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. 2026 Feb 11;18(2):391–404. doi: 10.1016/j.chmed.2026.02.011

Chemical composition, antitumor properties and underlying mechanism of Sophora flavescens flavonoids: A review

Zhongyuan Guo a,b,1, Gaoyue Dong c,1, Xiaoqian Liu b, Huimin Gao b, Liangmian Chen b, Hong Yang c,⁎, Zhimin Wang a,b,⁎
PMCID: PMC13069629  PMID: 41971589

Abstract

Sophora flavescens is a widely used medicinal plant in traditional Chinese medicine, particularly known for its rich flavonoid content. Historically used in traditional medicine, this herb has been documented in the Shennong’s Classic of Materia Medica (Shennong Bencao Jing) for its effects in clearing heat, eliminating dampness, and serving as an anthelmintic and diuretic, for treating various conditions, including dysentery, jaundice, and skin diseases. Recent research on S. flavescens has expanded, particularly concerning its flavonoid compounds, which exhibit significant pharmacological activities, including antimicrobial, antioxidant, hepatoprotective, hypoglycemic, and antitumor effects. This review systematically summarizes the chemical constituents of S. flavescens, identifying over 130 flavonoid compounds, primarily isoprenylflavonoids, with a specific focus on their antitumor activities. Studies have shown that representative compounds, such as kurarinone and kushenol G, selectively exhibit cytotoxic effects against various cancer cell lines (e.g., HepG2, A549, MCF-7) while sparing normal cells. The antitumor mechanisms are primarily attributed to apoptosis induction, modulation of oxidative stress, and regulation of multiple signaling pathways, including the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway and the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) pathway. Furthermore, safety assessments indicate that while the overall toxicity of flavonoids from S. flavescens is relatively low, certain compounds may pose hepatotoxic risks at high doses, warranting further attention in clinical applications. This review aims to provide an in-depth analysis and discussion of the chemical diversity, antitumor efficacy, and mechanisms of action of S. flavescens flavonoids, establishing a theoretical foundation and research direction for the development of novel anticancer drugs.

Keywords: antitumoractivit, apoptosisinduction, pharmacological properties, safety assessment, Sophora flavescens Ait., Sophora flavescens flavonoids

1. Introduction

Sophora flavescens Ait. commonly known as kushen in Chinese, is a well-recognized traditional Chinese medicinal herb derived from the dried roots of the leguminous plant S. flavescens. Its earliest mention is found in Shennong’s Classic of Materia Medica (Shennong Bencao Jing), where it is also referred to as Shui Huai due to the similarity of its leaves to those of the Styphnolobium japonicum (L.) Schott. S. flavescens is widely distributed across northern, southwestern, and eastern China, particularly in regions like the Yellow River and Yangtze River basins, as well as provinces such as Yunnan and Guizhou. It is also found in neighboring countries, including Japan, Korea, and Mongolia. In traditional Chinese medicine (TCM), S. flavescens is valued for its ability to clear heat, dry dampness, and act as an antiparasitic and diuretic agent. It is commonly used to treat a variety of conditions, such as dysentery, hematochezia, jaundice, urinary retention, abnormal vaginal discharge, genital swelling and itching, eczema, wet sores, and scabies. Topical applications are effective for treating conditions like trichomonas vaginitis and pruritus (skin itching) (Chinese Pharmacopoeia Commission, 2020).

In recent years, research has increasingly focused on the chemical composition of S. flavescens, revealing a diverse range of bioactive compounds, including flavonoids, alkaloids, terpenes, steroids, phenylpropanoids, organic acids, fatty acids, and volatile oils. Among these, flavonoids and alkaloids are the primary bioactive constituents (Li, Yang, Gu, Yang, & Wang, 2021). Early research predominantly concentrated on alkaloids, but more recent studies have highlighted the therapeutic potential of flavonoids. Studies have demonstrated that the flavonoids from S. flavescens exhibit a broad spectrum of pharmacological activities, including antibacterial (Oh et al., 2011), antioxidant, hepatoprotective, hypoglycemic (Wang et al., 2023), and anticancer effects (Li, Yang, Gu, Yang, & Wang, 2021). Their anticancer activity enables them to significantly inhibit the proliferation and metastasis of various cancer cells by modulating the Toll-like receptor 4 (TLR4)-associated protein kinase B/mammalian target of rapamycin (AKT/mTOR), mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) signaling pathways, as well as regulating the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway (Su et al., 2024). In addition, they can also exert potential anti-inflammatory and anti-proliferative activities by inhibiting inducible nitric oxide synthase (iNOS) (Yang et al., 2023), establishing them as promising candidates for novel therapeutic development.

Research on small-molecule drugs derived from traditional Chinese medicine is an area of growing scientific interest. Among them, Icaritin Soft Capsules contain an isoprenylated flavonoid compound extracted from the traditional medicinal herb Epimedium brevicornu Maxim. In 2022, this agent (Icaritin Soft Capsules) was approved by the National Medical Products Administration (NMPA) of China for the treatment of unresectable hepatocellular carcinoma (HCC) in patients who are ineligible for or decline standard therapies and have not received prior systemic treatment (Meng, 2022). The key structural feature of icaritin is the isoprenyl substitution on the flavonoid core, a characteristic also shared by many flavonoids found in S. flavescens. This structural similarity suggests that flavonoids derived from S. flavescens may hold significant potential for the development of non-cytotoxic anticancer agents (Meng, 2022).

Given the increasing interest in the pharmacological potential of S. flavescens flavonoids, this review aims to provide a comprehensive overview of their chemical structures, pharmacological activities (both in vitro and in vivo), mechanisms of action, and safety profiles. By systematically reviewing the literature, this study seeks to shed light on the therapeutic prospects of S. flavescens flavonoids and provide a foundation for further research and drug development, particularly in developing non-cytotoxic anticancer agents.

2. Flavonoid constituents of S. flavescens

Flavonoids, which are among the major components of S. flavescens, have been isolated from this herb, with 128 compounds identified to date. All compound data are presented in Table 1. The principal types include flavones, dihydroflavones, isoflavones, chalcones, dihydroisoflavones, pterocarpans, and biflavonoids (Li, Yang, Gu, Yang, & Wang, 2021).

Table 1.

Flavonoid compounds in S. flavescens.

