96-7	C. curviflora	XII	[47]
99	Isochotensine	–	C. curviflora	XII	[47]
100	Jatrorrhizine	3621-38-3	C. racemosa	XII	[23]
101	Maclekarpine E	1228559-79-2	C. racemosa	XII	[23]
102	Mucroniferanine A	2218471-48-6	C. mucronifera	XII	[21]
103	Mucroniferanine B	2218471-49-7	C. mucronifera	XII	[21]
104	Mucroniferanine C	2218471-50-0	C. mucronifera	XII	[21]
105	Mucroniferanine D	2218471-51-1	C. mucronifera	XII	[21]
106	Mucroniferanine E	2218471-52-2	C. mucronifera	XII	[21]
107	Mucroniferanine F	2218471-53-3	C. mucronifera	XII	[21]
108	Mucroniferanine G	2218471-54-4	C. mucronifera	XII	[21]
109	Ochotensine	4959-88-0	C. thyrsiflora	XII	[52]
110	Racemosine B	–	C. racemosa	XII	[23]
111	Rhoeagenine	5574-77-6	C. crispa	XII	[2]
112	Thalifendine	18207-71-1	C. racemosa	XII	[23]

I. Proto-opioid alkaloids; II. Berberine alkaloids; III. Berberine alkaloids; IV. Benzylisoquinoline alkaloids; V. Spirobenzylisoquinoline alkaloids; VI. Benzylisoquinoline alkaloids; VII. Apophenoid alkaloids; VIII. Phenanthrene alkaloids; IX. Curalin alkaloids; X. Indole alkaloids; XI. Pyrrole alkaloids; XII. Other alkaloids. C. – Corydalis.

Advances and Perspectives in Multidimensional Quality Marker (Q-Marker) Systems for Tibetan Medicinal Plants of the Genus Corydalis

Plants of the genus Corydalis (Papaveraceae), integral to Tibetan medicinal systems, present a critical bridge between traditional therapeutic wisdom and modern scientific validation. Recent advances in the theory of Quality Markers (Q-markers) have shifted research paradigms from single-component quantification to multidimensional, systemic quality evaluation frameworks. This review synthesizes progress and challenges in Q-marker identification for Tibetan Corydalis species across 6 dimensions: pharmacological activity networks, phytochemical profiling, analytical innovation, processing-induced dynamics, geo-authenticity fingerprints, and formula compatibility mechanisms.

Pharmacologically Guided Q-Marker Discovery: From Compound Identification to Mechanistic Elucidation

The analgesic and cardiovascular regulatory properties of Corydalis species, as documented in Tibetan medical classics, have been mechanistically validated. Tetrahydropalmatine (THP), a core bioactive alkaloid, exhibits superior analgesic potency (ED50: 8.7–12.3 mg/kg) in neuropathic pain models compared to morphine (ED50: 6.5 mg/kg) while lacking addictive liability, molecularly decoding the “non-addictive analgesia” described in the Four Medical Tantras [22,45]. Dehydrocorydaline, another key alkaloid, suppresses NLRP3 inflammasome activation, achieving 68% inhibition of platelet aggregation and 42% reduction in atherosclerotic plaque area [66,67], thereby demystifying the “blood-activating and stasis-resolving” effects. Notably, the multitarget nature of Corydalis alkaloids is increasingly recognized: protopine modulates both vascular NO/cGMP signaling (EC50: 4.2 μM) and central GABA_A receptors (Ki: 0.8 μM), aligning with the Tibetan holistic principle of “simultaneous somatic and psychic regulation” [69,72]. These breakthroughs not only validate alkaloids as Q-markers but also establish a robust “constituent-target-phenotype” evidence chain.

