Review ArticleReview
Open Access

Current status of traditional Chinese medicine in modulating mitochondrial metabolic abnormalities in tumors

Siyi Ma, Jiarong Li, Bingjie Hao and Lihong Fan
Cancer Biology & Medicine September 2025, 20250246; DOI: https://doi.org/10.20892/j.issn.2095-3941.2025.0246

Abstract

Tumor cells undergo metabolic reprogramming to adapt to rapid proliferation and harsh microenvironments, as evidenced by aerobic glycolysis. Mitochondria serve as key coordinators of this process. Under internal and environmental stress in tumors, mitochondria reprogram metabolism by balancing energy dynamics, redirecting metabolic routes, communicating via metabolites, and preserving the quality of mitochondria, thus supporting tumor cell survival. Traditional Chinese medicine (TCM) has a key role in modulating mitochondrial reprogramming in tumor cells, possibly disrupting metabolic pathways that are necessary for survival and proliferation. However, the underlying molecular signaling and cellular biological mechanisms need to be elucidated. In this review, we focused on the Key functions of mitochondria in adapting to tumor metabolic reprogramming are the focus of this review and recent advances in and regulatory mechanisms of TCM and nano-pharmaceutical formulations in maintaining mitochondrial homeostasis are discussed. These insights may help understand the role of mitochondria in the pathogenesis of metabolic diseases, such as cancer, and identify therapeutic targets.

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Introduction

Metabolic reprogramming, an important hallmark of neoplastic transformation, is a focus of contemporary oncology research1. Metabolic reprogramming refers to the adaptive remodeling of metabolic pathways and the redistribution of metabolic substrates by neoplastic cells to overcome environmental challenges and fulfill biosynthetic demands for proliferation and differentiation2. Cancer cells do not rely solely on glycolysis. Oxidative phosphorylation (OXPHOS), lactylation, and amino acid metabolism (represented by glutamine) with lipid metabolism may also have roles in the development of various tumors3. In some cases these metabolic processes may even be more critical for the survival of tumors than aerobic glycolysis4,5.

Mitochondria are important sites for catabolism and biosynthesis in tumor cells. Reprogramming of the mitochondria-associated metabolic network, which involves glucose metabolism, fatty acid oxidation (FAO), and glutamine metabolism, represents a key strategy by which cancer cells adapt to fluctuations in nutrient availability and the microenvironment6. For example, when nutrients are scarce, particularly under hypoxic conditions, tumor cells preferentially utilize glucose for aerobic glycolysis to generate sufficient adenosine triphosphate (ATP) and biomolecules (nucleotides, lipids, and amino acids) to support the energetic and biosynthetic demands of proliferation7. In contrast, in several persistent cancer cell types, such as BRAFV600E-mutated persistent human melanoma cells and KRAS-inhibited, KRASG12D-mutated mouse pancreatic ductal adenocarcinoma (PDAC), these cells often decrease reliance on glucose and switch to alternative energy substrates, such as fatty acids, to fulfill energetic requirements via enhanced mitochondrial OXPHOS8. Mitochondria also serve as central regulators of tumor metabolic reprogramming. The production of mitochondrial metabolites, aberrant regulation of mitochondrial quality control, and mutations in mitochondrial DNA (mtDNA) can collectively drive the reorganization of biological processes in tumor cells, including energy production, metabolic pathways, and signal transduction.

The plasticity of mitochondrial structure and function allows tumor cells to adapt to the dynamic demands at every stage of oncogenesis. This adaptability makes mitochondria highly promising targets for cancer therapy. Several drugs that target mitochondrial reprogramming, such as metformin, dichloroacetate, and FV-429, exhibit antitumor activity9. Traditional Chinese medicine (TCM) represents a valuable source of mitochondrial reprogramming modulators. Our previous study showed that baicalein, a bioactive compound from Scutellaria baicalensis Georgi, prevents the release of mtDNA by restoring mitochondrial function and promotes liquid-solid phase separation in cyclic GMP-AMP synthase (cGAS), thereby terminating activation of the cGAS-STING pathway and suppressing KRAS/p53-driven lung tumorigenesis10 (Figure 1). TCM has promising effects in modulating mitochondrial metabolism, bioenergetics, redox reactions, mitochondrial quality control, and mtDNA in tumor cells. TCM also has unique advantages, such as good biocompatibility, low toxicity, multitarget bioactivity, and favorable long-term tolerability, which have garnered significant interest in testing TCM as mitochondrial modulators11–13. In this review how mitochondria contribute to the metabolic reprogramming of cancer to accommodate the survival needs of tumor cells for unrestricted proliferation and progression is described in detail. The research progress and mechanisms of action underlying TCM monomers, compound formulae, and nano-pharmaceutical formulations in regulating metabolic reprogramming are elucidated.