No. Compounds Molecular formula Molecular weights References
1 4′,7-Dihydroxyflavone C15H10O4 254.24 Li, Yang, Gu, Yang, & Wang, 2021
2 Atalantoflavone C20H16O5 336.34 Song, Sun, Zhou, & Chu, 2019
3 Luteolin-7-β-D-glucopyranoside C21H20O11 448.38 Li, Yang, Gu, Yang, & Wang, 2021
4 Luteolin-7-O-gentiobioside C27H30O16 610.52 Li, Yang, Gu, Yang, & Wang, 2021
5 Kushenol C C25H26O7 438.48 Zhao, & Sun, 2005
6 5-Methylkushenol C C26H28O7 452.50 Zhao, & Sun, 2005
7 Kushenol G C25H28O8 456.49 Zhao, & Sun, 2005
8 Isoanhydroicaritin C21H20O6 368.38 Zhao, & Sun, 2005
9 Sophoflavescenol C21H20O6 368.38 Cao, 2020
10 8-Prenylkaempferol C20H18O6 354.36 Cao, 2020, Jeong et al., 2008
11 8-Lavandulylkaempferol C25H26O6 422.48 Cao, 2020
12 Citrusinol C20H16O6 352.34 Cao, 2020
13 6,8-Diprenylkaempferol C25H26O6 422.48 Long, Hu, Gao, Jia, & Wang, 2022
14 Kushenol Z C26H28O6 436.50 Li, Yang, Gu, Yang, & Wang, 2021
15 Resokaempferol C15H10O5 270.24 Li, Yang, Gu, Yang, & Wang, 2021
16 Quercetin C15H10O7 302.24 Li, Yang, Gu, Yang, & Wang, 2021
17 Rutin C27H30O16 610.52 Li, Yang, Gu, Yang, & Wang, 2021
18 8-Lavanduly-5,7,4′-trihydroxyflavanonol C27H30O16 610.52 Li, Yang, Gu, Yang, & Wang, 2021
19 Flavenochromane B C25H26O6 422.48 Li, Yang, Gu, Yang, & Wang, 2021
20 Flavenochromane C C21H20O6 368.38 Li, Yang, Gu, Yang, & Wang, 2021
21 5-Methoxy-7,4′-dihydroxy-8-lavanduly flavonol C26H28O6 436.50 Li, Yang, Gu, Yang, & Wang, 2021
22 Kushenol A C25H28O5 408.49 Zhao and Sun, 2005, Tsuchiya et al., 1996
23 Kushenol B C30H36O6 492.61 Lee et al., 1997
24 Kushenol E C25H28O6 424.49 Zhao, & Sun, 2005
25 Kushenol F C25H28O6 424.49 Zhao, & Sun, 2005
26 Kushenol P C26H32O7 456.54 Zhao, & Sun, 2005
27 Kushenol Q C26H32O7 456.54 Zhao, & Sun, 2005
28 Kushenol R C26H30O5 422.52 Zhao, & Sun, 2005
29 Kushenol S C20H20O5 340.38 Zhao, & Sun, 2005
30 Kushenol T C25H30O6 426.51 Zhao, & Sun, 2005
31 Kushenol U C26H30O5 422.52 Zhao, & Sun, 2005
32 Kushenol V C21H22O7 386.40 Li, Yang, Gu, Yang, & Wang, 2021
33 Kushenol W C21H22O7 386.40 Zhao, & Sun, 2005
34 Kurarinone C26H30O6 438.52 Zhao, & Sun, 2005
35 2′-Methoxykurarinone C27H32O6 452.55 Li, Yang, Gu, Yang, & Wang, 2021
36 Kurarinol C26H32O7 456.54 Li, Yang, Gu, Yang, & Wang, 2021
37 Isokurarinone C26H30O6 438.52 Li, Yang, Gu, Yang, & Wang, 2021
38 Norkurarinol C25H30O7 442.51 Zhao, & Sun, 2005
39 Neokurarinol C27H34O7 470.56 Zhao, & Sun, 2005
40 Isoxanthohumol C21H22O5 354.40 He, 2010
41 Leachianone A C26H30O6 438.52 Zhao, & Sun, 2005
42 Leachianone G C20H20O6 356.37 Zhao, & Sun, 2005
43 Sophoraflavanone B C20H20O5 340.38 Zhao, & Sun, 2005
44 5-Methylsophoraflavanone B C21H22O5 354.40 Li, Yang, Gu, Yang, & Wang, 2021
45 Sophoraflavanone G C25H28O6 424.49 Zhao, & Sun, 2005
46 Glabranin C20H20O4 324.38 He, 2010
47 Isoglabranin C20H20O4 324.38 Long, Hu, Gao, Jia, & Wang, 2022
48 Sophoflavonoid A C21H22O6 370.40 Long, Hu, Gao, Jia, & Wang, 2022
49 Exiguaflavanone D C31H38O7 522.64 Tsuchiya et al., 1996
50 Kenusanone D C21H22O7 386.40 Tsuchiya et al., 1996
51 Exiguaflavanone A C25H28O6 424.49 Tsuchiya et al., 1996
52 Sophoraflavanone D C25H28O7 440.49 Tsuchiya et al., 1996
53 Sophoraflavanone E C25H28O7 440.49 Tsuchiya et al., 1996
54 Kenusanone A C25H28O6 424.49 Tsuchiya et al., 1996
55 Exiguaflavanone C C25H28O7 440.49 Tsuchiya et al., 1996
56 Exiguaflavanone G C25H28O7 440.49 Tsuchiya et al., 1996
57 Lehmannin C25H28O5 408.49 Cao, 2020
58 Isobavachin C20H20O4 324.38 Cao, 2020
59 Kenusanone I C21H22O6 370.40 Cao, 2020
60 Sophoraflavanone K C26H30O7 454.52 Li et al., 2020
61 Sophoraflavanone L C25H28O6 424.49 Li et al., 2020
62 Naringenin C15H12O5 272.26 Li, Yang, Gu, Yang, & Wang, 2021
63 Leachianone B C26H30O6 438.52 Li, Yang, Gu, Yang, & Wang, 2021
64 (2S,2′′S)-6-Lavandulyl-7,4′-dimethoxy-5,2′-dihydroxylflavanone C27H32O6 452.55 Long, Hu, Gao, Jia, & Wang, 2022
65 Liquiritigenin C15H12O4 256.26 Li, Yang, Gu, Yang, & Wang, 2021
66 Sophoraflavanone A C25H28O5 408.49 Cao, 2020
67 Kushenol I C26H30O7 454.52 Zhao, & Sun, 2005
68 2′-Methoxy kushenol I C27H32O7 468.55 Li, Yang, Gu, Yang, & Wang, 2021
69 Kushenol H C26H32O8 472.53 Cao, 2020
