New growths produced by the expansion of local tissue cells in response to many tumorigenic triggers are referred to as 响应许多致瘤触发因素而由局部组织细胞扩增产生的新生长被称为“tumors”. It is primarily a mass protrusion that occupies space, also known as a neoplasm ^[1][2]. In terms of morbidity and mortality, cancer continues to be a major global public health issue, coming in second place only behind cardiovascular disease ^[3][4]. A report on worldwide cancer statistics published in 肿瘤”。它主要是占据空间的肿块突起，也称为肿瘤[1，2]。就发病率和死亡率而言，癌症仍然是一个主要的全球性公共卫生问题，仅次于心血管疾病[3，4]。国际癌症研究机构2020 by the International Agency for Research on Cancer indicated that, in this century, cancer might surpass cardiovascular disease as the major cause of premature death in the majority of countries. By 年发布的一份全球癌症统计数据报告指出，在本世纪，癌症可能超过心血管疾病，成为大多数国家过早死亡的主要原因。到2040, there are projected to be 28.4 million new cases of cancer worldwide, an increase of 47% from 2020 ^[5][6]. The pathogenic mechanisms of cancer include maintaining proliferative signals, eluding growth inhibitors, avoiding cell death, establishing replicative immortality, initiating angiogenesis, and triggering invasion and metastasis ^[7]. Over the last 50 years, a lot of strategies have been employed to slow the spread of cancer, namely surgery, radiotherapy, and systemic therapy ^[8][9]. These treatments, however, have numerous limitations and side effects, such as a high incidence of drug resistance and multidrug resistance, low efficacy of some targeted therapies, and severe adverse responses, whether administered alone or in combination ^[10][11]. Thus, developing novel anti-tumor medications and minimizing side effects have consistently been major areas of research in the anti-tumor field.年，预计全球将有28万新发癌症病例，比4年增加47%[2020，5]。癌症的致病机制包括维持增殖信号、躲避生长抑制剂、避免细胞死亡、建立复制性永生性、启动血管生成以及触发侵袭和转移[6]。在过去的7年中，已经采用了许多策略来减缓癌症的扩散，即手术、放疗和全身治疗[50，8]。然而，这些治疗存在许多局限性和副作用，例如耐药和多药耐药发生率高、某些靶向治疗疗效低以及单独或联合用药均存在严重不良反应[9，10]。因此，开发新型抗肿瘤药物和尽量减少副作用一直是抗肿瘤领域的主要研究领域。

Due to their multi-channel and multi-target characteristics, anti-tumor compounds derived from natural products are typically used to treat advanced cancer and relieve early cancer symptoms. Herbs used in traditional medicine are the source of most natural products ^[12][13][14]. Over the past few decades, natural products have been a significant source for the development of new anti-tumor drugs ^[11]. Currently, more than 由于其多通道和多靶点的特性，源自天然产物的抗肿瘤化合物通常用于治疗晚期癌症和缓解早期癌症症状。传统医学中使用的草药是大多数天然产物的来源[12，13，14]。在过去的几十年里，天然产物一直是开发新型抗肿瘤药物的重要来源[11]。目前，临床上有超过100 natural compounds are clinically used to treat cancers ^[15][16]. For example, studies have demonstrated that the active ingredient in Curcuma longa, curcumin, exerts anti-tumor effects by boosting apoptosis, inhibiting cell proliferation, obstructing tumor angiogenesis and metastasis, and inducing autophagy ^[17][18]. For example, paclitaxel exerts its anti-breast cancer effects by blocking mitosis (affecting 种天然化合物用于治疗癌症[15，16]。例如，研究表明，姜黄中的活性成分姜黄素通过促进细胞凋亡、抑制细胞增殖、阻碍肿瘤血管生成和转移以及诱导自噬来发挥抗肿瘤作用[17，18]。例如，紫杉醇通过阻断有丝分裂（影响B-cell lymphoma 细胞淋巴瘤2 (Bcl-2) phosphorylation), controlling microtubule polymerization, affecting calcium signaling, and regulating microRNA expression profiles ^[19]. Furthermore, significant anti-cancer efficacy is exhibited by artemisinin, which can generate reactive oxygen species in cancer cells, induce cell cycle arrest and autophagy, block cancer cell invasion and migration, and accelerate cancer cell apoptosis ^[20].（Bcl-2）磷酸化）、控制微管聚合、影响钙信号传导和调节microRNA表达谱来发挥其抗乳腺癌作用[19]。此外，青蒿素具有显著的抗癌功效，可在癌细胞中产生活性氧，诱导细胞周期停滞和自噬，阻断癌细胞侵袭和迁移，加速癌细胞凋亡[20]。