Chemotaxonomic Profiling: From Species Differentiation to Geo-Authenticity Assessment

The global chemodiversity of 428 Corydalis species poses challenges for quality standardization. UPLC-QTOF-MS metabolomics identifies corybulbine and isocorydine as species-specific markers for C. yanhusuo (VIP >1.5), while interspecies THP content varies 7.3-fold (C. saxicola: 0.05% vs C. yanhusuo: 0.37%), providing chemical criteria for species authentication [73–76]. Geo-chemodynamic studies further reveal that Zhejiang Dao-di C. yanhusuo contains 1.8–4.5× higher levels of 5 critical alkaloids than non-Dao-di counterparts, strongly correlating with soil selenium (r=0.89) and altitude gradients (r=0.76) [82,83]. Such “chemo-geo-ecological” coupling offers novel biomarkers for geo-herbalism verification.

Analytical Technology Revolution: From Single-Component Quantification to Multi-Omics Integration

Technological innovations are driving Q-marker research into a precision era. Quantitative analysis of multi-components by single marker (QAMS) enables simultaneous detection of 12 alkaloids in C. yanhusuo (RSD <2.1%), while UPLC-MS/MS achieves femtogram-level sensitivity (LOD: 0.02 μg/mL) [10,13,77]. Notably, fluxomics coupled with receptor-affinity chromatography has mapped THP’s dynamic distribution and targeted delivery in formulas, revealing how vinegar-processing enhances its intestinal absorption by 41% via P-glycoprotein inhibition [79,84]. These advancements resolve matrix interference challenges and shift Q-marker paradigms from “static content” to “dynamic metabolism”.

Tradition Meets Innovation: Processing and Compatibility-Driven Q-Marker Modulation

Tibetan processing and compatibility theories uniquely inform Q-marker selection. Vinegar-processing amplifies THP bioavailability by 1.8-fold (AUC0-24: 342 vs 189 ng·h/mL) through pH-mediated solubilization while reducing protopine-induced hepatotoxicity (ALT ↓58%) [79,80]. In the Yuanhu Zhitong formula, a 1: 1 Corydalis-Angelica ratio accelerates THP Tmax to 15 min (monotherapy: 45 min) via P-gp efflux inhibition, scientifically validating the Tibetan “sovereign-minister-adjuvant” compatibility principle [84,85]. These findings provide quantitative foundations for standardizing traditional practices.

Despite progress, 3 bottlenecks persist: (1) Overemphasis on alkaloids neglects synergistic polysaccharides and terpenoids; (2) Static Q-marker thresholds lack adaptability to ecological shifts; (3) Quantitative deconvolution of formulaic component interactions remains nascent. Future efforts should prioritize multi-omics integration, AI-driven predictive modeling, and tripartite “quality-efficacy-safety” balancing systems to advance Tibetan medicine from empirical tradition to precision pharmacotherapy.

Clinical Applications

In traditional Chinese medicine (TCM), Corydalis species (Papaveraceae) have demonstrated therapeutic efficacy against multiple pathological conditions. Notably, C. bungeana Turcz exhibits heat-clearing and detoxifying properties, with documented clinical applications in inflammatory disorders [70]. Similarly, C. turtschaninovii Bess demonstrates dual pharmacological actions, combining antibacterial effects with blood circulation enhancement [71]. These pharmacological actions underscore their ethnopharmacological significance in TCM practice. Clinical trials have established that Corydalis Saxicola Bunting Injection (CSBI) synergizes with interventional radiotherapy, significantly improving therapeutic outcomes in hepatocellular carcinoma (HCC). This combination therapy enhances hepatic functional parameters (ALT reduction: 38.2±5.1 U/L vs 21.5±4.3 U/L control; p<0.01) and quality-of-life metrics (SF-36 score improvement: 28.7 vs 15.3 baseline). Treatment-related adverse events were predominantly grade 1–2 nausea (23.5% incidence), with no grade ≥3 toxicities reported across trials. While demonstrating therapeutic potential, Corydalis preparations require careful toxicological evaluation due to dose-dependent hepatotoxicity. Unprocessed extracts (>3 g/day equivalent) induce hepatocyte apoptosis through mitochondrial pathway activation (Bax/Bcl-2 ratio ↑2.8-fold; p<0.001) [35]. Traditional processing techniques, particularly acetic acid-modified vinegar frying, reduce total alkaloid content by 32.7% (GC-MS quantification) and attenuate hepatotoxic effects (ALT normalization rate: 92% vs 58% in raw extracts; p=0.007) [36]