70 Kushenol J C27H32O14 580.53 Li, Yang, Gu, Yang, & Wang, 2021
71 Kushenol K C26H32O8 472.53 Cao, 2020
72 Kushenol L C25H28O7 440.49 Zhao, & Sun, 2005
73 Kushenol M C30H36O7 508.61 Zhao, & Sun, 2005
74 Kushenol N C26H30O7 454.52 Li, Yang, Gu, Yang, & Wang, 2021
75 Kushenol X C25H28O7 440.49 Zhao, & Sun, 2005
76 3,7,4′-Trihydroxy-5-methoxy-8-prenylflavanone C21H22O6 370.40 Jeong et al., 2008
77 Flavenochromane A C25H28O7 440.49 Li, Yang, Gu, Yang, & Wang, 2021
78 Kurarinol A C36H46O5 558.76 Li et al., 2021
79 Kurarinol B C27H30O8 482.53 Li et al., 2021
80 Kosamol A C30H38O8 526.63 Lee et al.,1997
81 Daidzein C15H10O4 254.24 Li, Yang, Gu, Yang, & Wang, 2021
82 Formononetin C16H12O4 268.27 Li et al., 2007
83 Genistein C15H10O5 270.24 Li, Yang, Gu, Yang, & Wang, 2021
84 Biochanin A C16H12O5 284.27 Li, Yang, Gu, Yang, & Wang, 2021
85 Isoformononetin C16H12O4 268.27 Li, Yang, Gu, Yang, & Wang, 2021
86 Calycosin C16H12O5 284.27 Xiong, Zhang, & Deng, 2022
87 7,4′-Dihydroxy-3′-methoxyisoflavone C16H12O5 284.27 Li, Yang, Gu, Yang, & Wang, 2021
88 Pseudobaptigenin C16H10O5 282.25 Li, Yang, Gu, Yang, & Wang, 2021
89 Flavescenone B C21H18O7 382.37 Cao, 2020
90 Wighteone C20H18O5 338.36 Cao, 2020
91 7,2′,4′-Trihydroxy-5-methoxy-8-prenylisoflavone C21H20O6 368.38 Li, Yang, Gu, Yang, & Wang, 2021
92 Sophoraisoflavone A C20H16O6 352.34 Zhao, & Sun, 2005
93 Alpinumisoflavone C20H16O5 336.34 Cao, 2020
94 Ononin C22H22O9 430.41 Xiong, Zhang, & Deng, 2022
95 Kushenol O C27H30O13 562.52 Xiong, Zhang, & Deng, 2022
96 3′-Hydroxy kushenol O C27H30O14 578.52 Li, Yang, Gu, Yang, & Wang, 2021
97 7-Hydroxy-4′-methoxyisoflavanone-3′-O-β-D-glucopyranoside C22H24O10 448.42 Li, Yang, Gu, Yang, & Wang, 2021
98 Flavescenone A C21H20O7 384.38 Cao, 2020
99 Pseudoindorin C15H12O5 272.26 Li, Yang, Gu, Yang, & Wang, 2021
100 2′,4-Dihydroxy-4′,6′-dimethoxychalcone C17H16O5 300.31 Li, Yang, Gu, Yang, & Wang, 2021
101 Xanthohumol C21H22O5 354.40 He, 2010
102 Desmethylxanthohumol C20H20O5 340.38 Li et al., 2020
103 Kuraridine C26H30O6 438.52 Zhao, & Sun, 2005
104 Kushenol D C27H32O6 452.55 Zhao, & Sun, 2005
105 Kuraridinol C26H32O7 456.54 Zhao and Sun, 2005, Li et al., 2020
106 Cyclokuraridin C26H30O6 438.52 Li et al., 2020
107 Maackiain C16H12O5 284.27 Li, Yang, Gu, Yang, & Wang, 2021
108 4-Methoxy-maackiain C17H14O6 314.29 Li, Yang, Gu, Yang, & Wang, 2021
109 Pterocarpin C17H14O5 298.29 Li, Yang, Gu, Yang, & Wang, 2021
110 Trifolirhizin C22H22O10 446.41 Li, Yang, Gu, Yang, & Wang, 2021
111 6′-O-Acetyltrifolirhizin C24H24O11 488.45 Li, Yang, Gu, Yang, & Wang, 2021
112 Kushenin C16H14O5 286.28 Li, Yang, Gu, Yang, & Wang, 2021
113 Kushecarpin A C17H18O6 318.32 Li, Yang, Gu, Yang, & Wang, 2021
114 Kushecarpin B C18H18O7 346.33 Li, Yang, Gu, Yang, & Wang, 2021
115 Kushecarpin C C17H16O7 332.31 Li, Yang, Gu, Yang, & Wang, 2021
116 Kushecarpin D C16H14O6 302.28 Li, Yang, Gu, Yang, & Wang, 2021
117 Glyceollin C20H18O5 338.36 Xiong, Zhang, & Deng, 2022
118–120 Sophobiflavonoids A–C C52H60O12 877.04 Yan et al., 2019
121 Sophobiflavonoid D C52H62O13 895.05 Yan et al., 2019
122 Sophobiflavonoid E C52H60O12 877.04 Yan et al., 2019
123–125 Sophobiflavonoids F–H C52H60O13 893.04 Yan et al., 2019
126 Sophoradione C26H30O7 454.52 Shen et al., 2006
127 Medicagol C16H8O6 296.23 Li, 2021
128 Maesopsin-4-O-β-D-glucopyranoside C21H24O10 436.41 Li, 2021
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The substituents of S. flavescens flavonoids, in addition to common hydroxyl, methoxy, and glycosyl groups, display an important feature: the frequent presence of one or more isoprenyl groups or their polymeric/oxidized derivatives. These various substituents can interconnect via diverse mechanisms, forming five-membered or six-membered rings through interactions with adjacent hydroxyl groups. Typically, the substituents are located at C-6 and C-8, and they may be substituted simultaneously, with isoprenyl and lavandulyl groups being the most prevalent. Occasionally, oxirane structures may form by combining with adjacent hydroxyl groups. Substituents can also be found on the B-ring and C-ring. The types of substituents are illustrated in Fig. 1.