In recent years, a lot of literature has been reported about the classical anti-tumor signaling pathways of natural products, which are found to have the advantages of multiple targets and pathways, providing a sufficient theoretical basis for natural products as more promising antitumor drugs. For instance, the phosphoinositide 近年来，关于天然产物的经典抗肿瘤信号通路的文献报道很多，发现天然产物具有多个靶点和通路的优点，为天然产物作为更有前途的抗肿瘤药物提供了充分的理论依据。例如，磷酸肌醇3-kinase (PI3K) signaling pathway is a crucial signaling pathway for normal cell physiological metabolism. By inhibiting this signaling pathway, tumor growth and metastasis can be prevented. Activation of PI3K can also assist in the phosphorylation of Akt and, ultimately, together play a crucial role in tumor progression ^[21]. For instance, 激酶（PI3K）信号通路是正常细胞生理代谢的关键信号通路。通过抑制这种信号通路，可以预防肿瘤生长和转移。PI3K的激活还可以帮助Akt的磷酸化，并最终共同在肿瘤进展中起关键作用[21]。例如，Yan et al. ^[22] found that baicalein induced apoptosis and autophagy in breast cancer cells by inhibiting 等人[22]发现黄芩素通过抑制PI3K /Akt signaling pathway. In addition to the PI3K signaling pathway, the signal transducer and activator of the transcription 3 (STAT3) signaling pathway is one of the key targets for cancer therapy, which is a significant intracellular signal transduction protein and transcription factor directly related to the growth of tumors ^[23]. Akt信号通路诱导乳腺癌细胞凋亡和自噬。除PI3K信号通路外，转录3（STAT3）信号通路的信号转导器和激活因子是癌症治疗的关键靶点之一，是与肿瘤生长直接相关的重要细胞内信号转导蛋白和转录因子[23]。Luo et al. ^[24] found that 等人[24]发现Bavachin induces iron death in osteosarcoma cells via inhibition of 通过抑制STAT3 activity. Additionally, mitogen-activated protein kinase (MAPK) is a crucial intracellular signal transduction system that controls a variety of processes in cells, including cell growth, proliferation, differentiation, apoptosis, adhesion, and migration. These processes have an impact on drug resistance, invasion, and metastasis, as well as tumorigenesis, making it one of the potential targets of anti-tumor medications ^[25].活性诱导骨肉瘤细胞中的铁死亡。此外，丝裂原活化蛋白激酶（MAPK）是一种关键的细胞内信号转导系统，可控制细胞中的各种过程，包括细胞生长、增殖、分化、凋亡、粘附和迁移。这些过程对耐药性、侵袭和转移以及肿瘤发生有影响，使其成为抗肿瘤药物的潜在靶点之一[25]。

With more than 已确认700 species recognized, the genus 多种，Selaginellacea of the family e家族的Selaginellaceae is extensively distributed around the world属广泛分布在世界各地; especially, it is primarily found in tropical and subtropical areas. These species have been reported to possess many bioactivities that include anticancer, anti-inflammatory, antibacterial, antiviral, antioxidant, anti-aging, hypoglycemic, and other activities ^[26][27]. However, the current pharmacological studies of 特别是，它主要分布在热带和亚热带地区。据报道，这些物种具有许多生物活性，包括抗癌、抗炎、抗菌、抗病毒、抗氧化、抗衰老、降血糖和其他活性[26，27]。然而，目前对Selaginella plants are mainly focused on anti-tumor effects. For example, Ethyl acetate fractions from 植物的药理研究主要集中在抗肿瘤作用上。例如，来自Selaginella doederleinii exhibited cytotoxicity effects for 的乙酸乙酯组分对A549 cell lines, 7721 cell lines, Hela cell lines and 细胞系、7721细胞系、Hela细胞系和Eca-109 cell lines, among which it has the strongest inhibitory effect on Hela cell lines with IC50 value of 37.53 μg/mL ^[28]. 细胞系表现出细胞毒性作用，其中对Hela细胞系的抑制作用最强，IC50值为37.53μg/mL[28]。Li et al. ^[29] discovered that ethyl acetate extract from 等人[29]发现来自Selaginella doederleinii induced autophagic death and apoptosis in colorectal cancer cells through the 的乙酸乙酯提取物通过PI3K-Akt-mTOR and AMPKα signaling pathways. Lei J et al. ^[30] found that the biflavonoid extracts from S. moellendorffii exhibited a noticeable negative effect on the growth rate of 和AMPKα信号通路诱导结直肠癌细胞的自噬死亡和凋亡。Lei J等人[30]发现，来自莫伦多菲链球菌的双黄酮类提取物对HCT-116 cell lines and 细胞系和HeLa cell lines in the range of 0 μg/mL to 500 μg/mL. Qin et al. ^[31] used proline细胞系的生长速率表现出明显的负面影响，范围为0μg/mL至500μg/mL。秦等[31]用脯氨酸-lactic acid to prepare biflavonoid extracts, which showed significant inhibitory activity against tumor 乳酸制备双黄酮提取物，对肿瘤A549 cells, sw1990 cells and HepG2 cells. Therefore, the researchers comprehensively discussed biflavonoids from Selaginella, which are the main active ingredient that exerts anti-tumor effects and devoted ourselves to elucidating its anti-tumor mechanism of action and its signaling pathway in the research. As shown in Figure 细胞、sw1990细胞和HepG2细胞具有显著的抑制活性。因此，本文全面讨论了双黄酮类化合物，它是发挥抗肿瘤作用的主要活性成分，并致力于阐明其抗肿瘤作用机制和信号通路。如图1.所示。