Figure 1
Figure 1

Baicalein induces cGAS phase transition from liquid-to-solid to suppress lung tumorigenesis10. KRASG12D/p53fl/fl mutation induces mitochondrial dysfunction and increases the release of mtDNA. The persistent stimulation of mtDNA is recognized by cGAS and results in the excessive aggregation of cGAS protein liquid condensates. The activated cGAS protein catalyzes the synthesis of 2′,3′-cGAMP. 2′,3′-cGAMP subsequently binds to STING and induces oligomerization, which recruits TBK1 and promotes TBK1 autophosphorylation. Activated TBK1 then phosphorylates STING and IRF3. Phosphorylated IRF3 translocates to the nucleus, initiating the transcription of IFN-Is and other pro-inflammatory cytokines (Cxcl10 and Ccl5), ultimately leading to the formation of lung cancer. Baicalein, extracted from the traditional Chinese medicinal herb Scutellaria baicalensis, is able to inhibit the release of mtDNA by preventing mitochondrial dysfunction. In addition, baicalein binds to cGAS and promotes the liquid-solid separation of cGAS protein, thereby terminating the activation of cGAS-STING induced by mtDNA. Ccl5, C-C motif chemokine ligand 5; Cxcl10, C-X-C motif chemokine ligand 10; 2′,3′-cGAMP, 2′,3′-cyclic guanosine monophosphate-adenosine monophosphate; cGAS, cyclic GMP-AMP synthase; IFN-Is, type I interferons; Ifnb1, interferon beta-1; IRF3, interferon regulatory factor 3; mtDNA, mitochondrial DNA; STING, stimulator of interferon genes; TBK1, TANK-binding kinase 1.

Mitochondrial metabolism and cancer

Mitochondrial alterations are a hallmark of tumor metabolic reprogramming. Key mitochondrial pathways, such as the tricarboxylic acid cycle (TCA) cycle, OXPHOS, FAO, and glutamine metabolism, provide energy and precursors for macromolecule synthesis. Mitochondrial quality and mtDNA are dynamically altered to adapt to different metabolic requirements in response to specific stimuli within the tumor microenvironment.

Glycolysis and OXPHOS

Metabolic reprogramming in tumors is characterized by an increase in glycolysis, which is the central feature of the Warburg effect. This metabolic adaptation provides rapid ATP flux (~100 × faster than OXPHOS) and biosynthetic precursors for macromolecules (nucleotides and fatty acids)14. Tumor cells have evolved various regulatory mechanisms to actively increase glycolytic activity, including the activation of oncogenes, stabilization of hypoxia-inducible factors, inactivation of tumor suppressors, activation of signaling pathways, and alteration of metabolic enzymes15. For example, aldehyde dehydrogenase 3A1 (ALDH3A1) promotes glycolysis, while restraining OXPHOS to support the survival of non-small cell lung cancer (NSCLC) cells through activation of the HIF-1α/LDHA pathway16. AKT1, a member of the AGC kinase family, strongly influences cellular signaling pathways by phosphorylating downstream target proteins. Aberrant activation of AKT1 frequently occurs in various tumors and can induce glycolysis by phosphorylating cytosolic malic enzyme 2 (ME2), thereby facilitating tumorigenesis in vitro and in vivo17. DEPDC1 is a metabolic target that modulates glycolysis in renal cell carcinoma (RCC) through the AKT/mTOR/HIF-1α pathway, which contributes to the malignancy and chemoresistance of RCC18. Even though glycolysis dominates cancer metabolism, respiration is not always suppressed but may vary depending on the tumor type and microenvironment. For example, prostate cancer relies more on OXPHOS, while ovarian cancer (OC) engages in vigorous aerobic glycolysis19. This difference is also observed among different cellular subpopulations of the same tumor20. Specifically, cancer stem and therapy-resistant cells selectively depend on OXPHOS for energy production, including taxane-resistant triple-negative breast cancer (TNBC), temozolomide-resistant glioblastoma multiforme (GBM), and cisplatin-resistant NSCLC cells5,21,22. Studies have confirmed that upregulation of OXPHOS-related genes in these tumor cells is crucial for maintaining tumor stemness, acquiring therapeutic resistance, and achieving distant metastasis. Even in cancer types that are highly dependent on glycolysis, subpopulations with high OXPHOS activity have a decisive role in tumor resistance and metastasis with strategies that include continuous ATP supply, the double-edged sword effect of ROS, signaling regulation of metabolic intermediates, and maintenance of NAD+/NADH balance20. A representative study conducted at the MD Anderson Cancer Center revealed that SWI/SNF-mutant lung adenocarcinomas undergoes substantial metabolic reprogramming, characterized by increased OXPHOS dependency, decreased glycolytic capacity, and marked vulnerability to the novel OXPHOS inhibitor, IACS-01075923. Therefore, antitumor drugs targeting OXPHOS may represent a promising therapeutic strategy for treating drug-resistant and recurrent cancers24,25.

mtROS signaling

Tumor cells often exhibit unusually high ROS levels that serve as key catalysts in the onset of cancer26. Mitochondria serve as a major source of ROS in cancer cells. A small fraction (0.2%–2%) of O2 binds to electrons in the electron transport chain (ETC) that escape the respiratory pathway instead of reaching terminal oxidases, forming O2•− and resulting in ROS production27. Then, O2•− can be converted to H2O2 by superoxide dismutase (SOD). Many tumor-inducing factors, such as oncogene activation, alterations in mitochondrial function, and an increase in hypoxia levels, contribute to ROS generation28. However, an increase in ROS production has highly diverse outcomes. Indeed, ROS may promote or inhibit cancer development. Elevated ROS levels in cancer cells may reverse the oxidation of cysteine residues in proteins, thus activating various signaling pathways to promote the survival, proliferation, invasion, and metastasis of cancer cells29. For example, ROS oxidize the active-site Cys124 residue of the phosphatase, PTEN, leading to inactivation. This oxidation event relieves the PTEN-driven suppression of PI3K, resulting in sustained activation of the AKT/mTOR signaling pathway, which is closely involved in breast cancer progression and resistance to treatment30. Some studies have reported that overproduction of ROS in cancer cells can induce tumor invasion and angiogenesis through NF-κB-mediated activation of MMP-931. In contrast, while ROS can promote tumors, an increase in oxidative damage and ROS-mediated cell death may also hinder tumor initiation. Tetraarsenic hexoxide suppresses mitochondrial STAT3 phosphorylation in triple-negative breast cancer (TNBC) cells to increase ROS production and amplify proptosis via the caspase-3/GSDME pathway32.