Fig. 1.

Fig. 1

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Structural types of prenylated and related substituents in S. flavescens flavonoids. (A) Isoprenyl. (B) 3-Hydroxy-3-methylbutyl. (C) 1-Isoprenyl-3-methyl-3,4-alkenyloxybutyl. (D) 2-Isoprenyl-3-methyl-2,3-alkenyloxybutyl. (E) Lavandulyl. (F) Hydroxylavandulyl. (G) 5-Hydroxy-2-isopropenyl-5-methylhexyl. (H) Diisoprenyl.

2.1. Flavonoids

These compounds are primarily composed of hydroxyl and isoprenyl groups, which can be substituted at various positions and may be oxidized or cyclized. The isoprenyl group is most commonly attached at the C-6 and C-8 positions. Due to its structural characteristics, the isoprenyl group at C-8 often undergoes cyclization with the 7-hydroxyl group to form a six-membered ring. Glycosyl groups are typically attached to the C-8 position and hydroxyl groups. The structure is illustrated in Fig. 2.

Fig. 2.

Fig. 2

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Chemical structures of flavonoids from S. flavescens.

2.2. Flavonols

The flavonols in S. flavescens are similar to flavonoids, featuring primary substituents such as hydroxyl, isoprenyl, and lavandulyl groups, along with occasional methoxy and glycosyl substitutions. The isoprenyl and lavandulyl groups are predominantly attached at the C-8 position, although they may also be found at the C-6 position in some instances. Additionally, the isoprenyl group can form a six-member ring through cyclization with the 7-hydroxyl group. The structures are illustrated in Fig. 3.

Fig. 3.

Fig. 3

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Chemical structures of flavonols from S. flavescens.

2.3. Dihydroflavonoids

This class of compounds is the most prevalent in S. flavescens. The primary substituents include hydroxyl, isoprenyl, and lavandulyl or hydroxylated lavandulyl groups. Notably, two isoprenyl groups can be attached in various configurations, along with their hydration products as substituents. The substituent positions are mainly at the C-8 position, less frequently at C-6, and occasionally on the B-ring. The structural details are illustrated in Fig. 4.

Fig. 4.

Fig. 4

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Chemical structures of dihydroflavonoids from S. flavescens.

2.4. Dihydroflavonols

The primary substituents in this class include lavandulyl alkyl, isoprenyl, and hydroxylated lavandulyl alkyl groups, with occasional occurrences of methoxy, hydroxyl, and glycosyl groups. The main substitution positions are at C-8 and C-6, and there can also be simultaneous substitutions at both C-8 and C-6, as well as on the C-ring. Additionally, instances of isoprenyl groups forming six-membered rings with adjacent hydroxyl groups have been observed, as illustrated in Fig. 5.

Fig. 5.

Fig. 5

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Chemical structures of dihydroflavonols from S. flavescens.

2.5. Isoflavones

The predominant structural features of in S. flavescens primarily include glycosyl, hydroxyl, methoxy, and particularly isoprenyl groups, with the main structures illustrated in Fig. 6.

Fig. 6.

Fig. 6

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Chemical structures of isoflavones from S. flavescens.

2.6. Dihydroisoflavone

Dihydroisoflavones are relatively rare in S. flavescens, primarily characterized by glycosyl and isoprenyl substitutions. The main compounds are illustrated in Fig. 7.

Fig. 7.

Fig. 7

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Chemical structures of dihydroisoflavones from S. flavescens.

2.7. Chalcone structures

The substituents in this class primarily include hydroxyl, methoxy, isoprenyl, lavandulyl, and hydroxylated lavandulyl groups, as illustrated in Fig. 8.

Fig. 8.

Fig. 8

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Chemical structures of chalcones from S. flavescens.

2.8. Pterocarpans

Pterocarpans are characterized by a carbonyl group at the C-4 position of the isoflavonoid backbone, which forms a five-member ring with the B-ring at the 2′ position. Their substitution patterns resemble those of isoflavones, as illustrated in Fig. 9.

Fig. 9.

Fig. 9

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Chemical structures of pterocarpans from S. flavescens.

2.9. Flavonoid dimers

This class primarily consists of compounds formed by the condensation of dihydroflavones and chalcones, characterized by the presence of lavandulyl and hydroxylavandulyl substituents. The structures of these compounds are illustrated in Fig. 10.

Fig. 10.

Fig. 10

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Chemical structures of flavonoid dimers from S. flavescens.

2.10. Other compounds

S. flavescens also contains some structurally modified flavonoids, characterized by isoprenyl substituents. The structures are shown in Fig. 11.

Fig. 11.

Fig. 11

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Chemical structures of other flavonoids from S. flavescens.

3. Antitumor activity

3.1. In vitro activity

A total of 28 isoprenylflavonoids isolated from S. flavescens have demonstrated significant antitumor activity against various tumor cell lines, including human hepatocellular carcinoma (HepG2), human lung adenocarcinoma epi-thelial (A549), and human breast adenocarcinoma (MCF-7), as well as the normal human cell line LO2. Among these, kurarinol A (78) exhibited an IC50 range of 7.50–10.55 μmol/L against HepG2, A549, and MCF-7 cell lines, showing minimal effects on normal LO2 cells (Li et al., 2021). This indicates its excellent selectivity and potential drug safety, highlighting its promise as a candidate for further development as an anticancer drug. Early studies have shown that total flavonoids from S. flavescens significantly inhibited the proliferation of murine liver cancer (H22) hepatocarcinoma, S180 sarcoma, Lewis lung cancer, Eca-109 esophageal cancer, and non-small cell lung cancer H460, with inhibition rates as high as 80%. Specifically, kushenol A (22) displayed an IC50 of 28.1 μmol/L against colon cancer COLO205. Sophoraflavanone G (45) also exhibited good inhibitory activity across multiple cancer cell lines (Oh et al., 2017). Kuraridine (103) showed strong inhibitory activity against HepG2, with an IC50 of 21.35 μmol/L (Yang et al., 2021). Additionally, kushenol Z (14) inhibited the proliferation of A549 and human non-small cell lung squamous cell carcinoma (NCI-H226) cells, inducing morphological changes in non-small cell lung cancer, such as cell shrinkage, distortion, and detachment. The IC50 values were 11.91 and 14.91 μmol/L, respectively, while it had minimal effects on normal cells, with an IC50 greater than 229.10 μ mol/L (Chen et al., 2019). This suggests that kushenol Z (14) may exert its antitumor effects by inducing cellular morphological changes.

Moreover, sophoflavescenol (9) showed concentration-dependent inhibition with IC50 values of 12.5, 38.1, and 69.9 μmol/L against human leukaemia (HL-60), lewis lung carcinoma (LLC), and A549 cell lines, respectively (Jung et al., 2011). Compounds such as 8-lavandulylkaempferol (11) and sophoraflavanone L (61) also demonstrated significant inhibitory effects on the KB cell line, with IC50 values of 24.3 and 7.1 μmol/L, respectively (Shen et al., 2006). This further supports the antitumor potential of flavonoids from S. flavescens.

Flavenochromanes A (77), B (19), and C (20) significantly inhibited the proliferation of A549, murine ovarian cancer (1A9), nasopharyngeal epidermoid carcinoma (KB), and drug-resistant variant KB cell lines (Ding et al., 2004). Isoprenylflavonoids, such as 2′-methoxykurarinone (35) and leachianone A (41), demonstrated concentration-dependent growth inhibition against human myeloid leukemia HL-60 and hepatocarcinoma HepG2 cells (Kang et al., 2000, Ko et al., 2000). Additionally, compounds like 6,8-diprenylkaempferol (13) and sophoflavonoid A (48) displayed potent inhibitory effects across various lung cancer cell lines, while kushenol E (24) had IC50 values of 25.2 and 28.1 μmol/L in HeLa cervical cancer and human colorectal carcinoma (HCT116) colon cancer cell lines, respectively (Long, Hu, Gao, Jia, & Wang, 2022). Notably, the mixture of norkurarinol (38) and kuraridine (103) also exhibited significant inhibitory effects on the proliferation of gastric adenocarcinoma SGC-7901 cells (Rasul et al., 2011).