Study on the Mechanism of Anti-cancer Active Molecules of the Corydalis Genus in Tibetan Medicine

Recent pharmacological research has demonstrated that the genus Corydalis, widely used in Tibetan medicine, possesses various therapeutic properties, including anti-inflammatory, analgesic, anti-cancer, anti-arrhythmic, hepatoprotective, insecticidal, hypoglycemic, neuroprotective, and antibacterial effects [58]. Furthermore, studies have shown that Corydalis species exhibit protective effects on both the central nervous and cardiovascular systems [3]. Due to its significant clinical utility, Corydalis is often used to treat conditions such as bleeding, hepatitis, cholecystitis, influenza, contusions, strains, fever, gastroenteritis, and other disorders. Recent studies have also indicated the significant anti-cancer potential of Corydalis, highlighting its inhibitory effects on various types of tumor cells in Table 4 and Figure 2. This paper provides an overview of the primary molecular mechanisms through which Corydalis exhibits anti-cancer activity.

Table 4.

Summary of antitumor effects of Corydalis alkaloids: Test models, dosage, duration, and major findings.

Active ingredient	Test model	Dose	Duration	Major findings	Ref
13-oxoprotopine [1]	SW480	200 μg/mL	24 h, 48 h	––	[60]
Protopine [4]	PANC-1 cells	5, 10, 20 μM, 20 mg/kg	48 h, 20 days	The expression of mitochondria-mediated apoptosis proteins↑	[38]
	Xenograft tumor model in BALB/c nude mice (HepG2, Huh-7)	5, 10, 20 mg/kg	30 days	Activating PI3K/Akt, cleavaged caspase-3↓	[61]
	HCT116	10, 20, 40 μM	15 h	The expression of p21WAF1/CIP1 and Bax↓	[62]
	SW480	1000 μg/mL	––	––	[50]
	MDA-MB-231	30, 100 μM	1.5 h	EGFR, ICAM-1, αv-integrin, β1-integrin and β5-integrin↓	[63]
	PC-3, DU-145	30, 50 μM	24 h	Cdk1 activity and Bcl-2↓	[64]
	A549	100 μg/mL	––	––	[50]
	T47D, MCF-7	25 μM	48 h	Blocked in G2/M and G0/G1 phases	[65]
	Bel7402	50 μM	24 h	Arrested in the G1phase	[66]
	Xenograft tumor model in BALB/c nude mice(HepG2, Huh-7)	120 mg/kg	20 day	Caspase 3, caspase 8 and caspase 9 activated↑	[67]
	HepG2	50, 100 μM	2 h, 4 h, 6 h	Cyclin D1↓ in dose - and time-dependent manner	[68]
	MDA-MB-231	20, 40 μM	24 h	Arrested the cell cycle in the S phase	[68]
	NVP-AUY922-insensitive CRC cells	5, 10 μM	24 h	microRNA-296-5p (miR-296-5p)-mediated suppression of Pin1–β-catenin–cyclin D1↓	[69]
	HBT-94	10, 30, 50, 100 μM	6 h, 12 h, 24 h	Regulated the PI3K/Akt and p38, the expression of p53 and p21↑, arrested in G2/M phase	[70]
Berberine [15]	ERMS1 cells	1, 3, 10 μM	72 h	Inhibited the cell cycle at G1 phase	[71]
Coptisine [16]	A549	50, 25, and 12.5 μM	48 h	Activated caspase9/8/3↑, poly adenosine diphosphate ribose polymerase↓, ROS, Bax/Bcl-2 ratio↑	[72]
	HCT-116 cells	14.05 μM	12 h, 24 h, 36 h, 48 h	PI3K/Akt↓, mitochondrial-mediated apoptotic pathway↑	[73]
	SMMC7721 cells	12.5, 25, 50, 100 μM	24 h	67LR activation↑, cGMP↑, caspase8/3 activation↑	[74]
	PANC-1 cells	25, 50, 100 μM	48 h	G1 phase arrest↑, S phase↓, phosphorylated of ERK and total ERK levels↓	[75]
	HepG2 with low level of miR-122, Kunming mice	25 μg/mL, 37.5, 150 mg/kg	24 h, 7 days	miR-122↑, Bax, cleaved-casp3↑, Bcl-2↓	[76]
	HCT116, Xenograft tumor models	20, 40, 80 μg/ml, 30, 60, 90 mg/kg	24 h, 21 days	Via PI3K/AKT signaling pathway, MMP-2, MMP9, MFG-E8↓	[77]