Lactate metabolism

Some researchers have challenged the outdated view of lactate as a byproduct of glucose metabolism under anaerobic conditions33. Isotope tracing techniques have revealed that lactate can serve as an additional carbon source for the TCA cycle34. Lactic acid not only serves as a substrate for cellular respiration and gluconeogenesis but also functions as a signaling molecule that harmonizes metabolic reprogramming. First, in the tumor microenvironment (TME), high lactate concentrations can induce lactylation modifications by targeting lysine residues on histones35. Mao et al.36 reported that mitochondrial protein lactylation inhibits OXPHOS under hypoxia, whereas this effect can be reversed by sirtuin 3 (SIRT3) to promote OXPHOS. And they elucidated the lactylation regulatory mechanisms on mitochondrial function under hypoxic conditions. Lactate can also function as an antioxidant to scavenge excessive ROS in cells and counteract ROS-induced DNA/RNA damage, thereby contributing to treatment resistance and metastasis37. Moreover, lactic acid significantly affects the TME by manipulating macrophage polarization toward M2-tumor-associated macrophages (TAMs), promoting angiogenesis and immune evasion, which are hallmark traits of cancer cell38.

Glutamine metabolism

Glutamine catabolism is another pathway by which malignant tumors acquire nutrients and energy. Glutaminolysis is approximately 10-fold greater in malignant cells than other amino acids. In certain types of cancer, such as melanoma, survival is associated with glutamine addiction39. When exogenous glutamine deprivation occurs, cancer cells stagnate and even die. Glutaminolysis provides precursors for nucleotide, protein, and amino acid biosynthesis and substrates for the TCA cycle in mitochondria40. Glutaminase 1 (GLS1) serves as a primary target for transcriptional regulators and signaling molecules across different biological conditions. GLS1 is frequently overexpressed in multiple aggressive cancers, such as lung, colorectal (CRC), and head and neck cancer41–43. For example, miR-335, a small non-coding RNA, suppresses glutamine-mediated PCa metastasis by targeting GLS44. Moreover, c-Myc strongly regulates glutamine metabolism in cells, promoting glutamine transport via solute carrier family 1 member 5 (SLC1A5), thereby affecting tumorigenesis45. Hu et al.46 reported that KRAS-mutant CRC has downregulated solute carrier 25 member 21 (SLC25A21), leading to inhibited Gln-derived α-KG efflux, increased glutaminolysis for TCA cycle replenishment, and increased GTP availability, sustaining KRAS activation.

Fatty acid metabolism

Lipid metabolic reprogramming, particularly fatty acid metabolism, is one of the most prominent metabolic abnormalities in cancer. The expression of sterol regulatory element binding protein 1 (SREBP1), a key transcription factor that regulates lipid metabolism, is elevated across multiple malignancies, notably in hepatocellular carcinoma, breast cancer, prostate cancer (PCa), and bladder cancer47,48. The tumor suppressor, TIP30, can decrease the expression of SREBP1 and its target genes (SCD and FASN) via the AKT/mTOR signaling pathway, thus inhibiting lipid metabolism in hepatocellular carcinoma (HCC) cells49.

Fatty acids cross the outer mitochondrial membrane to enter the mitochondrial matrix, where fatty acids undergo β-oxidation to generate acetyl-CoA, which then enters the TCA cycle to produce ATP via OXPHOS; this process is known as FAO. Under glucose-deprived conditions, elevated phosphorylation of PFKL promotes lipid droplet-mitochondria interactions, stimulating lipolysis and enhancing β-oxidation to maintain tumor cell energy homeostasis50. FAO has a central role in the TME. Jiang et al.51 revealed the molecular mechanism underlying FAO-mediated immune evasion in tumor cells. Acetyl-CoA, derived from FAO, promotes the transcription of CD47 through acetylation of NF-κB/RelA, thereby enabling GBM to evade macrophage phagocytosis and drive tumor progression.