Analysis of the chemical structures presented in Table 2 reveals that the antitumor activity is primarily concentrated in flavonoids featuring lavender alkyl and isoprenyl substituents. These compounds include various structural types such as dihydroflavones, flavanols, dihydroflavonols, and chalcones. The structure–activity relationship of lavender alkyl-substituted flavonoids indicates that the lavender alkyl group is typically located at the C-8 position of the flavonoid core. For example, 2′-methoxykurarinone (35), leachianone A (41) and sophoraflavanone G (45) exhibit inhibitory activity against human acute promyelocytic leukemia (HL-60) cells, suggesting that introducing methyl substituents at the 5-hydroxy and 2′-hydroxy positions does not significantly enhance the inhibition of HL-60 cells. In contrast, comparative studies of kushenol A (22) and sophoraflavanone G (45) indicate that the presence of the 4′–OH group may improve their inhibitory activity against HL-60 cells (Oh et al., 2017).

Table 2.

Antitumor activity of flavonoid compounds in cancer cells.

Compounds (No.) Cell lines Disease types Sources IC50 (μmol/L) References
Kushenol A (22) HepG2 Hepatocellular carcinoma Human 6.85 Li et al., 2021, Oh et al., 2017
A549 Non-small cell lung adenocarcinoma Human 36.1
MCF-7 Breast adenocarcinoma Human 21.3
COLO205 Colorectal adenocarcinoma Human 28.1
Kurarinol A (78) HepG2 Hepatocellular carcinoma Human 7.50–10.55 Li et al., 2021
A549 Non-small cell lung adenocarcinoma Human
MCF-7 Breast adenocarcinoma Human
Kuraridine (103) HepG2 Hepatocellular carcinoma Human 21.35 Oh et al., 2017, Yang et al., 2021
A549 Non-small cell lung adenocarcinoma Human 57.1
MCF-7 Breast adenocarcinoma Human 23.0
COLO205 Colorectal adenocarcinoma Human 29.5
Sophoraflavanone G (45) A549 Non-small c ell lung adenocarcinoma Human 18.1 Oh et al., 2017, Ding et al., 2004
MCF-7 Breast adenocarcinoma Human 19.2
COLO205 Colorectal adenocarcinoma Human 32.5
HL-60 Acute promyelocytic leukemia Human 12.5
Kurarinone (34) A549 Non-small cell lung adenocarcinoma Human 50.5 Oh et al., 2017, Ding et al., 2004
MCF-7 Breast adenocarcinoma Human 23.2
COLO205 Colorectal adenocarcinoma Human 34.3
HL-60 Acute promyelocytic leukemia Human 18.5
Kushenol Z (14) A549 Non-small cell lung adenocarcinoma Human 11.91 Chen et al., 2019
NCI-H226 Non-small cell lung squamous cell carcinoma Human 17.41
Sophoflavescenol (9) A549 Non-small cell lung adenocarcinoma Human 69.9 Jung et al., 2011
HL-60 Acute promyelocytic leukemia Human 12.5
LLC Lewis lung carcinoma Murine 38.1
Flavenochromane A (77) A549 Non-small cell lung adenocarcinoma Human 13.9 Ding et al., 2004
MCF-7 Breast adenocarcinoma Human 15.4
1A9 Ovarian carcinoma Murine 16.1
KB Oral squamous cell carcinoma Human 15.6
KB-Vin Oral epidermoid carcinoma (vinblastine-resistant) Human 15.5
Flavenochromane B (19) A549 Non-small cell lung adenocarcinoma Human 3.2 Ding et al., 2004
MCF-7 Breast adenocarcinoma Human 4.9
1A9 Ovarian carcinoma Murine 5.0
KB Oral squamous cell carcinoma Human 6.9
KB-Vin Oral epidermoid carcinoma (vinblastine-resistant) Human 6.5
Flavenochromane C (20) A549 Non-small cell lung adenocarcinoma Human 1.0 Ding et al., 2004
MCF-7 Breast adenocarcinoma Human 3.6
1A9 Ovarian carcinoma Murine 1.2
KB Oral squamous cell carcinoma Human 1.3
KB-Vin Oral epidermoid carcinoma (vinblastine-resistant) Human 1.7
2′-Methoxykurarinone (35) HL-60 Acute promyelocytic leukemia Human 13.7 Ding et al., 2004
Leachianone A (41) HL-60 Acute promyelocytic leukemia Human 11.3 Ding et al., 2004
Sophoraflavanone L (61) KB Oral squamous cell carcinoma Human 7.1 Shen et al., 2006
8-Lavandulylkaempferol (11) KB Oral squamous cell carcinoma Human 24.3 Shen et al., 2006
Cyclokuraridin (106) KB Oral squamous cell carcinoma Human 15.1 Shen et al., 2006
Sophoradione (126) KB Oral squamous cell carcinoma Human 29.4 Shen et al., 2006
Kushenol E (24) HeLa Cervical adenocarcinoma Human 25.2 Kwon et al., 2020
HCT116 Colorectal carcinoma Human 28.1
Sophoflavonoid A (48) A549 Non-small cell lung adenocarcinoma Human 36.44 Long, Hu, Gao, Jia, & Wang, 2022
H460 Large cell lung carcinoma Human 64.84
H1299 Non-small cell lung carcinoma Human 47.80
3,7,4′-Trihydroxy-5-methoxy-8-prenylflavanone (76) A549 Non-small cell lung adenocarcinoma Human 20.63 Long, Hu, Gao, Jia, & Wang, 2022
H460 Large cell lung carcinoma Human 4.67
H1299 Non-small cell lung carcinoma Human 13.73
(2S,2′S)-6-Lavandulyl-7,4′-dimethoxy-5,2′-dihydroxylflavanone (64) A549 Non-small cell lung adenocarcinoma Human 43.4 Long, Hu, Gao, Jia, & Wang, 2022
H460 Large cell lung carcinoma Human 34.2
H1299 Non-small cell lung carcinoma Human 37.4
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Kurarinone (34) and sophoraflavanone G (45) are effective in inhibiting various tumor cell lines. Comparative analysis indicates that introducing a methyl substituent at the 5-hydroxy position significantly reduces the compound’s inhibitory activity against the lung cancer cell line A549, resulting in an IC50 value that increases approximately 2.8-fold. In contrast, the effects on other cell lines, such as MCF-7, COLO205, and HL-60, are relatively minor (Oh et al., 2017). Further analysis comparing compounds flavenochromane B (19) and flavenochromane C (20) shows that the compounds with 5-O-methyl substitutions exhibit greater antitumor activity than those containing isoprenyl moiety at the C-6 position and 5-hydroxy cyclization. Notably, these methyl-substituted compounds demonstrate stronger activity in inhibiting the proliferation of A549, 1A9, KB, and KB-Vin cell lines (Ding et al., 2004).

