Apoptosis is the process by which cells automatically terminate their lives under certain physiological or pathological conditions, and it is controlled by intrinsic genetic mechanisms. Apoptosis eliminates redundant cells, non-functional cells, cells that have developed abnormally, or harmful cells. The key characteristics of apoptosis include the condensation and fragmentation of nuclear chromatin, expansion of the endoplasmic reticulum, retention of organelles, and cytoplasmic shrinkage. The treatment of glioma patients involves promoting the apoptosis of cancer cells, thereby inhibiting the proliferation of glioma cells. Apoptosis is initiated by apoptotic signals, followed by the interaction of apoptosis regulatory molecules to activate protein hydrolases (caspases), leading to a continuous cascade of reactions. Numerous molecules regulate apoptosis, including the following: (1) apoptosis inhibitory molecules such as P35, FLIPs, and Inhibitors of Apoptosis (IAPs); and (2) the Bcl-2 family which includes Mcl-1, NR-B, A1, Bcl-w, and Bcl-x.

Necroptosis is a programmed lytic cell death pathway believed to be involved in eliminating pathogen-infected and/or damaged cells in specific degenerative or inflammatory diseases. It shares key morphological features with apoptosis, leading to cell swelling, formation of pores in the suprabasal layer cell membrane, rupture of the plasma membrane, and moderate chromatin condensation. However, the precise role of necroptosis in glioma remains unclear. Numerous regulators of necrotic cell death exist, including PRK1, RIPK3, long non-coding RNA (lncRNAs), and mixed lineage kinase domain-like pseudokinase (MLKL), among others.

Autophagy (38) is a process in which damaged proteins or organelles are enclosed in autophagic vesicles with a bilayer membrane structure and then transported to lysosomes (in animals) or vacuoles (in yeast and plants) for degradation and recycling. Electron microscopy revealed that organelles such as the Golgi apparatus had swollen, the nucleus had solidified, numerous phagocytic vesicles had formed, and the cytoplasmic membrane had undergone specialization. Cellular autophagy can be categorized into macroautophagy, microautophagy, and molecular chaperone-mediated autophagy (CMA). Autophagy occurs in five stages: (1) phagocytosis or nucleation. (2) conjugation of the ATG5-ATG12 complex, its interaction with ATG16L, and multimerization of the phagocytic vacuole, (3) processing of LC3 and its insertion into the swollen phagocytic mass membrane, (4) capture of selected targets for degradation, and (5) fusion of the autophagosome with the lysosome, followed by proteolytic degradation by the lysosomal protease contained in the absorbed molecule undergoes proteolytic degradation. The relationship between cellular autophagy and tumors is more complex. On the one hand, normal cells with increased autophagy can inhibit tumorigenesis. On the other hand, tumor cells can enhance their stress response, including autophagy, to counter hypoxia, metabolite and therapeutic agent induction. This response is influenced by nutrient availability, microenvironmental stress, pathogenic conditions, and the presence of the immune system (39, 40). Therefore, the inhibition of tumor cell growth through autophagy needs to be analyzed on a case-by-case basis. The regulatory factors that have been found to be associated with glioma include Phosphatase and Tensin Homolog (PTEN), Epidermal growth factor receptor (EGFR), ATG family, Beclin1, and Mammalian target of rapamycin (mTOR).

Ferroptosis is a regulated form of cell death characterized by the iron-dependent accumulation of lipid peroxidation to lethal levels. When cellular cysteine transport proteins are inhibited (e.g., erastin), intracellular glutathione (GSH) is depleted, which eventually leads to the inactivation of glutathione peroxidase (GPX4). This leads to the buildup of lipid peroxidation to a level that triggers cell death, which can also be directly caused by the inhibition of GPX4 enzymes (e.g., GSH peroxidase 4 inhibitors like RSL3) (57). The morphological features of ferroptosis are quite specific, including a reduction (disappearance) of the mitochondrial cristae, rupture of the outer mitochondrial membrane, wrinkling, darkening of the mitochondria, iron-dependent nuclei without rupture, and cell membrane rupture. Ferroptosis can inhibit tumor growth in several ways. For example, it sensitizes GBM to Anti-PD1/L1 immunotherapy and promotes M2 to M1 polarization (70). Numerous factors regulate ferroptosis, including Erastin, RSL3, RAS, FSP1, circular RNAs (circRNAs), SLC7A11, NRF2, GPX4, Ferrostatin-1, and Liproxstatin-1.

Pyroptosis, also known as cellular inflammatory necrosis, is a form of RCD characterized by continuous cellular distention until the cell membrane ruptures. This leads to the release of cellular contents, activating a strong inflammatory response (75). Cystathione activation is linked to necrosis and apoptosis. Initially, scorch death was thought to be related to cysteine-1 related cell death (76). Recent studies have shown that other cystathionases, such as cystathione-2/3/4/5/6/7/8/9/10/11, also induce damage in various cells and play significant roles in innate immunity and tumorigenesis.

