Silibinin is a flavonoid extracted and isolated from the fruit of the chrysanthemum plant Silybum marianum (Tuli et al., 2021). It has been widely used for the treatment and prevention of various hepatobiliary disorders, including alcoholic liver disease, non-alcoholic fatty liver disease, and mushroom poisoning (Abenavoli et al., 2018; Hosseinabadi et al., 2019; Wang et al., 2020a). Recent studies have demonstrated the broad-spectrum anti-cancer effects of silibinin against most types of cancer cells(Jahanafrooz et al., 2018). For example, it can inhibit the migration and invasion of breast cancer MDA-MB-231 cells through induction of mitochondrial fusion(Si et al., 2020). In hepatocellular carcinoma, silibinin has been found to effectively abate hepatocarcinogenesis and hepatocellular carcinoma growth by regulating various signaling pathways including HGF/c-Met, Wnt/β-catenin and PI3K/Akt/mTOR(Yassin et al., 2022). In cholangiocarcinoma, silibinin has the ability to inhibit cholangiocarcinoma through the ERK/mitochondrial apoptotic pathway, which makes silibinin a potential anti-tumor drug candidate for cholangiocarcinoma treatment(Bai et al., 2022).

Considering that silibinin has extremely high antioxidant and anti-tumor properties, it has drawn our attention to its potential use in the treatment of GBM.BNIP3, a member of the Bcl-2 family of pro-apoptotic proteins and a receptor for mitophagy, exhibits context-dependent roles in cancer(Gorbunova et al., 2020; Gorbunova et al., 2020; Vara-Perez et al., 2021).It targets mitochondria and could induce mitochondrial damage and nuclear translocation of AIF6 (Su et al., 2016). A study using GBM cell lines and nude mice with xenografted GBM has confirmed that silibinin could induce mitophagy in GBM, and that autophagy can promote silibinin-induced BNIP3 overexpression and its accumulation in the mitochondria, thereby triggering AIF-dependent death in GBM cells (Wang et al., 2020b). Moreover, silibinin has also been shown to inhibit GBM cell migration by inhibiting MMP-2 and -9 and improving TMZ-resistance in GBM cells (Zhai et al., 2021; Wong et al., 2023). Silibinin have potential uses for patients with GBM. However, like other polyphenols, faces the challenge of low bioavailability, which impedes its potential as a transformative chemotherapeutic drug(Tuli et al., 2021). At the same time, further clinical research is also needed to better understand the potential toxicity and risks associated with the drug’s use in treating GBM. This will provide more reliable evidence to support clinical treatment of GBM.

Cannabidiol (CBD), the main active component of medical cannabis, is extracted from the wild hemp (Karimi-Haghighi et al., 2022). It easily passes through the BBB, is highly safe, and has anti-proliferation and anti-invasion activities against various cancers (Valenti et al., 2022; Ammendolia et al., 2023). The literature indicates that in many animal cancer models, CBD has shown potential in inhibiting the progression of various types of cancers, including in GBM, breast(Kiskova et al., 2019; Valenti et al., 2022), lung(Milian et al., 2022; Misri et al., 2022), prostate(Mahmoud et al., 2023), colon cancer(Jeong et al., 2019; Lee et al., 2022b; Yuksel et al., 2023), and melanoma(Bachari et al., 2020). CBD has emerged as a promising agent in the treatment of glioma cells due to its ability to inhibit their proliferation and promote cell death. This effect is mainly achieved by targeting the mitophagy pathway, which has gained significant attention in recent research.

Transient receptor potential vanilloid 4 (TRPV4) is a widely expressed multimodal-gated ion channel that plays a pivotal role in many physiological and pathophysiological processes (Grace et al., 2017; Muller and Reggio, 2020). Its expression in human brain basement membrane tissue is closely related to tumor grade and prognosis (Yang et al., 2020). CBD can induce mitophagy by activating endoplasmic reticulum stress via the TRPV4–ATF4–DDIT3–TRIB3–AKT–MTOR axis. TRPV4 expression in human GBM tissues correlates with both tumor grade and poor survival, suggesting that TRPV4 could be an attractive therapeutic target and biomarker for GBM (Huang et al., 2021a). CBD can also lead to abnormal stability of the plasma membrane by affecting the homeostasis of GBM lipid metabolism, thereby promoting the phagocytosis of tumor cells by macrophages and exerting an anti-GBM effect (Khodadadi et al., 2021; Genovese et al., 2022). These two mechanisms synergistically inhibit the formation and development of GBM, indicating that CBD has great clinical application prospects as an anti-GBM medicine et al., 2021).