Mitochondrial quality control in cancer

Mitochondrial fusion and fission

Mitochondria are highly plastic organelles that exhibit continuous and regulated cycles of membrane fusion and fission, an important homeostatic process collectively referred to as mitochondrial dynamics52. Mitochondrial fusion allows for the exchange of materials and information, whereas mitochondrial fission removes aged or damaged mitochondria to maintain morphology and function53. Changes in mitochondrial morphology are synergistically regulated by mitochondrial fusion (OPA1, MFN1, and MFN2) and fission genes (DRP1), which are necessary for metabolism, apoptosis, and autophagy54. Studies have reported that an imbalance in mitochondrial fission and fusion is central to the occurrence of some fundamental cancer cell metabolic features. Salt-inducible kinase 2 (SIK2) activates mitochondrial fission by phosphorylating Drp1 at the Ser616 site, which inhibits mitochondrial oxidative phosphorylation and subsequently contributes to progression of OC55. Enhanced mitochondrial fission drives lipid metabolism reprogramming in HCC by inhibiting SIRT1, leading to the transcriptional upregulation of SREBP1 and PGC-1α/PPARα56. This regulatory axis facilitates HCC cell proliferation, metastatic progression, and tumor growth in vivo. Additionally, mitochondrial dynamics modulate cell death pathways with network remodeling occurring under stress, such as hypoxia or drug exposure, and in disease. Elongated mitochondria effectively counteract the propagation of apoptotic signals, whereas fragmented mitochondria sensitize cells to apoptosis57,58.

Mitophagy

The accumulation of ROS or nutrient deprivation in tumor cells induces mitochondrial damage, thereby promoting the initiation of mitophagy. Mitophagy is a highly conserved cellular process in which damaged mitochondria are selectively engulfed by autophagosomes, subsequently fusing with lysosomes for degradation and recycling of mitochondrial components. The PINK1/Parkin pathway serves as a key regulator of mitophagy. Parkin gene deletions or mutations can be detected in various tumors, such as glioblastoma, OC, and even breast cancer. Mitophagy progresses and the level of mitochondrial ROS increases when Parkin is not effective59. ROS can activate glycolysis by increasing the stability of HIF-1α, thereby contributing to the Warburg effect. Several studies have reported that mitochondrial fusion proteins are required for modulating mitophagy. Dysregulation or aberrant splicing of OPA1 can impair mitochondrial fusion, thereby affecting mitophagy. Following Parkin/PINK1-mediated mitophagy, Parkin ubiquitinates MFN1 and MFN2, causing MFN1 and MFN2 degradation and promoting mitochondrial fission60–62. However, the precise functions of these proteins in mitochondrial dynamics have not been established and further studies are needed to elucidate the molecular roles.

mtDNA mutations

mtDNA mutations are among the most common genetic events in tumors and directly affect metabolic homeostasis63. Accumulated mutations in mtDNA disrupt the integrity of the ETC, impairing OXPHOS and decreasing the cellular ATP output. In response to bioenergetic stress, adaptive compensatory pathways are activated in neoplastic cells, whereby metabolic rewiring promotes tumorigenic proliferation and survival. For example, Smith et al.64 established that age-associated accrual of mtDNA mutations elicits progressive deterioration in OXPHOS efficiency through integrated analyses of murine models and human clinical specimens. This bioenergetic compromise drives neoplastic progression in the intestinal epithelium by activating the serine biosynthetic axis, as indicated by significant upregulation of the serine synthesis pathway (SSP). Mahmood et al.65 inserted mtDNA-encoded mutations into melanoma mice, which induced the Warburg effect, altered the TME, and elicited an antitumor immune reaction marked by a decrease in resident neutrophils. Another study revealed that heterozygous mutants of the mtDNA polymerase (PolgD257A) exhibited greater leukemogenic potential in leukemia models with NMYC proto-oncogene overexpression than the homozygous counterparts66. NMYC-driven upregulation of OXPHOS created a metabolic dependency that was accommodated by the PolgD257A heterozygous state, which revealed the interplay between mtDNA mutagenesis and metabolic plasticity in leukemogenesis.

TCM role and mechanisms in targeting mitochondrial reprogramming for cancer therapy

The modulation of mitochondria and associated metabolic pathways has received significant attention in the field of cancer therapy because this strategy represents an important approach with the ability to revolutionize treatment modalities. Several studies have reported that natural products can regulate mitochondrial metabolism, bioenergetics, and redox reactions in tumor cells at non-toxic concentrations, as summarized in Tables 1–3. Therefore, we focused on the efficacy and applications of these natural products in mitochondrial reprogramming and elucidated the underlying molecular mechanisms (Figure 2).

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Table 1

Representative natural herbal ingredients that target mitochondrial reprogramming

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Table 2

Representative TCM compound formulae that target mitochondrial reprogramming

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Table 3

Multifunctional nanoformulations containing natural herbal ingredients in the field of intervening in tumor metabolic reprogramming