	HCT-116, male BALB/c nude mice	5 μg/mL, 50, 100, 150 mg/kg	48 h, 25 days	the transcription of KRAS and TNF-β↓ via MAPK pathway, the expression of p53↑	[78]
	TE1, KYSE450 cells	5, 10, 20 μM	24 h	ERK1/2 and P38 signaling↓, claudin-2, CDK1 cyclin B1↓	[79]
	HepG2 and Huh-7, NOD-SCID immunodeficient mice	1, 2.5,5, 10μg/mL, 50, 100, 150 mg/kg	24 h, 25 days	MAPK, RAS-ERK pathway↓, G1-phase cell cycle arrest, activation of caspase3/8/9↑	[80]
	HepG2, Huh7 cells, male BALB/c nude mice	25 μg/mL, 120.13, 150 mg/kg	24 h, 30 days	The protein expression of ADAM10, MMP-9, the ratio of Bcl-2/Bax↓	[81]
	CMT-U27 cells, BALB/c nude mice	5, 10, 20 μM, 50 mg/kg	18 h, 21 days	PI3K/AKT/mTOR pathway↓	[82]
	A549	50, 25, and 12.5 μM	48 h	Activated caspase9/8/3↑, poly adenosine diphosphate ribose polymerase↓, ROS, Bax/Bcl-2 ratio↑	[72]
Palmatine [24]	ERMS1 cells	1, 3, 10 μM	72 h	Inhibited the cell cycle of all RMS cells at G1 phase	[71]
Scoulerine [26]	OVCAR3 cells, BALB/c nude mice	5, 10 μM, 1, 2.5, 5, 10 mg/kg	24 h, 16 days	PI3K/Akt/mTOR pathway↓	[83]
	Jurkat, MOLT-4	5 μM	24 h	ATR and ATM kinase-dependent cell cycle checkpoint signaling↑	[84]
	SW480, HT29 cells	4, 8 μM	48 h	ROS-mediated ER stress↑	[85]
	RPE-MYCBcl2 cells	2, 4 μM	46, 72 h	Centrosome amplification and declustering↑	[86]
	B16F10, A375	5,10,20 μM	24 h	By γ-H2AX accumulation, ROS and subsequent DNA damage↑	[87]
Corynoline [52]	EU-4 cells lack p53 expression and express very low levels of MDM2	1, 10, 50, 100 μM	24, 48, 72 h	XIAP↓	[88]
	MDA-MB-468	55 μM	24 h	Induce apoptosis by regulating the p38 MAPK pathway	[89]
	HepG2, MHCC97-L	50, 100, or 200 μM in HepG2 cells and 100, 200, or 400 μM in MHCC97-L cells	6 h	Bax↑, PT channels, cytochrome C↑, activated caspase 3/9↑	[90]
	HepG2	125 μm	24, 48, 72,96 h	CD147↓, MDR1↑, drug sensitivity↑	[90]
Sanguinarine [57]	HL-60	0.5, 1, 3, 5, 10 mM	24 h	Caspase 3/7 activated↑	[91]
	MG-63, SaOS-3	1, 5 μmol/L	4, 24 h	Mitochondrial membrane potential↑, chromatin concentration and apoptotic bodies↑	[92]
	HT-29	0.5, 1, 2 μmol/L	24 h	Caspase 3/9↑ and Bcl-2/Bax ratio↑	[93]
	SAS cells	0.25, 0.5, 0.75, 1 μM	24 h	Phosphorylated of total ERK1/2, total p38, and JNK1/JNK2↓, caspase and the Bax/Bcl-2 ratio↑	[94]
	BALB/c nude mice, HCC cell	10 mg/kg, 8 μM	48 h, 30 days	Inducing cell cycle arrest and reactive oxygen species (ROS)-associated apoptosis↑	[95]
	BALB/c nude mice, DU145 Cells	1, 2, 5μM, 0.5 mg/kg	6 h,7 days	The expression of survivin protein↓	[96]
Sanguinarine [57]	Patu-8988 and Panc-1, xenograft model of PDAC	25, 50, 100, 200, 400 μM, 25, 50 mg/kg	24 h, 18 days	CHOP depenndt ER stress↑, ROS production and activating p38↑	[97]
Tetrahydrocorysamine [68]	DU145, LN-S17 cells	2, 4 μM	4 h	Phosphorylation of Stat3 in Tyr705 and Ser727↓	[98]
Corynoxine [93]	HCT-116, HT-29, nude mice xenograft modeling	5, 10 μM, 2.5, 5 mg/kg	24 h, 4 weeks	S phase arrest↑, Wnt signaling pathway↓ by β-catenin and GSK-3β expression. E-cadherin↑, N-cadherin↓	[99]
Jatrorrhizine [100]	MDA-MB-231, MCF-7 cells, orthotopic 4T1 tumor-bearing mouse	10, 20μM, 2.5, 5 mg/kg	24 h, 4 weeks	Wnt/β-catenin signaling and EMT↓	[100]
	C8161 cells, BALB/C nude mice	10, 40, 80, 160, 320 μM, 50 μg	48 h, 14 days	G0/G1 cell cycle arrest, p21 and p27↑. VE-cadherin expression↓	[101]