Simultaneously, compared with single drug treatment alone, the combined treatment of CBD and TMZ more effectively targeted GBM patients, significantly inhibiting the growth of GBM cells and prolonging survival time, suggesting that CBD can effectively enhance the anti-tumor effect of TMZ in GBM (Lopez-Valero et al., 2018; Huang et al., 2021b). Furthermore, in the first study on the CBD-induced anti-tumor effects of RELA Ser311 phosphorylation, ROS was shown to serve as a biomarker for stratifying patients who may benefit from CBD treatment (Volmar et al., 2021).

Gossypol (2,2ʹ-bis-(formyl-1,6,7-trihydroxy-5-isopropyl-3-methylnaphthalene), a BH3-mimetic compound naturally present in cottonseed, exerts anti-tumor effects by targeting various signal transduction pathways. It has been extensively studied in clinical trials, where it has shown good tolerability and safety (Benvenuto et al., 2018; Yurekli et al., 2018). However, recent studies have found that it is the (-)-enantiomer of gossypol, namely (-)-gossypol (also known as AT-101), rather than (+)-gossypol or racemic gossypol, that has significant anti-cancer properties (Benvenuto et al., 2018). Therefore, the development of single-isomer pharmaceutical preparations can avoid potential adverse reactions. Thus far, AT-101 has been considered a promising anti-cancer drug for the treatment of various tumors, including multiple myeloma (Ailawadhi et al., 2023), adrenal cortical carcinoma (Yurekli et al., 2018), esophagus cancer (Que et al., 2019), breast cancer (Bulut et al., 2020), lung cancer (Ahmad et al., 2021; Renner et al., 2022), and prostate cancer (Aktepe and Yukselten, 2022).

HMOX1 is an inducible enzyme that catalyzes the degradation of oxidized preheme and is also involved in mitochondrial biogenesis and mitophagy (Constantin et al., 2012; Hull et al., 2016). AT-101 can promote GBM cell death by inducing overactivation of HMOX1 and the autophagy receptors BNIP3 and BNIP3L, causing early mitochondrial dysfunction and marked loss of mitochondrial mass/protein (Meyer et al., 2018). It also suppresses the growth of TMZ-resistant glioblastoma (Kim et al., 2019). Mitochondrial respiration and mitochondrial permeability transition pore opening were impaired after AT-101 treatment, suggesting that mitochondrial dysfunction is a key driver of AT-101-induced cell demise (Meyer et al., 2018). Because the AT-101 molecule is hydrophobic, oral administration greatly reduces its bioavailability, and gastrointestinal side effects can easily be caused. Therefore, the cyclic RGD (cRGD)-decorated mixed liposome (cRGD-LP) nanopreparation for the tumor-targeted delivery of AT-101 (abbreviated as Gos hereafter) came into being (Xie et al., 2019a; Liu et al., 2022). This nanoformulation enhanced tumor engraftment in vivo, possibly due to cRGD binding to the αvβ3 integrin on tumors and tumor cells, enhancing tumor targeting (Liu et al., 2022). Moreover, some studies have also shown that arsenic trioxide-mediated hedgehog/notch inhibition can interfere with DNA double-stranded break repair by reducing the expression of CHEK1 and CHEK2, synergistically targeting GSC along with AT-101 (Linder et al., 2019). AT-101 combined with demethoxycurcumin can enhance the inhibitory effect on the proliferation of glioblastoma cells (Mehner et al., 2020), suggesting that combination therapy with different agents may be an option to overcome drug resistance in GBM cells effectively, in a long-term treatment strategy.