In th在过去的二十年中，科学家发现Se last two decades, scientists have discovered that laginella植物具有广泛的活性成分，主要分类为生物碱，Selaginella plants have a wide range of active components, mostly classified as alkaloids, selaginellins and phenolic acids. ins和酚酸。已发现Selaginellin components have been found to have potential anti-tumor activity due to their unique triple-bond structure. For example, 组分由于其独特的三键结构而具有潜在的抗肿瘤活性。例如，Zhang et al. ^[32] isolated five selaginellin derivatives from 等人[32]从柽柳Selaginella tamariscina, and two of the new selaginellins were structurally characterized by spectroscopic analysis. Cytotoxic activity assessment showed that the two new selaginellins exhibited moderate toxicity against human cancer cell lines (中分离出五种血清素衍生物，其中两种新的血清素通过光谱分析进行了结构表征。细胞毒性活性评估显示，两种新的血清素对人癌细胞系（U251, ，HeLa, MCF-7). In addition, ，MCF-7）表现出中等毒性。此外，Thamnarak et al.等人 [33] ^[33]分离出两种新的正木脂素硫芥醇 isolated two new ortholignans siamensinols (（1–-2)） and seven known compounds agatharesinol (和七种已知化合物阿加他树脂醇 （3), syringaresinol）、丁香树脂醇-glucoside (葡萄糖苷 （4),）、来自 noreugenin from Selaginella siamensis 的去甲糖素 (（5), ）、8-methyleugenitol (甲基丁香糖醇 （6),）、美拉色酮 melachromone (（7),）、优西诺苷 uncinoside A (A （8),） and daucosterol (和多科斯特罗 （9). Among them, compounds ）。其中，化合物1–-2 showed moderate inhibitory effects on 对MOLT-3 cells, while compounds 细胞表现出中等抑制作用，而化合物6–-8 showed moderate inhibitory effects on three tumor cells (对2种肿瘤细胞（HepG2, A549 and 549、A1和HuCCA-1).<>）表现出中等抑制作用。

Biflavonoids are the primary active ingredients of 双黄酮类化合物是Selaginella plants, exerting anti-cancer effects ^[26]. 植物的主要活性成分，具有抗癌作用[26]。SFB species exert anti-tumor effects by inhibiting cancer cell proliferation, inducing cancer cell apoptosis, inhibiting tumor metastasis and angiogenesis, inducing autophagy, and impacting the tumor microenvironment. As shown in Figure 种通过抑制癌细胞增殖、诱导癌细胞凋亡、抑制肿瘤转移和血管生成、诱导自噬、影响肿瘤微环境等方式发挥抗肿瘤作用。如图2. 所示。SFB has been shown to have anti-cancer effects on a variety of tumors, including ovarian cancer, lung cancer, prostate cancer, breast cancer and digestive system tumors.已被证明对多种肿瘤具有抗癌作用，包括卵巢癌，肺癌，前列腺癌，乳腺癌和消化系统肿瘤。