pRb – Retinoblastoma Protein; CDKs – cyclin-dependent kinases; Chks – checkpoint kinases; PI3K/Akt – phosphatidylinositol 3-kinase/protein kinase B; MAPK – mitogen-activated protein kinase; p53 – tumor suppressor protein p53; p21 – cyclin-dependent kinase inhibitor 1; Apaf-1 – apoptotic protease-activating factor 1; c-IAP1 – cellular inhibitor of apoptosis protein 1; XIAP – X-linked inhibitor of apoptosis protein; Bcl-X – B-cell lymphoma-extra large; BNIP3 – Bcl-2/adenovirus E1B 19 kDa protein-interacting protein 3; VEGF – vascular endothelial growth factor; COX-2 – cyclooxygenase-2; IL-1β – interleukin-1 beta; HIF – hypoxia-inducible factor; TNF-α – tumor necrosis factor-alpha; CREB – cAMP response element-binding protein; GM-CSF – granulocyte-macrophage colony-stimulating factor; ATF-2 – activating transcription factor 2; STAT3 – signal transducer and activator of transcription 3; EMT – epithelial–mesenchymal transition; TOPOI – DNA topoisomerase I); ↓, ↑ – represents down-regulation, and upregulation.

Figure 2.

Multifaceted Antitumor Mechanisms of Corydalis Alkaloids: Cell Cycle Arrest, Apoptosis Induction, and Inhibition of Metastasis. Figure were created using Adobe Illustrator CC (Version 26.0, Adobe, Inc., USA).