Xanthohumol (XN), a natural compound found in hops, is an isoprene flavonoid with a wide range of biological activities, including anti-inflammatory, anti-oxidant, anti-cancer, antibacterial, and lipid lowering (Lin et al., 2022c; Neumann et al., 2022). Since flavonoids readily cross the BBB in vivo, they are considered potential drug leads for treating disease. Several studies have shown that XN has anti-GBM effects. It can not only inhibit the IGFBP2/AKT/BCL-2 pathway and activate the P53 signaling pathway to participate in XN-induced GBM cell apoptosis (Chen et al., 2016), but it also induces apoptosis of glial pathway cells by increasing ROS and activating MAPK pathways (Festa et al., 2011). Hou et al. confirmed that XN can inhibit C6 proliferation, trigger mitochondrial stress, and induce cell death in a concentration- and time-dependent manner (Hou et al., 2021). Following treatment of GBM cells with XN, the cell cycle was blocked at the G0/G1 phase, and XN induced AIF-mediated apoptosis, which was accompanied by mitochondrial structure and function impairment, as well as mitophagy blockage (Hou et al., 2021). In contrast, mitochondrial injury not only disrupts ATP synthesis in cells but also consumed large amounts of ATP to maintain intracellular stability. This vicious cycle exacerbates cellular energy consumption. The DNA repair machinery is a tool to remove DNA damage for the maintenance of genomic integrity in normal cells and paradoxically plays a crucial role in driving the development of drug resistance and tumor recurrence (Huang and Zhou, 2021). The results of Ho et al. showed that XN could enhance the cytotoxicity of TMZ by inhibiting the DNA repair system and could be used as an adjuvant drug in the treatment of patients with GBM with DNA repair activation (Ho et al., 2020). Moreover, XN also reduces the invasiveness of GBM cells by inhibiting the signaling of stromal interacting molecule 1 (STIM1), indicating that XN may be a good GBM therapeutic agent (Ho et al., 2018). Elucidating the XN-mediated molecular mechanism may provide novel strategies for future drug development and tumor research.

As a methylated derivative of resveratrol, pterostilbene (PTE) has higher biological activity and safety than resveratrol and is mainly found in blueberries and grapes (Rimando et al., 2004; Ruiz et al., 2009; Chang et al., 2012). PTE has a wide range of biological functions, including anti-tumor, anti-oxidation, anti-inflammatory, apoptosis, cardiovascular protection, anti-proliferation, and antibacterial activities (Chen et al., 2020), gallbladder (Tong et al., 2021), breast (Harandi-Zadeh et al., 2021; Kumar et al., 2021), colon (Wawszczyk et al., 2022), cervical (Shin et al., 2020), prostate (Hemani et al., 2022), and lung cancers (Bracht et al., 2019). In GBM, PTE can induce the loss of mitochondrial membrane potential and production of reactive oxygen species (ROS) (Gao et al., 2021) and activate the FAS/FASL pathway and caspase-3, thereby inhibiting proliferation and inducing GBM cell apoptosis (Tan et al., 2019; Gao et al., 2021). Moreover, given that PTE presents highly bioavailability and easily crosses the BBB, PTE administration can serve as a novel treatment for patients with GBM (Ma et al., 2019). Based on the abovementioned experimental results, PTE has a high research value and development prospects in the field of GBM drug treatment.

Chrysophanol (1, 8-dihydroxy-3-methyl-9, 10-anthraquinone) is a phytochemical extracted from Rheum officinale (rhubarb), which has been utilized as a traditional Chinese herbal medicine (Yusuf et al., 2019; Su et al., 2020). It has various pharmacological effects, including anti-cancer, antioxidant, neuroprotective, antibacterial, antiviral, and blood lipid-regulation effects. Studies have shown that chrysophanol can attenuate hepatic stellate cell-induced endoplasmic reticulum fibrosis by regulating hepatitis B virus stress and iron concentration (Kuo et al., 2020). Moreover, it can inhibit the growth and metastasis of T-cell acute lymphoblastic leukemia through the miR-9/PD-L1 axis (Yin et al., 2021), regulating the effect of the microRNA-27b-3p/peroxisome proliferator-activated receptor γ axis on sepsis-induced acute myocardium damage protection (Park et al., 2022).

Moreover, the application of chrysophanol for cancer treatment is also increasing. For instance, chrysophanol promotes cell morphological changes, induces cell apoptosis through DNA damage, and arrests S phase cell cycle among patients with liver cancer (Ni et al., 2012). In patients with lung cancer, chrysophanol expresses anti-cancer activity by regulating the ROS/HIF-1a/VEGF signaling pathway (Zhang et al., 2020a; Zhang et al., 2021a). In patients with GBM, it has been discovered that chrysophanol increased the accumulation of ROS in the mitochondria of GBM cells, promoting the release of Cyt-C from the mitochondria to the cytoplasm and, thereby, causing GBM cell apoptosis (Gu et al., 2021). Chrysophanol regulates the anti-cancer effect on GBM cells by activating the mitochondrial apoptosis pathway, indicating that it may serve as an innovative chemotherapeutic agent for GBM. However, chrysophanol has obvious hepatotoxicity and nephrotoxicity. Nevertheless, pharmacokinetics has shown that chrysophanol combined with other drugs can reduce toxicity and improve efficacy (Xie et al., 2019b).