Researchers conducted a comprehensive analysis of pyroptosis in glioma, utilizing the CGGA and TCGA databases, GDSC database, and GSVAR software. They concluded that pyroptosis-related genes effectively classified glioma patients well into two-dimensional distribution and that prognostic features based on these genes hold high clinical value. Finally, the expression of neuro CASP8 expression was higher in glioma compared to controls. The highest expression was observed in WHO IV, followed by WHO III, and the lowest in WHO II. Elevated CASP8 expression was associated with poor overall survival. These results suggest that CASP8 plays an oncogenic role in gliomas (77). Pyroptosis levels strongly indicate that the thermal tumor immune microenvironment has a high presence of CD8 ⁺ T cells and other T cell subtypes, as well as activation of P53 pathway, DNA repair, KRAS signaling, epithelial-mesenchymal transformation (EMT), IL6 JAK STAT3 signaling, IL2 STAT5 signaling, PI3K signaling, AKT signaling, mTOR signaling, and oncogenic pathways are enriched in the pyroptosis-Hi subgroup of cancer (132).

However, the role of pyroptosis in glioma has been less studied, and a comprehensive analysis of pyroptosis regulators in glioma, their correlation with clinical features, and their prognostic value has not yet been reported.

Necrosis is the death of local tissue cells in vivo and is characterized by changes in enzymatic solubility. Its morphological features include cell expansion, cell membrane rupture, release of cell contents, gradual nuclear changes, and incomplete DNA degradation, all of which contribute to a severe local inflammatory response. Necroptosis can be induced by the TNF receptor superfamily (80), T-cell receptors (81), interferon receptors, Toll-like receptors (TLR) (82), cellular metabolism, genotoxic stress, or the activation of various anticancer drugs, such as necrosis inhibitor-1 (Nec-1) (83).

Parthanayos is a PARP1-dependent, cysteine-dependent cell death pathway characterized by chromosome condensation and DNA fragmentation. Many molecules, including PARP1, PARG, ARH3, AIF, and MIF (97).

PARP-1, also known as poly (ADP-ribose) synthase 1 or poly (ADP-ribose) transferase 1, exhibits higher basal levels in glioma cells compared to neurons and is positively associated with glioma malignancy and poor patient survival (98). Inhibiting PARP-1 has been a strategy for developing new drugs to overcome the resistance of glioma cells to radiotherapy or chemotherapy-induced apoptosis. Deoxypodophyllotoxin (DPT), the primary lignan and active component of the traditional plant camphor, suppresses the viability of glioma cells and induces their death by generating an excess of reactive oxygen species (ROS), which leads to abnormal germination of glioma cells (99).

Parthanayos is mainly dependent on PARP1-dependent and cysteine aspartic proteases, and recent studies have shown a clear role of PPAR1 in neurons. Inhibiting PARP-1 has been a strategy for developing new drugs to overcome the resistance of glioma cells to radiation- or chemotherapy-induced apoptosis. Current studies show that drugs like DPT (99) also play a role in treating GBM, offering the potential for glioma treatment.

Lysosome-dependent cell death (LCD), also known as lysosomal cell death, is a form of RCD mediated by hydrolases (histones) or iron released by lysosome membrane permeabilization (LMP), characterized by lysosomal rupture (100), including Cathepsins, STAT3, TP53, NF-κB, MCOLN1 and other regulators (100). The results of Wei Zhou et al. showed that a newly synthesized lysosomal biological agent, Lys05, induced lysosomal membrane permeabilization in an LMP-dependent manner and increased radiosensitivity in GBM (101), thereby enhancing the therapeutic efficacy for glioma.

The main process of cuproptosis depends on the accumulation of intracellular Cu ions. Cu ions can directly bind to the lipid-acylated components of the tricarboxylic acid (TCA) cycle, leading to blockage. As a result, the accumulation and dysregulation of these proteins can lead to proteotoxic stress and ultimately cell death (105, 106). The primary regulators of coproptosis include FDX1, proteolipid acylation, DLAT, LIAS, pyruvate, α-ketoglutarate, and HSP70.

Cuproptosis has now been shown to have a role in cancers such as breast cancer (106). Wang et al. predicted that cuproptosis would likely help predict the prognosis, biological characteristics, and appropriate treatment of patients with glioma (107). Cuproptosis provides new targets and approaches for glioma treatment. Human H-ferritin (HFn), regorafenib, and Cu²⁺ were rationally designed as brain-targeted nanoplatforms (HFn-Cu-REGO NPs), with the aim of enhancing the effectiveness of Cu²⁺ and regorafenib in the treatment of GBM by modulating autophagy and prolapse (108).

Cuproptosis is an RCD modality that has only been proposed in the past two years and induces cell death through the TCA cycle in the mitochondria. Various researchers have predicted that cuproptosis may influence the prognosis and drug effectiveness in patients with glioma, offering a new target and approach for treating the condition.