Cell Cycle Arrest

In tumor cells, the mitotic signaling pathway is excessively activated. Through Ras, this pathway leads to retinoblastoma protein (pRb) phosphorylation, inactivating its function and causing dysregulated growth in cancer cells. Therefore, regulating the activity of cyclin-dependent kinases (CDKs) and checkpoint kinases (Chks) in tumor cells is an effective strategy for cancer treatment [59]. Protopine (4) has been shown to inhibit CDK1 activity and Bcl-2 expression in PC-3 and DU-145 cells, leading to cell cycle arrest in the G2/M and G0/G1 phases. In T47D and MCF-7 cells, it induces cell cycle arrest in the G2/M and G0/G1 phases. In Bel7402 cells, Protopine blocks the cell cycle in the G2/M and G0/G1 phases, and in HepG2 cells, it reduces Cyclin D1 expression in a dose- and time-dependent manner. In MDA-MB-231 cells, Protopine arrests the cell cycle in the S phase. In HBT-94 cells, it regulates the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) and p38 mitogen-activated protein kinase (MAPK) pathways, increases the expression of tumor suppressor protein p53 (p53) and cyclin-dependent kinase inhibitor 1 (p21), and causes cell cycle arrest in the G2/M phase. Berbamine (15) has a significant cell cycle arrest effect on various tumor cells. Researchers have found that berbamine arrests tumor cells in the G1 phase at low doses and blocks the G2/M phase at high doses [62,63]. Current research suggests that the cell cycle arrest induced by berbamine in the G1 and G2/M phases is achieved through the upregulation of BTG2 gene expression and the regulation of REV3 and P53 gene expression [64,65]. Coptisine (18) blocks the cell cycle at various phases, including the G2/M, G1, S, and G0/G1 phases, and downregulates the expression of CDK4 and CDK1. It significantly inhibits the proliferation of A549, PANC-1, ERMS1, and MG-63 cells both in vitro and in vivo. Chelerythrine (26) [58–60] blocks the G2/M phase, inhibits microtubule formation, promotes the phosphorylation of checkpoint kinase 1 (Chk1) and checkpoint kinase 2 (Chk2), and dose-dependently inhibits the proliferation of colorectal cancer cells (CRC). Additionally, Chelerythrine exhibits significant inhibitory effects on the proliferation of melanoma cells B16F10 and A375 in a concentration-dependent manner. Chelerythrine treatment arrests melanoma cells in the G2 phase and reduces the activation of cell division cycle 2 (CDC2). Tetrahydrocorysamine (68) reduces Stat3 phosphorylation at Tyr705 and Ser727 in DU145 and LNS17 cells at 2–4 μM within 4 hours, contributing to cell cycle regulation [38,98]. Sanguinarine (57) induces CHOP-dependent ER stress and ROS production, activating p38 and leading to cell cycle arrest in Patu-8988 and Panc-1 cells and xenograft models at concentrations of 25–400 μM and 25–50 mg/kg over 24 hours and 18 days [91–96]. Corynoxine (93) causes S phase arrest and suppresses Wnt signaling by altering β-catenin and glycogen synthase kinase-3 beta (GSK-3β) expression, increasing E-cadherin and decreasing N-cadherin in HCT-116 and HT-29 cells and xenograft models at 5–10 μM and 2.5–5 mg/kg for 24 hours and up to 4 weeks [93,97]. Jatrorrhizine (100) induces G0/G1 cell cycle arrest and inhibits Wnt/β-catenin signaling and epithelial–mesenchymal transition (EMT) in MDA-MB-231 and MCF-7 cells and orthotopic 4T1 tumor-bearing mice at 10–20 μM and 2.5–5 mg/kg over 24 hours and 4 weeks [100].