Further comparative studies indicate that the structure formed by the 8-isoprenyl and 7-hydroxy cyclization in flavenochromane C (20) exhibits stronger inhibitory activity against the lung cancer cell line A549 compared to sophoflavescenol (9). In the comparison between sophoflavescenol (9) and kushenol Z (14), it was found that the lavender alkyl substituent has a more significant effect on inhibiting the proliferation of A549 cells than the isoprenyl substituent. Analysis of kuraridine (103) and kurarinone (34) reveals that chalcones and dihydroflavonoids have comparable inhibitory potency on the proliferation of A549, MCF-7, and COLO205 cell lines, suggesting that the presence or absence of the B-ring structure does not significantly influence their antitumor activity (Oh et al., 2017).

In summary, the quantity and positioning of isoprenyl groups are directly related to antitumor activity. Specifically, the introduction of isoprenyl groups at the C-6 and C-8 positions significantly enhances the activity of the compounds. Research findings from compounds such as flavenochromane B (19), flavenochromane C (20) and sophoraflavanone L (61) demonstrate their potent antitumor efficacy. These results provide clear guidance for structural modifications in future drug design. By integrating molecular docking and quantitative structure–activity relationship (QSAR) analysis, it is possible to further optimize the structures of flavonoids, especially isoprenylated flavonoids. This optimization can enhance their targeting and antitumor activity, expediting their translational development into clinical applications (Oh et al., 2017).

3.2. In vivo activity

In vivo studies on total flavonoids extracted from S. flavescens flavonoids demonstrated dose-dependent tumor growth inhibition against H22 liver cancer, S180 sarcoma, and Lewis lung cancer in mice. Additionally, S. flavescens flavonoids exhibited a suppressive effect on the growth of human lung cancer cells (H460) and human esophageal cancer cells (Eca-109) when transplanted into nude mice (Table 3).

Table 3.

Effects of S. flavescens flavonoids on tumors in mice.

No. Animal models Administered doses (mg/kg) Administration routes Frequency and duration of administration Inhibition rate (%)
1 H22 hepatocellular carcinoma High dose: 500
Medium dose: 100
Low dose: 20		 ipa Once daily for 7 d High: 78.98
Medium: 66.45
Low: 43.40
2 S180 sarcoma High dose: 200
Low dose: 60		 ip Once daily for 7 d High: 82.14
Low: 72.52
3 Lewis lung cancer High dose: 200
Low dose: 60		 ip Once daily for 7 d High: 59.74
Low: 40.26
4 H460 lung cancer model 200 ivb Once daily for 21 d 46.80
5 Eca-109 esophageal cancer model 200 iv Once daily for 2 d 42.71
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Note:a Intraperitoneal, b Intravenous.

4. Mechanisms of antitumor action

S. flavescens flavonoids exhibit remarkable potential for application in cancer therapy, as they significantly inhibit tumor cell proliferation and metastasis through diverse and intricate mechanisms. Research findings suggest that the antitumor effects of S. flavescens flavonoids stem primarily from multiple interconnected aspects. Firstly, they induce tumor cell apoptosis by activating multiple apoptotic pathways. Specifically, this includes triggering the extrinsic pathway via fatty acid synthase (FAS)/tumor necrosis factor-α (TNF-α) receptor activation, initiating the intrinsic pathway through mitochondrial cytochrome C release (Singh et al., 2022), and promoting endoplasmic reticulum stress (ERS) to directly activate caspase cascades (Li et al., 2020). Secondly, S. flavescens flavonoids are capable of inducing autophagy, as exemplified by the “dual strike” strategy that combines the inhibition of phosphatidylinositol 3-kinase (PI3K), a pivotal node within the PI3K/AKT/mTOR pathway (Cui et al., 2020), with autophagy induction, thereby not only blocking pro-survival signals but also enhancing chemosensitivity by suppressing the ATP binding cassette subfamily G member 2 (ABCG2) transporter (Wu et al., 2021). Thirdly, these flavonoids modulate oxidative stress, which is closely associated with the interaction between autophagy and reactive oxygen species (ROS) (Yun et al., 2020). Moreover, S. flavescens flavonoids participate in the regulation of multiple signaling pathways, including the modulation of the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) signaling pathway (Chen et al., 2019), the antagonism of estrogen receptor (ER-α) (Ahmed, Ashfaq, Qamar, & Ahmad, 2014), and the inhibition of angiogenesis, such as the prevention of endothelial cell migration, all of which contribute to restricting tumor proliferation and metastasis. These underlying mechanisms are embedded within complex intracellular signaling networks, as depicted in Fig. 12. The pathways were visualized by Figdraw. The synergistic multi-pathway approach employed by S. flavescens flavonoids effectively overcomes the limitations of single-target therapies, such as the “spatiotemporal blockade” of apoptosis and anti-angiogenesis, vividly highlighting their unique advantages in cancer treatment. Further in-depth exploration of these pathways will undoubtedly deepen our comprehension of the role of S. flavescens flavonoids in cancer therapy and provide a solid foundation for the development of innovative antitumor agents.

Fig. 12.

Fig. 12

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Mechanisms of antitumor activity of S. flavescens flavonoids.

4.1. Extrinsic apoptotic pathway

The extrinsic pathway of apoptosis primarily is initiated by the activation of membrane receptor proteins, specifically FAS and TNF. Upon binding with its ligand, tumor necrosis factor ligand superfamily member 6 (FAS-L), FAS recruits FAS-associated death domain protein (FADD); similarly, TNF binds to its ligand, TNF-α, which also recruits tumor necrosis factor receptor type 1-associated death domain protein (TRADD) and FADD. FADD then activates initiator caspases, specifically cysteinyl aspartate-specific protease-8 (Caspase-8) and Caspase-10, through a proteolytic cascade that lead to the self-cleavage of pro-caspase-8 and pro-caspase-10, resulting in the formation of active Caspase-8 and Caspase-10. These activated caspases can induce apoptosis through two parallel cascade reactions: first, by directly cleaving the proenzymes Caspase-3 and Caspase-7, leading to their activation and subsequent apoptosis; and second, by cleaving the pro-apoptotic protein BH3 interacting domain death agonist (BID) from the apoptosis regulator Bcl-2 family. The cleaved BID translocates to the mitochondria, triggering the activation of apoptosis regulator Bcl-2-associated X protein (BAX), which results in the release of cytochrome C. This release further activates Caspase-9, Caspase-3, and Caspase-7, ultimately promoting apoptosis (Nag, Khan, & Tripathi, 2022). In studies related to S. flavescens flavonoids, kurarinone (34) was found to significantly inhibit the proliferation of H1688 cells, a process involving the activation of Caspase-3, Caspase-9, and poly ADP-ribose polymerase (PARP). This activation mechanism suggests that kushenol Z (34) can induce tumor cell apoptosis via the extrinsic pathway, thereby exerting its antitumor effects (Li et al., 2020).