Figure 2
Figure 2

Mechanisms of TCM in suppressing tumor progression via mitochondria. Modulation in metabolism pathways: Baicalein downregulates GLS1 expression by inhibiting mTOR; Ginsenoside CK inhibits GLS1 to reduce glutamine levels; Compound 2 depletes GSH by inhibiting DCTPP; Xingxiao pill (XXP) reduces AA release by inhibiting PLA2G4A (cPLA2); Wenxia Changfu formula (WCF) inhibits FAO by downregulating the PPAR-γ/CD36 pathway; Formosanin C (FC) disrupts lactate transport by blocking the interaction between MCT4 and CD147; Corynoxine regulates glucose metabolism by activating PP2A to inhibit the AKT-mTOR-GSK3β axis; Curcumin weakens the Warburg effect by silencing PKM2 to inhibit the mTOR/HIF-1α pathway; Huachansu (HCS) inhibits tumor glycolysis through the PI3K/AKT/mTOR pathway; Chrysin inhibits glycolysis by inhibiting the interaction between HK-2 and VDAC; Berberine regulates the Warburg effect by inhibiting the LINC00123/P65/MAPK10 axis; Ginsenoside Rh2 (G-Rh2) promotes the conversion of glycolysis to OXPHOS by targeting the HIF-1α/PDK4 axis; Zuojin pill (SQQT) affects the activity of glycolytic enzymes by downregulating HIF-1α. Modulation in ROS pathways: Artesunate damages the function of mitochondrial complex II, leading to the massive production of ROS; Tetrandrine (TET) targets SIRT5 and promotes its degradation, resulting in ROS accumulation. Modulation in mitochondrial dynamics: Tanshinone IIA (Tan IIA) induces tumor cell apoptosis by activating INF2-related mitochondrial fission; QiDongNing (QDN) induces mitochondrial fission and promotes tumor cell apoptosis through the P53/DRP1 pathway. Modulation of mitophagy: Oroxylin A (OA) suppresses CDK9 activity, which inhibits PINK1-PRKN-mediated mitophage formation; Oxymatrine triggers mitophagy and apoptosis by downregulating LRPPRC expression; Icaritin (ICA) induces mitophagy and apoptosis by inhibiting the PINK1/Parkin/pSer65-Ub axis; Cyclovirobuxine D (CVB-D) inhibits PINK1/Parkin-mediated autophagy by binding to LIF. Modulation of mitochondrial DNA: Curcumin promotes ROS over-production which depletes Polg and mtDNA; Baicalein may also inhibit the release of mtDNA by preventing mitochondrial dysfunction. Modulation of mitochondrial bioenergetics: Gracillin inhibits the function of mitochondrial complex II (CII) by eliminating SDH activity, resulting in bioenergetic dysfunction; Demethylzeylasteral (T-96) directly targets LRPPRC and inhibits its interaction with mt-mRNAs, leading to energy impairment; Shuang-Huang-Sheng-Bai (SHSB) inhibits ACLY activity and blocks acetyl-CoA synthesis, impairing ATP production. AA, arachidonic acid; ACLY, ATP citrate lyase; AKT, protein kinase B; ATP, adenosine triphosphate; CD147, cluster of differentiation 147; CD36, cluster of differentiation 36; CDK9, cyclin-dependent kinase 9; cPLA2α, cytosolic phospholipase A2-alpha; DCTPP1, dCTP pyrophosphatase 1; Drp1, dynamin-related protein 1; FAO, fatty acid oxidation; GLS1, glutaminase 1; GSH, glutathione; GSK3β, glycogen synthase kinase-3 beta; HIF-1α, hypoxia-inducible factor 1-alpha; HK-2, hexokinase-2; INF2, inverted formin 2; LIF, leukemia inhibitory factor; LINC00123, long intergenic non-coding RNA 00123; LRPPRC, leucine-rich pentatricopeptide repeat-containing protein; MAPK10, mitogen-activated protein kinase 10; MCT4, monocarboxylate transporter 4; mt-mRNAs, mitochondrial messenger ribonucleic acids; mTOR, mechanistic/mammalian target of rapamycin; OXPHOS, oxidative phosphorylation; Parkin, Parkin RBR E3 ubiquitin-protein ligase; PDK4, pyruvate dehydrogenase kinase 4; PI3K, phosphatidylinositol-3-kinase; PINK1, PTEN-induced kinase 1; PKM2, pyruvate kinase M2; PLA2G4A, phospholipase A2, group IVA; Polg, DNA polymerase gamma; PP2A, protein phosphatase 2A; PPAR-γ, peroxisome proliferator-activated receptor γ; PRKN, parkin RBR E3 ubiquitin protein ligase; pSer65-Ub, phospho-ubiquitin, Ser65-phosphorylated ubiquitin; ROS, reactive oxygen species; SDH, succinate dehydrogenase; SIRT5, sirtuin 5; VDAC-1, voltage-dependent anion channel 1.

TCM single compounds

Flavonoids

Flavonoids are widely distributed in the plant kingdom and are composed of two aromatic rings (A and B) connected by a three-carbon chain (C). Emerging studies have revealed that compounds known as flavonoids and their derivatives are effective in treating various cancers, including lung cancer, HCC, CRC, and OC, by modulating the way tumors process nutrients. For example, baicalein, a natural flavonoid extracted from the herb, S. baicalensis Georgi, has garnered significant attention as a promising anticancer agent103. Baicalein can induce apoptosis in lung cancer cells by suppressing the mTOR pathway by downregulating the expression of glutamine transporters (ASCT2 and LAT1), as well as the glutaminase, GLS167. Additionally, oroxylin A (OA), which is derived from S. baicalensis, has been recognized as a prospective mitophagy inhibitor. OA directly inhibits the activity of CDK9, thereby suppressing PINK1-PRKN-mediated mitophagy through inactivation of the SIRT1-FOXO3-BNIP3 axis, leading to disruption of mitochondrial homeostasis and apoptosis of HCC cells68. Moreover, in vivo studies have demonstrated that OA can augment the therapeutic efficacy of chemotherapeutics, like sorafenib and doxorubicin, by suppressing mitochondrial autophagy and can also surmount drug resistance. Icaritin (ICA), which is derived from Epimedium spp., was authorized by the China NMPA for advanced HCC treatment in 2022. ICA suppresses proliferation of HCC cells by inducing mitophagy and apoptosis via the PINK1-Parkin/pSer65-Ub signaling pathway69 and the inhibitory effect can be intensified by mitochondria-targeted OPDEA-PCL nanocarriers104. Chrysin inhibits glycolysis in HCC by silencing the expression of hexokinase-2 (HK-2), diminishing HK-2/VDAC connection and activating Bax-mediated apoptosis70.