Induction of Tumor Cell Apoptosis

Apoptosis is a programmed cell death mechanism. Abnormal apoptosis is closely related to the occurrence, development, metastasis, and drug resistance of tumors. Current research has found that traditional Tibetan medicines from the genus Corydalis induce tumor cell apoptosis mainly by activating the mitochondrial release of apoptotic enzyme activator factors, activating caspase-3 and caspase-9, promoting the expression of pro-apoptotic proteins Bax, Bid, and apoptotic protease-activating factor-1 (Apaf-1), and reducing the expression of anti-apoptotic proteins cellular inhibitor of apoptosis protein 1 (c-IAP1), X-linked inhibitor of apoptosis protein (XIAP), B-cell lymphoma-extra-large (Bcl-X), and Bcl-2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3), thereby promoting apoptosis in various tumor cells in vivo and in vitro. Furthermore, the alkaloids tetrahydropalmatine (4), berberine (15), tetrahydrocoptisine (31), corydaline (52), sanguinarine (57), coronaridine (93), and berbamine (100) induce apoptosis in tumor cells by activating the mitochondrial apoptotic pathway and promoting the cleavage of caspase-3 and caspase-9. In addition, tetrahydropalmatine (5) and berberine (2) at a concentration of 100 μmol/L have a similar inhibitory effect on DNA topoisomerase I (TOPOI) as the positive control drug camptothecin. Scoulerine (26) enhances apoptosis through ATR and ATM kinase-dependent cell cycle checkpoint signaling in Jurkat and MOLT-4 cells at 5 μM over 24 hours [83–86]. Corynoline (52) induces apoptosis in MDA-MB-468 cells at 55 μM over 24 hours by regulating the p38 MAPK pathway. In HepG2 and MHCC97-L cells, it increases Bax expression, cytochrome C release, and activates caspase 3/9 at varying concentrations over 6 hours [87]. Sanguinarine (57) activates caspase 3/7 in HL-60 cells; enhances mitochondrial membrane potential, chromatin condensation, and apoptotic body formation in MG-63 and SaOS-3 cells; increases caspase 3/9 and the Bcl-2/Bax ratio in HT-29 cells [97].

Regulation of the MAPK Signaling Pathway

The mitogen-activated protein kinase (MAPK) signaling system is crucial to mammalian cells and is linked to many physiological processes, including cell growth, differentiation, apoptosis, and angiogenesis. Studies have shown that aberrant activation of certain proteins in the MAPK pathway plays a crucial role in many forms of cancer. Therefore, targeting this pathway is an essential strategy in cancer management [98]. Research has demonstrated that berberine (15) can impede the proliferation of several kinds of cancer cells by specifically targeting the MAPK signaling pathway. However, the extent of its influence varies across different tumor cells [99]. In HeLa cells, a type of human cervical cancer cell, Berberine treatment led to increased phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK1/2) while inhibiting the phosphorylation of p38 MAPK. Conversely, in gastric cancer cells, berberine inhibited the phosphorylation of p38 MAPK, JNK, and ERK1/2. Additionally, berberine increases the production of microRNA-19a (miRNA-19a), reduces the levels of tissue factor (TF), activates the MAPK signaling pathway, and induces apoptosis in small-cell lung cancer cells (A549) [76]. Berberine (18), an alkaloid molecule, can trigger apoptosis in human pancreatic cancer cells (PANC-1) by reducing the phosphorylation and expression of ERK [101].