Apoptosis is one of the most extensively researched forms of RCD. Several natural compounds have been found to induce apoptosis and inhibit the growth of glioma, including rosmarinic acid (RA) (24), matrine (25), xanthatin (26), and Polyphyllin VII (PP7) (27), etc. RA, a natural compound primarily found in the leaves of Rosmarinus officinalis, has demonstrated efficacy in inhibiting proliferation, invasion, and inducing apoptosis of GBM cells through the PI3K/Akt/NF−κB pathway (24). Matrine that has a variety of pharmacological properties, such as anti-inflammatory, antioxidant, and anti-fibrotic effects. It can also inhibit the growth of various cancer cells, including those of stomach cancer, chronic myelogenous leukemia, and breast cancer, by inducing apoptosis and autophagy. This is achieved through the downregulation of circ-104075 and Bcl-9 expression, which inhibits the PI3K/AKT and Wnt-β-catenin pathways in GBM cells (25). Xanthatin, a natural bioactive sesquiterpene lactone that has anti-angiogenic, antiviral, anti-inflammatory, antifungal, antibacterial effects and plays an anti-cancer role in non-small cell lung cancer, stomach cancer, breast cancer, melanoma and leukemia isolated from the aerial part of Xanthium strumarium L., induces apoptosis and inhibits tumor growth via activating the endoplasmic reticulum stress-dependent CHOP pathway (26). PP7, a class of saponins that has anti-cancer effects in liver, lung, breast and colorectal cancer cells isolated from Paris polyphylla var. yunnanensis induces astrooblastoma and GBM cells death and autophagy via AKT/mTORC1 signaling (27). These natural drugs can inhibit the growth of gliomas by inducing apoptosis, and thus become backup drugs for the treatment of gliomas.

Furthermore, multiple studies have demonstrated that drugs can trigger necroptosis and effectively suppress the growth of gliomas. For example, Shikonin, a natural naphthoquinone isolated from the roots of Lithospermum erythrorhizon, can induce apoptosis and necrotic of GBM cells (35) by inhibiting EGFR phosphorylation and decreasing phosphorylation of EGFR downstream molecules, including AKT, P44/42MAPK and PLCγ1. Dehydrobastidine, a natural tumor seserpene lactone from Artemisia douglassiana Besser (Argentina) and Gynoxys verrucosa (Ecuador), has been shown to induce the phosphorylation of the tumor protein TP73. This process regulates apoptosis, autophagy, and necroptosis in astroblastoma and GBM cells (36), providing prospects for the treatment of glioma.

Furthermore, numerous natural products effectively inhibit the growth of gliomas and promote ferroptosis. For example, pseudolaric acid B (PAB), a diterpenoid acid that has anti-cancer effects in prostate cancer, cervical cancer and breast cancer isolated from the roots and bark of the trunk of the cortex of Pseudolaric pine, has been shown to trigger ferroptosis in astroblastoma and GBM cells by activating Nox4 and inhibiting xCT (68). Plumbagin (PLB; 5-hydroxy-2-methyl-1,4-naphthoquinone) inhibits GBM growth in vitro and in vivo through ferroptosis mediated by targeting NAD(P)H quinone dehydrogenase 1 (NQO1) and GPX4 (69).

Understanding the mechanisms that underlie pyroptosis in cancer will contribute to developing new therapeutic strategies and clinical transformations. For drug effects, the compound benzimidazoles can induce apoptosis and pyroptosis of human GBM cells by blocking the cell cycle (78), while the natural drug isobavitazarone (IBC). as a compound isolated from Psoralea corylifolia Linn seeds, can relieve pyroptosis and thus contribute to enhancing apoptosis of GBM cells (79). Moreover, IBC exerts an anti-cancer effect on leukemia, colorectal cancer, liver cancer, breast cancer, prostate cancer, stomach cancer, cervical cancer, ovarian cancer, tongue squamous cell carcinoma and myeloma.

In the field of drug research, numerous studies have demonstrated that natural compounds can trigger necrosis and inhibit the growth of cancer. For example, berberine was isolated from Aim. For example, berberine was isolated from Aim. Rosin can induce necrosis in prostate cancer cells (92) and Icaritin can trigger the necrosis of colorectal cancer cells (93). In gliomas, the natural product pristimerin, a natural quinonemethide triterpenoid isolated from various plant species in the Celastraceae and Hippocrateaceae families, activates c-Jun terminal kinase to induce apoptosis in astroblastoma and GBM cells, leading to programmed necrosis (94). Pristimerin also has anti-cancer effects in ovarian cancer, hepatocellular carcinoma, cervical cancer and breast cancer. 2-methoxy-6-acetyl-7-methyljuanone (MAM) that induced necrotic apoptosis of lung cancer and colorectal cancer cells inhibited glioma growth by inducing programmed necrosis of GBM cells by targeting NQO1 (95). This finding also offers potential for future glioma treatment.

Some naturally sourced compounds with specific molecular targets have shown promising therapeutic effects by blocking signaling proteins that promote cancer development. We summarized the relationship between natural drugs and RCD (such as apoptosis, necroptosis, pyroptosis, necrosis and ferroptosis) to achieve better precise treatment and clinical effects. These RCD related targeting drugs have been proven in the treatment of GBM, and the effect of other regulatory methods on glioma remains to be proven. Therefore, natural small molecule compounds may become clinical agents of GBM by regulating RCD.