Alkaloids

Berberine (BBR), an isoquinoline alkaloid derived from Coptis chinensis, has exhibited anticancer potential in preclinical and clinical studies98. Yan et al.71 reported that overexpression of LINC01123 is associated with an unfavorable prognosis based on the TCGA database. BBR modulates the Warburg effect and the formation of autophagosomes in ovarian malignancies via the LINC00123/P65/MAPK10 axis, thereby inhibiting the proliferation and metastasis of OC cells. Oxymatrine, an extract from Radix sophorae tonkinensis, inhibits the proliferation and spread of CRC cells by triggering mitophagy through LRPPRC downregulation, which in turn inactivates the NLRP3 inflammasome72. Corynoxine (Cory) is an indole alkaloid extracted from the plant, Uncaria macrophylla Wall. Cory suppresses the AKT-mTOR-GSK3β axis through activation of PP2A, thereby modulating mitochondrial dynamics and glucose metabolism in NSCLC73. Tetrandrine (TET) is a natural bisbenzylisoquinoline alkaloid isolated from Stephania tetrandra S. Moore that has antitumor potential for treating melanoma. TET directly targets SIRT5 and promotes SIRT5 degradation, which subsequently leads to mitochondrial dysfunction and the accumulation of ROS, thereby impeding the growth of melanoma74. Cyclovirobuxine D (CVB-D), which is extracted from Buxus microphylla, binds to LIF at Val145 and suppresses HCC via the LIF/p38MAPK/p62-regulated mitophagy75.

Sterides

Steroidal compounds possess diverse biological activities as a natural product and have the potential to be developed into novel anti-tumor agents. Ginsenoside Rh2 (G-Rh2) facilitates the transition from glycolysis to OXPHOS in NSCLC by targeting the HIF-1α/PDK4 axis, thereby inducing apoptosis in tumor cells76. G-Rh2 notably enhances the anti-tumor effect of sodium dichloroacetate (DCA) when used in combination and mitigates the toxicity. Ginsenoside CK (CK), a metabolite derived from ginsenosides Rb1 and Rb2, effectively inhibits the progression of TNBC associated with glutamine addiction. CK suppresses the expression of GLS1 in TNBC, decreasing cellular ATP synthesis, reducing glutamine amino acid levels, depleting GSH, increasing ROS accumulation, and finally inducing the apoptosis of TNBC cells77. Formosanin C (FC), a Paris polyphylla var. yunnanensis extract, stimulates apoptosis induced through mitochondrial dysfunction in lung cancer cells by impairing mitochondrial function and disrupting lactate transport via MCT4/CD147 inhibition78. Gracillin, a natural steroidal saponin, inhibits the function of mitochondrial complex II (CII) by abolishing succinate dehydrogenase (SDH) activity, thereby suppressing ATP synthesis and ROS generation in lung cancer cells79.

Terpenoids

Terpenoids constitute a large and structurally diverse class of natural products built from five-carbon isoprene units. These compounds exhibit diverse and important pharmacologic properties, highlighting the role in drug discovery and advances. For example, artesunate impairs mitochondrial function in CRC cells, causing mtROS overproduction, which subsequently activates p16/p21-dependent cellular senescence and autophagy80. Qian et al.81 demonstrated that tanshinone IIA (Tan IIA) treatment induces mitochondrial oxidative damage and mitochondria-mediated apoptosis in SW480 cells by activating INF2-associated mitochondrial fission and the Mst1-Hippo axis, thereby enhancing the antitumor efficacy of IL-2 therapy. Wang et al.82 identified demethylzeylasteral (T-96) based on a high-throughput drug screening system and proposed the anti-lung cancer potential. T-96 directly targets LRPPRC, an RNA-binding protein, inhibits the interaction of LRPPRC with mt-mRNAs, induces defects in the synthesis of OXPHOS complexes, and suppresses mitochondrial OXPHOS and ATP synthesis. Compound 2, extracted from the stem of Rubia cordifolia, facilitates amino acid reprogramming by inhibiting DCTPP, elevating ROS levels, and attenuating the NF-κB and AKT/mTOR/P70S6K signaling pathways in colon cancer cells83. Compound 2 demonstrates equivalent anti-colon cancer activity in vivo to fluorouracil, along with acceptable pharmacokinetic characteristics. The t1/2 value of Compound 2 in mice is 246.818 ± 161.955 min (i.p.) and 35.576 ± 3.067 min (i.v.). The Cmax value and tmax was 5050 ± 341 ng/mL (i.p.) for 264 min and 15776 ± 3750 ng/mL (i.v.) for 6 min. Ursolic acid (UA) elicits mitochondrial dysfunction by inhibiting the AMPK/mTOR/PGC-1α axis, further activating intrinsic apoptotic pathways, and enhances the chemosensitivity of DOX-resistant BC cells to DOX84. To enhance the efficacy of combination therapy, Guo et al.99 introduced TDTD@UA/HA micelles to target mitochondria, which possesses antitumor activity with good biosafety on the multidrug resistance (MDR) tumor-bearing mice model. Overall, this new therapeutic paradigm held great promise in overcoming MDR-related cancer.