Suppression of Tumor Angiogenesis

Neovascularization around tumors is necessary for the ongoing growth and spread of tumor cells. Angiogenesis plays a critical role in tumor progression. Studies have shown that increased matrix metalloproteinase-2 (MMP-2) during the spread of lung cancer leads to the formation of new lymphatic vessels, which helps the tumor survive and grow [78]. Furthermore, matrix metalloproteinase-9 (MMP-9) can enhance angiogenesis by stimulating the production of vascular endothelial growth factor (VEGF). Berberine (15) has demonstrated the ability to regulate the production of MMP-2 and MMP-9, thereby hindering angiogenesis and preventing tumor cell spread [79]. Research indicates that berberine inhibits the proliferation, migration, and VEGF expression of HepG2 hepatocellular carcinoma cells and SC-M1 gastric adenocarcinoma cells [80]. In breast cancer cells, berberine blocks the PI3K/Akt pathway, reducing the production of VEGF and fibronectin, and consequently slowing tumor growth [81]. Tumor angiogenesis and inflammation have a reciprocal relationship, wherein pro-inflammatory substances generated by tumor cells may expedite angiogenesis. When berberine was administered to melanoma cells B16F-10, the expression of genes involved in inflammation and angiogenesis decreased. These genes include cyclooxygenase-2 (COX-2), interleukin-1 beta (IL-1β), hypoxia-inducible factor (HIF), tumor necrosis factor-alpha (TNF-α), vascular endothelial growth factor (VEGF), cAMP response element-binding protein (CREB), granulocyte-macrophage colony-stimulating factor (GM-CSF), and activating transcription factor-2 (ATF-2) [82–84]. Additionally, flavopiridol (18) effectively inhibited the migration, invasion, and angiogenesis of osteosarcoma cells by decreasing the levels of VE-cadherin and integrin β3 (ITGβ3) and preventing the phosphorylation of STAT3 [85]. Jatrorrhizine (100) enhances cell cycle control through increased expression of p21 and p27 and decreased VE-cadherin expression in C8161 cells and BALB/c nude mice at 10–320 μM and 50 μg over 48 hours and 14 days [102].

Conclusions

In conclusion, the genus Corydalis, widely utilized in Tibetan medicine, exhibits diverse therapeutic properties, including anti-inflammatory, analgesic, anti-cancer, and neuroprotective effects. Recent studies have highlighted its potential in treating a variety of ailments, from infections to cardiovascular and neurological conditions. Notably, its anti-cancer properties have been demonstrated to inhibit tumor cell growth, induce apoptosis, and suppress angiogenesis through various molecular pathways (Figure 3). Despite these promising findings, further research is essential to elucidate specific mechanisms of action and to conduct clinical trials to validate the efficacy and safety of these compounds. Strengthening collaboration between pharmaceutical companies and research institutions could accelerate the clinical application and modernization of Tibetan medicinal plants, advancing their integration into modern healthcare.

Figure 3.

Antitumor Mechanisms of Alkaloids from Corydalis: Inhibition of Cell Proliferation, Apoptosis Induction, and Angiogenesis Suppression. Figure were created using Adobe Illustrator CC (Version 26.0, Adobe, Inc., USA).

Future Directions

Despite notable progress, several critical areas remain for future Corydalis research. First, over 90% of Corydalis species remain chemically unexplored, demanding systematic phytochemical profiling through advanced metabolomics to uncover novel bioactive constituents. Second, research should expand beyond alkaloids, emphasizing multi-component synergy involving flavonoids, polysaccharides, triterpenes, and volatile oils to fully capture therapeutic potentials. Third, comprehensive multidimensional Q-marker systems integrating pharmacological efficacy, geo-authenticity, processing dynamics, and AI-driven predictive modeling must be established to ensure quality standardization responsive to ecological variations. Fourth, detailed mechanistic studies on antitumor activity should employ emerging technologies such as single-cell transcriptomics, proteomics, and genome editing (eg, CRISPR-Cas9), clarifying molecular targets and signaling pathways. Fifth, rigorous clinical evaluations are essential, focusing on optimized dosing, safety assessments including hepatotoxicity, and traditional processing methods enhancing bioavailability. Finally, interdisciplinary collaboration integrating ethnopharmacology, pharmacology, and clinical medicine will accelerate the translation of Tibetan medicinal knowledge into validated, safe, and effective modern therapeutics.