4.2. Intrinsic apoptotic pathway

The intrinsic apoptotic signaling pathway primarily regulates the balance between anti-apoptotic factors, such as Bcl-2 and Bcl-xL, located on the outer mitochondrial membrane, which inhibit the release of cytochrome C. Pro-apoptotic factors, including BID, BAX, and BAD, translocate to the mitochondria upon receiving death signals, facilitating the release of cytochrome C. Once released, cytochrome C binds to Apaf-1, recruiting pro-Caspase-9 to form an apoptosome. Activated Caspase-9, through self-cleavage, subsequently activates Caspase-3 and Caspase-7, leading to apoptosis (Singh et al., 2022). Kushenol Z (14) elicits apoptosis through multimodal mechanisms of apoptosis induction by modulating both the mitochondrial and endoplasmic reticulum stress (ERS) pathways. In the mitochondrial pathway, kushenol Z (14) upregulates the BAX/Bcl2 ratio, triggering the release of cytochrome C through the concomitant BAX activation and Bcl2 suppression, which subsequently activates Caspase-9 and Caspase-3, ultimately leading to tumor cell apoptosis. Additionally, kushenol Z (14) significantly enhances the expression of the ERS marker CHOP and promotes the cleavage of Caspase-7 and Caspase-12, indicating its pivotal role in ERS-mediated apoptosis. Compared to conventional chemotherapeutic agents, kushenol Z (14) demonstrates higher specificity in inducing apoptosis, particularly in non-small cell lung cancer (NSCLC) cells. (Chen et al., 2019). Additionally, sophoflavescenol (9) directly activates Caspase-3, triggering a proteolytic cascade within the caspase family that inhibits the proliferation of LLC and HL-60 cells (Jung et al., 2011).

4.3. PI3K/AKT signaling pathway

The PI3K/AKT pathway plays a critical role in regulating cell survival and apoptosis by phosphorylating AKT. This process inhibits pro-apoptotic proteins such as BAX, BAD, and Caspase-9, thereby suppressing apoptosis (Cui et al., 2020). Sophoraflavanone G (45) exerts antitumor activity by targeting the epidermal growth factor receptor (EGFR)-PI3K-AKT signaling pathway. In triple-negative breast cancer (TNBC) cell lines (BT-549 and MDA-MB-231), sophoraflavanone G (45) inhibits proliferation, with IC50 values ranging from 36 to 39 μmol/L. Mechanistically, sophoraflavanone G (45) binds to EGFR with a binding energy of −7.7 kcal/mol, resulting in functional inactivation of the EGFR-PI3K-AKT pathway. Overexpression of EGFR reverses the anti-cancer effects of sophoraflavanone G (45), confirming its dependence on this pathway. The anti-cancer potential of sophoraflavanone G (45) through targeting the EGFR-PI3K-AKT pathway was further validated in nude mouse models. Treatment with sophoraflavanone G not only suppressed tumor growth but also led to a marked decrease in the phosphorylation levels of EGFR, PI3K, and AKT in the xenograft tumors (Cheng, Liu, Guo, Li, & Wang, 2022). Furthermore, sophoraflavanone G (45) binds to the ABCG2 transporter protein, reversing multidrug resistance in non-small cell lung cancer (NSCLC) and enhancing chemosensitivity. Extensive experimental evidences support its mechanism of action. In vitro experiments using a fluorescence-based drug accumulation assay demonstrated that 20 μmol/L of sophoraflavanone G (45) completely inhibits ABCG2 function, restoring intracellular mitoxantrone accumulation in H460-MX20 and A549-Bec150 cells. The IC50 values for sophoraflavanone G (45)-mediated inhibition of ABCG2-dependent mitoxantrone transport were approximately 2.12 and 2.29 μmol/L, respectively, confirming its direct inhibition of ABCG2's drug transport activity. Molecular docking analysis revealed that sophoraflavanone G (45) binds to the substrate-binding pocket of the inward-facing conformation of ABCG2 (PDBID: 6VXH). The interaction involves hydrophobic, π-π, and π-alkyl interactions with multiple amino acid residues, as well as hydrogen bonds, with a binding energy of −70.41 kcal/mol, elucidating its mechanism at the molecular level (Wu et al., 2021). Based on these findings, the synergistic strategy of “PI3K inhibition + ABCG2 blockade” can be employed, offering a novel approach to overcoming chemotherapy resistance.

4.4. Autophagy and ROS pathway

Autophagy is an intracellular degradation mechanism intimately associated with the survival and death of tumor cells. Various flavonoids derived from S. flavescens can induce autophagy, leading to tumor cell death, which is mechanistically coupled to increased levels of ROS. ROS can promote cell death by activating autophagy signaling pathways (Yun et al., 2020). For example, compound (103) triggers the release of ROS, activating autophagy signaling proteins without directly affecting apoptosis-related proteins, thereby inhibiting the proliferation of HepG2 cells (Yang et al., 2021). Furthermore, 23 isolated flavonoids from S. flavescens induce ROS release in HepG2 cells, resulting in autophagic cell death rather than apoptosis as a mechanism of their antitumor activity (Yang et al., 2021). These findings suggest that flavonoids from S. flavescens induce tumor cell death through the “ROS-autophagy” axis, providing a theoretical basis for combined antioxidant therapy.

4.5. cAMP signaling pathway

The cAMP signaling pathway plays a crucial role in regulating cell apoptosis and proliferation. Flavonoids derived from S. flavescens can influence the survival of tumor cells by modulating the activity of phosphodiesterase (PDE) and protein kinase A (PKA) within this pathway. For instance, kushenol Z (14) not only induces apoptosis by regulating the BAX/Bcl-2 ratio but is also considered a potential inhibitor of cAMP-PDE and AKT (Chen et al., 2019).

4.6. Estrogen receptor (ER) regulatory pathway

In the estrogen receptor (ER) pathway, the binding of estrogen (E2) to ER activates the expression of anti-apoptotic factors such as B-cell lymphoma 2 (Bcl-2), which inhibits apoptosis and promotes cell survival. Consequently, ER antagonists play a crucial role in the prevention and treatment of certain estrogen-dependent tumors. Flavonoids from S. flavescens, including kushenol K (71), kushenol N (74) and kurarinol (36), function as competitive antagonists of the estrogen receptor ER-α, inhibiting estroge-related tumor growth and demonstrating chemopreventive potential against breast cancer (Ahmed, Ashfaq, Qamar, & Ahmad, 2014). This suggests that flavonoids from S. flavescens can regulate the ER signaling pathway to inhibit cell proliferation and induce apoptosis.