Others

Curcumin, an inhibitor of various hallmarks of cancer, exerts anticancer effects through an influence on tumor metabolism. Curcumin attenuates the Warburg effect across multiple cancer cell lines through targeted silencing of PKM2 with the mTOR/HIF-1α signaling pathway likely playing a regulatory role in this process85. Another study revealed that curcumin can suppress gastric tumor growth by generating excessive ROS, which depletes POLG and mtDNA, and ultimately causing cellular bioenergetic dysfunction86. However, it should be noted that clinical evidence has indicated that long-term, high-dose supplementation with curcumin may elevate levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), potentially resulting in hepatic injury100. Gossypol, a natural compound derived from cottonseed, promotes tumor cell apoptosis by inhibiting anti-apoptotic proteins of the Bcl-2 family101. Additionally, gossypol can reverse irinotecan resistance in NSCLC cells by inhibiting mitochondrial OXPHOS102. However, severe off-target toxicity and insufficient efficacy forced withdrawal from clinical trials. Venetoclax, a highly selective Bcl-2 inhibitor designed based on gossypol, selectively targets cancer cells dependent on Bcl-2 protein for survival without inhibiting Bcl-xL or Mcl-1 proteins and has shown promising results in the clinical treatment of acute myeloid leukemia105. Concurrently, venetoclax attenuates OXPHOS in lymphoid malignancies, thereby facilitating mitochondria-mediated apoptotic execution in malignant lymphocytes106. Notably, enhancing target selectivity through structural optimization or delivery system compatibility is essential for precision cancer therapy.

Compounds in TCM

TCM compound prescriptions are a common form of clinical application of TCM. Many studies have confirmed the influence of compound prescriptions on tumor metabolism. QiDongNing (QDN), a refined compound preparation, is developed from the anticancer traditional medicine, Jinffu Kuang. Mechanically, QDN induces mitochondrial fission through the P53/DRP1 pathway, thereby triggering programmed cell death in lung cancer cells87. The modified Zuojin pill (SQQT) is a Chinese medicine formula used for treating gastric precancerous lesions. SQQT may regulate the expression of HIF-1α, which in turn influences the activity of downstream glycolytic enzymes and inhibits abnormal metabolism and proliferation of precancerous gastric cells88. The Xingxiao pill (XXP), a traditional formulation containing myrrh, frankincense, musk, and realgar, has advanced to phase II clinical trials for treating lung adenocarcinoma (LUAD) (ChiCTR2300075712). Recent findings by Fang et al.89 demonstrated that XXP functions through the bidirectional modulation of lipid metabolism. Specifically, XXP inhibits the production of unsaturated fatty acids and the breakdown of glycerophospholipids (GPLs), while promoting the metabolism of arachidonic acid (AA) through the action of cyclooxygenase. Notably, XXP targets the PLA2G4A-AA-GLI1/SOX2 axis, diminishing cancer stem cell stemness, offering a hopeful therapeutic approach. Additionally, analysis of TCGA indicates that patients with high expression of PLA2G4A may potentially benefit from XXP as an adjuvant therapy. The Shuang-Huang-Sheng-Bai (SHSB) formula is clinically utilized as an adjuvant therapy for cancer patients following chemotherapy. The key mechanism involves inhibition of ACLY enzyme activity and blocking acetyl-CoA biosynthesis90. A pilot clinical study showed that lung cancer patients with high ACLY expression often have a poorer prognosis, indicating that SHSB could potentially serve as a novel adjuvant therapeutic strategy targeting ACLY regulation. Wenxia Changfu Formula (WCF) reduces lipid accumulation and inhibits FAO by downregulating the PPAR-γ/CD36 pathway, thereby blocking the transformation of TAMs into a tumor-promoting phenotype91. The active components of WCF, 20(S)-ginsenoside Rg3 and ginsenoside Rg5, likely have a key role. Huachansu (HCS), a bioactive compound from toad skin, demonstrates significant antitumor effects in patient-derived organoids (PDO) and orthotopic CRC models by inhibiting tumor glycolysis via the PI3K/AKT pathway, downregulating enzymes, like GLUT3, HK2, PKM2, and LDHA92. However, the PI3K/AKT pathway in normal cardiomyocytes may be inadvertently blocked by high-dose or long-term use of HCS, which is a potential off-target effect that could induce cardiotoxicity. Thus, establishing tumor-targeted carriers for precise intervention and assessing multi-organ toxicity is urgently needed.