Shikonin is the main bioactive component extracted from the root of Lithospermum erythrorhizon, which has various bioactivities related to cancer treatment, inflammation, and wound healing. Many studies have shown that shikonin has strong anti-cancer effects on leukemia, gastrointestinal cancer, pancreatic cancer, lung cancer, breast cancer, and urogenital organ cancer, by inhibiting cell proliferation and migration, and inducing apoptosis and necroptosis (Guo et al., 2019). A clinical trial conducted by Guo et al. reported that, among 19 patients suffering from late-stage lung cancer who were not subjected to surgery, chemotherapy, or radiotherapy, the tumor diameter decreased by more than 25% after treatment with shikonin, posing a remission rate of 37% and a 1-year survival rate of 47% (Boulos et al., 2019). Shikonin is a potent inducer of necrotizing apoptosis in cancer cells. In terms of pharmacological mechanism, anti-glioma effect of shikonin by interfering with endoplasmic reticulum stress-mediated tumor apoptosis targeting Caspase-3, and Bax/Bak-induced mitochondrial outer membrane permeabilization (MOMP) triggering cancer cell apoptosis (Ma et al., 2020). ROS is the executor of necrotizing apoptosis. Shikonin increases intracellular ROS levels by targeting both NOX1 and the mitochondrial respiratory chain complex (Yang et al., 2014). RIP1 and RIP3 can modulate shikonin-induced ROS overproduction by targeting the mitochondria and promoting RIP1/RIP3-dependent necroptosis in GBM cells (Lu et al., 2017). Shikonin has shown great promise as a potential drug for treating glioma by targeting the mitochondrial apoptosis pathway. In order to achieve greater precision and efficacy in treating glioma, it is necessary to consider the shikonin’s ability to cross the blood-brain barrier. Wang et al. developed an AS1411 aptamer/hyaluronic acid-bifunctionalized microemulsion co-loading shikonin and docetaxel (AS1411/SKN&DTX-M), which has the ability to penetrate the BBB according to their research report. The codelivery of shikonin and docetaxel through bifunctionalization with hyaluronic acid and AS1411 aptamer presents a promising approach for anti-GBM therapy using dual-drug therapy (Wang et al., 2019).

Grape seeds are the seeds of Vitis vinifera. Grape seed proanthocyanidins (GSP) is a general term for a large class of polyphenolic compounds that have antioxidant activity. GSP has various biological activities and has been proven to have good anti-tumor effects, as well as certain inhibitory effects on cervical cancer (Li et al., 2022a), carcinoma of the urinary bladder (Yang et al., 2021a), lung cancer (Xu et al., 2021a; Zhang et al., 2021; Mao et al., 2023), colon cancer (Aiello et al., 2019; Zhang et al., 2019), liver cancer (Feng et al., 2019), prostate cancer (Chen and Yu, 2019), among others. In a study on liver cancer cells, GSP was found to trigger ROS production, decrease matrix-metalloproteinases (MMPs), and increase caspase-3 activity in HepG2 cells (Wang et al., 2020), proving that GSPs may induce ROS production and, consequently, lead to MMP reduction and caspase-3 activation. This ultimately induces HepG2 cell apoptosis. GSP can reverse EMT by inhibiting the TGF-β signaling pathway, effectively inhibiting the migration and invasion of bladder cancer (BC) cells (Yang et al., 2021b), suggesting that GSP can be used as a potential chemotherapy drug for BC. GSP can also reduce the proliferation activity of cancer cells (Habib et al., 2022). The mechanism of GSP pertaining to GBM is related to the inhibition of proliferation, induction of apoptosis, arrest of the cell cycle, and inhibition of angiogenesis and metastasis (Yang et al., 2021b). Grape seed, as a natural anti-cancer drug, holds great promise for the treatment of glioma. However, further clinical research is necessary to fully elucidate its role in the treatment mechanism.