Biflavonoids, a unique class of flavonoids, are primarily soluble in ethyl acetate. Their basic structural unit is made up of two molecules of flavonoids, generally in accordance with a C–C or C–O–C link. Currently, 71 different types of biflavonoids have been discovered in Selaginella plants [34]. They can be divided into five categories based on the various connection methods. As shown in Figure 3: ① amentoflavone-type (C′3-C″8)(I), of which there are 24 species, mainly represented by amentoflavone and isoginkgetin; ② robustaflavone-type (C′3-C″6)(II), with 23 species, mainly represented by robustaflavone; ③ hinokiflavone-t (C′4-O-C″6)(III), with ten species, mainly represented by hinokiflavone and isocryptomerin; ④ delicaflavone-type (C3-O-C4‴)(IV), of which there are four species, mainly represented by delicaflavone; and ⑤ biphenylether-type (C′3-O-C‴4)(V), of which there are two species.

Over the past 5 years, scientists have discovered numerous novel biflavonoids in Selaginella plants [35]. Nine species of bioflavonoids from Selaginella doederleinii have been recently discovered ^[29][30][31][29,30,31]. As shown in Figure 4. Among these, compound 2 [36] showed modest selectivity to A549 cells and MCF-7 cells; compound 4 [37] demonstrated potent cytotoxicity against the human cancer cell lines SMMC-7721, A549, and MCF-7; and compounds 6–9 [38] considerably inhibited the proliferation of non-small cell lung cancer. The most active compound, 9, caused apoptosis and cycle arrest in A549 cells. A new robustaflavone, (2S, 2′S)-2,3,2′,3′-tetrahydrorobustaflavone 7,4′,4‴-trimethyl ether (10), was isolated from a 75% ethanolic aqueous extract of Selaginella uncinate [39]. Selaginella trichoclada was extracted with 70% ethanol, and five novel biflavonoids were discovered. Among them, compounds 11 and 12 [40] demonstrated moderate cytotoxicity to human cancer cell lines A549 and HepG2; compound 13 [41] was effective against breast cancer via the mitochondrial pathway; compound 14 [42] demonstrated moderate cytotoxicity to human cancer cell lines DU145, MCF-7, and PC3; and compound 15 [43] showed cytotoxicity to the human breast cancer cell line MCF-7. A new biflavonoid (16) was isolated from a 70% ethanolic extract of Selaginella braunii, which showed significant antiproliferative effects on SMMC-7721, MCF-7, and A549 cells [44]. From Selaginella siamensis and Selaginella bryopteris, three novel biflavonoids known as siamamenflavones A–C (17–19) were isolated. One of them, siamamenflavone B (18), exhibited potent inhibition of wild-type EGFR protein [45]. Selaginella tamariscina yielded three novel biflavonoids: involvenflavone G (20), H (21), and I (22); H and I may have potent hypoglycemic effects [46].

Biflavonoids derived from plants other than those of the genus 来自Selaginella also have si属以外的植物的双黄酮类化合物也具有显着的抗肿瘤作用。据报道，抑制Egnificant anti-tumor effects. According to reports, inhibiting Eg5 can cause apoptosis and mitotic arrest. Eg5 inhibitors are therefore becoming the focus of anticancer drug research. As a mitotic kinesin 5可引起细胞凋亡和有丝分裂停滞。因此，Eg5抑制剂正成为抗癌药物研究的焦点。作为有丝分裂驱动蛋白Eg5抑制剂，藤黄黄酮与Eg5 inhibitor, morelloflavone from Garcinia dulcis binds to the variable site of 的可变位点结合，从而抑制Eg5, thereby inhibiting the 的ATPase activity and motor function of Eg5 ^[47]. Chamaejasmenin isolated from 酶活性和运动功能[47]。从Stellera chamaejasme L. roots in根中分离的Chibited the proliferation of cells from eight human solid tumor cell lines (HepG2, SMMC-7721, A549, MG63, U-2 OS, and KHOS, HCT-116 and HeLa) ^[48]. amaejasmenin抑制了2种人实体瘤细胞系（HepG7721，SMMC-549，A63，MG2，U-116 OS和KHOS，HCT-48和HeLa）的细胞增殖[49]。Japoflavone D, a biflavonoid from Lonicera japonica flower buds with significant antioxidant activity, has a dual regulatory effect on the apoptosis of liver cancer cells under various oxidative circumstances ^[49].是一种来自粳花蕾的双黄酮类化合物，具有显着的抗氧化活性，在各种氧化情况下对肝癌细胞的凋亡具有双重调节作用[<>]。