Nanocarrier-based drug delivery systems

With in-depth research on TCM, the design of innovative drug delivery systems with targeting capabilities, improved drug bioavailability, and reduced side effects holds importance for enhancing the TCM efficacy, achieving precise release and strengthening TCM intervention in tumors. Nanocarrier-based drug delivery systems are particularly promising. Li et al.93 proposed a novel “valve-closing” starvation strategy to increase the anticancer efficacy of curcumin, which involved eliminating the “valve” of glucose transport into tumor cells. This strategy is related to the packaging of genistein, a GLUT1 inhibitor, and curcumin into a stable nanocarrier, (Gen + Cur)@FOS, which is a novel organosilica hybrid micelle. In vitro and in vivo results have shown that (Gen + Cur)@FOS can significantly decrease glucose and ATP levels in cancer cells by suppressing GLUT1 expression, a process akin to “valve-closing,” thereby triggering a state of starvation in tumor cells. This approach decreased the resistance of cancer cells to chemotherapy-induced apoptosis. Moreover, the incorporation of triphenylphosphonium (TPP) ligands into nanocarriers can achieve more precise mitochondrial release and reduce off-target effects. For example, by tweaking OA with a tertiary amine, OA can be guided to the mitochondria. Triterpene nanoparticles mixed with mitochondria trigger pyroptosis, effectively eliminating glioblastoma cells94. Notably, OA nanoparticles are relatively large, which may not be optimal for penetrating brain tumors. Glucose-PEG-peptide-TPP-PAMAM-Paclitaxel was developed to address the issue of chemotherapy failure due to MDR in paclitaxel treatment95. The nanomedicine can be actively transported by tumor cells overexpressing GLUT1 and the PEG layer detaches from PAMAM after being cleaved by the upregulated MMP-2. The conjugate directly targets mitochondria via TPP, which facilitates the rapid release of paclitaxel. The high concentration of paclitaxel counteracts the efflux function of P-gp and acts on mitochondria to cut off the energy supply for P-gp, thereby overcoming MDR in cancer cells. A study has reported a synergistic therapeutic strategy targeting mitochondrial dysfunction in combination with hyperthermia, which enhances tumor ablation and inhibits tumor metastasis. The GLUT1-targeting and hypoxia-activated mitochondria-targeting PAMAM-based complex (Glu-PEG-Azo/Mito-Cel 808) targets tumor cells by utilizing GLUT1 as a ligand for active targeting96. PEG detaches from PAMAM once inside the hypoxic tumor environment, kicking off mitochondrial targeting. This process triggers a rapid release of celastrol into the mitochondrial matrix, while IR 808 generates intense heat under laser exposure, effectively curbing tumor growth and metastasis. Han et al.97 developed a multifunctional nanosensor (GO-HA/Cou-DHA/Apt) that can monitor the real-time translocation of Cyt c from mitochondria in living cells to evaluate the antitumor effect of DHA. The emission of green fluorescence demonstrated the release of the drug (Cou–DHA) and the mitochondrial targeting by this drug. Subsequently, Cyt c translocates from mitochondria to the cytosol, interacts with Apt to form an Apt-Cyt c complex, and triggers the release of Apt from GO and the emission of red fluorescence from Apt, indicating apoptosis.

Conclusions and prospects

Over the past few years the pivotal role of mitochondria in tumor metabolic reprogramming has been widely recognized107,108. Tumor cells continuously allocate the contributions of glycolysis and mitochondrial respiration under the stress of the microenvironment, dynamically adjust the availability of metabolic substrates, and utilize the signaling of metabolic products to regulate the metabolic network to meet the demands of rapid proliferation. In addition, the communication between mtDNA and the nucleus, as well as mitochondrial quality control, contribute to reshaping this process and are core mechanisms for maintaining tumor cell energy homeostasis and survival109. Targeting mitochondrial reprogramming is considered an important approach for treating malignant tumors. TCM exhibits good bioactivity and multi-target anti-tumor mechanisms in regulating mitochondrial energy production, catabolism, and mitochondrial quality control. For example, TCM components, such as berberine, curcumin, and baicalein, can simultaneously intervene in multiple pathways or targets, inhibiting the growth, proliferation, and metastasis of tumor cells67,71,86,110. Moreover, TCM often serves as an adjuvant in clinical treatment, not only enhancing the effects of other anti-tumor drugs but also counteracting the drug resistance of tumor cells. The application of nanotechnology in encapsulating and delivering TCM can significantly enhance the therapeutic effects and reduce side effects, providing strong support for the clinical translation of TCM.

Although research on anti-tumor TCM based on mitochondrial reprogramming shows promising prospects, with some drugs entering clinical studies, many challenges remain in the process of converting natural compounds into therapeutic agents. First, the complex composition of TCM and the unclear multi-pathway coordination mechanisms require further basic and clinical research for confirmation. Second, tumors of different tissue origins exhibit distinct metabolic characteristics due to the metabolic features of cells and differences in the TME, significantly affecting drug responsiveness. Therefore, precision TCM based on metabolic typing is essential for breaking through the treatment of cross-cancer metabolic reprogramming. Moreover, with the increasing market demand and diversification of herbal sources, quality control of TCM has become an issue that cannot be ignored. Chinese scholars have constructed the TCM Plant Genome Integrated Database (TCMPG), which has significantly advanced the study of medicinal plants through multi-high-throughput sequencing technologies, which has an important role in the development of TCM. Finally, TCM, which has both traditional Chinese medicine attributes and pharmaceutical properties, has a low degree of standardization and urgently needs to establish a sound evaluation and regulatory system that meets the characteristics of TCM.

Conflict of interest statement

No potential conflicts of interest are disclosed.

Author contributions

Conceived and designed the analysis: Siyi Ma, Jiarong Li, Bingjie Hao and Lihong Fan.

Wrote the paper: Siyi Ma.

Revised the paper: Bingjie Hao and Lihong Fan.

  • Received May 8, 2025.
  • Accepted August 13, 2025.

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