The alkaloid sinomenine (SIN), namely 7,8-didehydro-4-hydroxy-3,7-dimethoxy-17-methylmorphinan-6-one (C19H23NO4), is extracted from the rhizome of the traditional Chinese medicine plant Sinomenium acutum (Zheng et al., 2021). SIN has anti-inflammatory effects and has been used to treat rheumatoid diseases in humans (Lin et al., 2022b; Chen et al., 2022). In recent years, SIN and its derivatives have been reported to have strong anti-tumor activity against various tumors, including BC (Xu et al., 2021b), prostate (Xu et al., 2019), papillary thyroid (Zhang et al., 2022b), breast (Li et al., 2022b; Gao et al., 2022), ovarian (Qu et al., 2021), and lung cancers (Bai et al., 2021). SIN can inhibit cell proliferation (Sun et al., 2018a; He et al., 2018), induce apoptosis (Liu et al., 2019) and arrest the cell cycle at the G0/G1 phase in various cancers (Yang et al., 2021a). SINI-WCJ-33 (SW33, C33H51NO5), a SIN-derivative obtained by the acylation of 4-hydroxyl and 14-carboxylic acid, can inhibit the proliferation, migration, invasion, and colony formation of human glioblastoma cell lines (Zheng et al., 2021). This derivative has higher anti-GBM activity and safety than its parent compound (Liu et al., 2019). The CCNB1/CDC2 complex is a key mediator of the G2/M checkpoint (Park et al., 2000; Taylor and Stark, 2001; Cheng et al., 2016). The polo-like kinase (PLK1)-dependent phosphorylation of CDC25C is required for normal cell cycle progression from the G2/M phase (Liu et al., 2020b; Tang et al., 2020). SW33 can reduce the expression of P-CDC2, CDC2, and CCNB1, as well as the protein levels of P-PLK1 and PCDC25C in GBM cells. It can also increase the expression of P53 and its transcriptional target P21, finally leading to the arrest of the GBM cell cycle in the G2/M phase, causing mitochondrial dysfunction, consequently releasing Cyt-C, activating caspase 3/9, and inducing mitochondrial apoptosis (Zheng et al., 2021).

In addition, PI3K/AKT/MTOR, MAPK/MTOR, and AMPK/MTOR have been widely reported to activate mitophagy (Zhang et al., 2020b; Liu et al., 2021). Zheng et al. have shown that SW33 can induce autophagy through the PI3K/AKT/MTOR and AMPK/MTOR signaling pathways in patients with GBM, thus playing an anti-GBM role, significantly inhibiting tumorigenesis, without having obvious adverse effects on the body (Zheng et al., 2021). Taken together, all these results suggest that SW33 may be a promising drug for the treatment of GBM.

Resveratrol (3,5,4′-trihydroxystilbene) (RES) is a naturally occurring polyphenol and phytoalexin that is abundant in red wine, berries, peanuts, and soybeans and has anti-inflammatory, anti-oxidant, anti-cancer, cardioprotective, and neuroprotective effects (Baur and Sinclair, 2006; Catalgol et al., 2012; Neves et al., 2012). Resveratrol is effective in the treatment of GBM through various mechanisms, but its bioavailability is severely reduced due to its poor water solubility, short biological half-life (approximately 9–14 min for primary molecules), chemical instability (oxidation and photosensitivity), and rapid metabolism and elimination (Jhaveri et al., 2018). If its shortcomings as a free drug can be overcome, its in vitro activity could be enhanced, and the relevant therapeutic effect could be improved. Triphenylphosphine (TPP+) is a lipophilic cation that can couple many bioactive molecules to achieve mitochondrial targeting (Wang et al., 2021). According to a report, paclitaxel-loaded liposomes prepared using TPP- modified polyethylene glycol-phosphatidylethanolamine (PEGPE) have been shown to be effective in targeting mitochondria in cancer cells (Biswas et al., 2012). Loading RES into PEGylated liposomes (RES-Ls) has been reported to overcome its drawbacks as a free drug (Fu et al., 2021). Furthermore, transferrin is overexpressed on most cancer cells, and transferrin-targeted RES-Ls may be an effective nanomedicine for the treatment of various cancers, including GBM, even though their biodistribution in vivo and ability to cross the BBB remain unknown.

Berberine (BBR) is a natural compound isolated from Chinese herbal medicine, including the Coptis root (Huang Lian) and Amur corktree (Huang Bai). It has a wide range of pharmacological effects, including antidiarrheal, antibacterial, antioxidant, anti-inflammatory, and anti-tumor aspects (Li-Weber, 2013; Li et al., 2015). BBR can inhibit GBM cell growth, reduce cellular viability, and induce oncosis-like death (cell swelling, cytoplasmic vacuoles, and plasma membrane blebbing) (Sun et al., 2018b). We also found that BBR induces autophagy as a protective effect and decreases the oxygen consumption rate, which could inhibit mitochondrial aerobic respiration by repressing phosphorylated extracellular regulated protein kinases (p-ERK1/2), reducing its energy production efficiency and, thereby, reducing metabolic activity (Sun et al., 2018b). The most challenging aspect related to BBR or other therapeutics in GBM is crossing the BBB. Glucose-coated nanodrugs and fructose-coated nanoparticles can provide 10–100-times more uptake by tumor cells in various models (Hu et al., 2015). The formation of nanoshapes by simply dissolving BBR into 5% glucose solution provides a promising strategy for drugs to cross the BBB (Wang et al., 2020).