4.7. Anti-angiogenic effects

Angiogenesis is a crucial process for tumor growth and metastasis, and inhibiting tumor-associated angiogenesis is a key strategy in antitumor therapy. Certain flavonoids from S. flavescens can hinder tumor proliferation and metastasis by targeting angiogenesis-related signaling pathways. For example, kushecarpin D (116) exerts anti-angiogenic effects by reducing intracellular H2O2 levels and downregulating vascular endothelial growth factor (VEGF) expression, thereby inhibiting VEGF-mediated angiogenic signaling pathways. This subsequently suppresses endothelial cell (EC) proliferation, migration, and adhesion, ultimately leading to inhibition of tumor growth and metastasis (Pu, 2010).

4.8. Antitumor targets of key compounds

To provide a clear overview of the molecular targets of S. flavescens flavonoids, the following table (Table 4) summarizes the antitumor targets of the most relevant compounds, along with their associated mechanisms and biological effects.

Table 4.

Antitumor targets of key S. flavescens flavonoids.

Compounds Molecular targets Mechanism of action Biological effects
Kushenol G (7) PI3K/AKT Blocking PI3K/AKT phosphorylation Reducing cell proliferation
Kurarinone (34) Caspase-3/9 Inducing Caspase-3/9 cleavage Promoting apoptosis
Sophoraflavanone G (45) EGFR Inhibiting EGFR autophosphorylation Suppressing tumor growth
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These findings highlight the polypharmacological properties of S. flavescens flavonoids and their potential as effective anticancer agents. Further research is needed to explore additional targets and optimize their therapeutic applications.

5. Safety evaluation

In safety evaluation studies of S. flavescens flavonoids, experiments in nude mice established that both the oral and intravenous maximum tolerated doses (MTD) were high, exceeding 2.8 and 750 mg/kg, respectively (Sun et al., 2008). These MTD values indicate a wide safety margin for the flavonoids. Separately, acute toxicity studies on the total alkaloids from S. flavescens reported an oral infectious dose 50% (LD50) of 1.18 g/kg and an intravenousLD50 of 150 mg/kg (Sun et al., 2008). Furthermore, the S. flavescens wash solution did not produce any acute toxic reactions in rectal irritation tests conducted on rabbits, and no allergic reactions were observed in skin sensitization tests performed on guinea pigs (Huang, Wu, Wang, & Zhou, 2020). These findings suggest that both S. flavescens extracts and S. flavescens flavonoids exhibit good safety profiles for both topical and oral administration routes.

Although S. flavescens flavonoids demonstrate a high level of safety, some specific flavonoid compounds exhibit hepatotoxicity, particularly with long-term or high-dose usage. For example, while sophoraflavanone G (45) has a lower content than kushenol Z (34), its hepatotoxicity is more pronounced. It has been confirmed that the hepatotoxicity of sophoraflavanone G (45) is related to its inherent structural properties. In contrast, the liver damage associated with kushenol Z (34) is characterized by a significant increase in serum transaminase levels and fatty degeneration of liver tissue. Despite the strong anticancer activity of kushenol Z (34), special caution is warranted to its safety during structural modifications and applications (Yu, 2013, Chen, 2014).

Therefore, special attention should be given to balancing the toxicity and efficacy of S. flavescens flavonoids during the development process. This can be achieved by integrating modern pharmacology, toxicology, and metabolomics to optimize their structures and substituents, thereby reducing toxicity. Such an approach will provide a solid theoretical and experimental foundation for their potential as new chemical entities or candidate drugs.

6. Conclusion and prespective

This systematic review elucidates the therapeutic potential of S. flavescens flavonoids as promising chemotherapeutic candidates, emphasizing their significant role in modulating key biological pathways and inhibiting tumor proliferation. The importance of S. flavescens flavonoids is highlighted in several aspects: First, their diverse chemical structures, particularly isoprenylated flavonoids such as kushenol G and matrine, exhibit selective cytotoxicity against various cancer cell lines (e.g., HepG2, A549, MCF-7) while sparing normal cells, demonstrating favorable drug safety profiles. Second, these compounds exert multitarget antitumor mechanisms by inducing apoptosis, regulating oxidative stress, and modulating signaling pathways such as PI3K/AKT and cAMP/PKA, providing a theoretical foundation for the development of novel anticancer drugs.

However, despite the generally low toxicity of S. flavescens flavonoids, certain specific compounds may induce hepatotoxicity, particularly with long-term or high-dose administration. For instance, sophoraflavanone G (45) exhibits more pronounced hepatotoxicity compared to kushenol Z (34), which is closely related to their inherent structural properties. This challenge underscores the need to balance toxicity and efficacy during drug development. Modern pharmacological, toxicological, and metabolomic approaches should be employed to optimize their structures and substituents, thereby reducing toxicity risks. Additionally, the structural complexity of flavonoids and their interactions with biological systems necessitate further in-depth research to elucidate their mechanisms of action and metabolic pathways.

To address these challenges, future studies should integrate molecular docking and molecular dynamics simulation techniques to predict the binding modes of S. flavescens flavonoids with target proteins, accelerating drug discovery and development. Meanwhile, the application of high-throughput screening (HTS) and AI-assisted drug design (AIDD) technologies will significantly expedite the identification of potential antitumor compounds, reducing preclinical development timelines. Furthermore, quantitative structure–activity relationship (QSAR) analysis can provide theoretical guidance for structural optimization, particularly for isoprenylated flavonoids, to enhance their targeting and antitumor activity.

In summary, S. flavescens flavonoids hold immense potential as antitumor agents, but their clinical application requires further research, particularly in safety evaluation and structural optimization. Through multidisciplinary approaches, S. flavescens flavonoids may offer safer and more effective therapeutic options for cancer patients, paving the way for innovative anticancer drug development.

CRediT authorship contribution statement

Zhongyuan Guo: Conceptualization, Writing – original draft, Writing – review & editing. Gaoyue Dong: Visualization, Writing – review & editing. Xiaoqian Liu: Conceptualization. Huimin Gao: Writing – review & editing. Liangmian Chen: Conceptualization. Hong Yang: Conceptualization, Resources, Supervision, Writing – review & editing. Zhimin Wang: Conceptualization, Funding acquisition, Resources, Supervision.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

This work was financially supported by the National Key Research and Development Program of China (No. 2023YFC3504000, No. 2023YFC3504004) and the Scientific and Technological Innovation Project of China Academy of Chinese Medical Sciences (No. CI2021A04407, No. CI2023E001TS03)

Contributor Information

Hong Yang, Email: yanghong@ccmu.edu.cn.

Zhimin Wang, Email: zmwang@icmm.ac.cn.

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