Cancer Stem Cells Metabolism Research Articles

Targeting Lipid Metabolism in Cancer Stem Cells for Anticancer Treatment.

Cancer stem cells (CSCs), or tumor-initiating cells (TICs), are small subpopulations (0.0001-0.1%) of cancer cells that are crucial for cancer relapse and therapy resistance. The elimination of each CSC is essential for achieving long-term remission. Metabolic reprogramming, particularly lipids, has a significant impact on drug efficacy by influencing drug diffusion, altering membrane permeability, modifying mitochondrial function, and adjusting the lipid composition within CSCs. These changes contribute to the development of chemoresistance in various cancers. The intricate relationship between lipid metabolism and drug resistance in CSCs is an emerging area of research, as different lipid species play essential roles in multiple stages of autophagy. However, the link between autophagy and lipid metabolism in the context of CSC regulation remains unclear. Understanding the interplay between autophagy and lipid reprogramming in CSCs could lead to the development of new approaches for enhancing therapies and reducing tumorigenicity in these cells. In this review, we explore the latest findings on lipid metabolism in CSCs, including the role of key regulatory enzymes, inhibitors, and the contribution of autophagy in maintaining lipid homeostasis. These recent findings may provide critical insights for identifying novel pharmacological targets for effective anticancer treatment.

Fatty acid synthase inhibitor cerulenin hinders liver cancer stem cell properties through FASN/APP axis as novel therapeutic strategies

Hepatocellular carcinoma (HCC) poses significant treatment challenges due to high postoperative recurrence rates and the limited effectiveness of targeted medications. Researchers have identified the unique metabolic profiles of cancer stem cells (CSCs) as the primary drivers of cancer recurrence, metastasis, and drug resistance. Therefore, to address the therapeutic conundrum, this study focused on rewinding metabolic reprogramming of CSCs as a novel therapeutic strategy. HCC CSCs exhibited elevated fatty acid (FA) metabolism compared with parental cells. To specifically target FA metabolism in CSCs, we utilized cerulenin, a fatty acid synthase (FASN) inhibitor. Surprisingly, cerulenin can diminish CSC-like characteristics, including stemness gene expression, spherogenicity, tumorigenicity, and metastatic potential. In addition, sorafenib, a multikinase inhibitor used as targeted therapy for advanced HCC, was employed in combination with cerulenin, demonstrating a great synergistic effect, particularly in CSCs. Importantly, our RNA sequencing analysis disclosed that the amyloid protein precursor (APP) is a crucial downstream effector of FASN in regulating CSC properties. We found that APP plays a crucial role in CSCs’ characteristics that can be inhibited by cerulenin. By focusing on FA metabolism, this study identified the FASN/APP axis as a viable target to develop a more potent therapy strategy for advanced HCC.

Cancer stem cells: a target for overcoming therapeutic resistance and relapse.

Cancer stem cells (CSCs) are a small subset of cells in cancers that are thought to initiate tumorous transformation and promote metastasis, recurrence, and resistance to treatment. Growing evidence has revealed the existence of CSCs in various types of cancers and suggested that CSCs differentiate into diverse lineage cells that contribute to tumor progression. We may be able to overcome the limitations of cancer treatment with a comprehensive understanding of the biological features and mechanisms underlying therapeutic resistance in CSCs. This review provides an overview of the properties, biomarkers, and mechanisms of resistance shown by CSCs. Recent findings on metabolic features, especially fatty acid metabolism and ferroptosis in CSCs, are highlighted, along with promising targeting strategies. Targeting CSCs is a potential treatment plan to conquer cancer and prevent resistance and relapse in cancer treatment.

Regulating Lipid Metabolism via Mitochondrial Dynamics in Tongue Squamous Cell Carcinoma Cancer Stem Cells.

Cancer stem cells (CSCs) are a sub-population of cancer cells present in many kinds of malignant tumors that have the potential for self-proliferation and differentiation. These cells have been demonstrated as the main cause of tumor recurrence and metastasis. Strong evidence indicates that CSCs prefer reprogrammed fatty acid β-oxidation over oxidative phosphorylation for sustaining energy supply. Although mitochondrial dynamics participate in the regulation of cancer stemness, the correlation between the inhibition of mitochondrial fission and the regulation of lipid metabolism in CSCs remains poorly understood. The human tongue squamous cell carcinoma (TSCC) cell lines CAL27 and SAS were used to obtain the CSCs by 3D Spheroid Culture. Then,western blot methods, RT-PCR and flow cytometry analysis were used to identify the TSCC CSCs. Next, Immunofluorescence method, transmission electron microscopy detection and western blot methods were used to evaluate the mitochondrial morphology and the quantity of lipid droplets (LDs). Lastly, lipidomic analysis was applied to explored the lipidomic alterations of TSCC CSCs with different mitochondrial morphology. Here, we show that the quantity of lipid droplets containing intracellular triglyceride (TG) can be decreased by regulating mitochondrial morphology. Lipidomic analysis using ultraperformance liquid chromatography-mass spectrometry (UPLC-MS) also compared alterations in lipid metabolites in tongue squamous cell carcinoma (TSCC) CSCs, TSCC cells (non-CSCs), and CSCs with different mitochondrial morphology. Discriminant lipids of statistical significance were successfully annotated, including phosphatidylcholines (PCs), phosphatidylethanolamines (PEs), sphingomyelins (SMs), triacylglycerols (TGs), phosphatidylglycerols (PGs), phosphatidylserines (PSs), lysophosphatidylcholines (LPCs), and lysophosphatidylethanolamines (LPEs). This study provides a deeper insight into the alterations of lipid metabolism associated with TSCC CSCs, non-CSCs and CSCs regulated by mitochondrial dynamics and thus serves as a guide toward novel targeted therapies.

Metabolomics, Transcriptome and Single-Cell RNA Sequencing Analysis of the Metabolic Heterogeneity between Oral Cancer Stem Cells and Differentiated Cancer Cells.

Understanding the distinct metabolic characteristics of cancer stem cells (CSC) may allow us to better cope with the clinical challenges associated with them. In this study, OSCC cell lines (CAL27 and HSC3) and multicellular tumor spheroid (MCTS) models were used to generate CSC-like cells. Quasi-targeted metabolomics and RNA sequencing were used to explore altered metabolites and metabolism-related genes. Pathview was used to display the metabolites and transcriptome data in a KEGG pathway. The single-cell RNA sequencing data of six patients with oral cancer were analyzed to characterize in vivo CSC metabolism. The results showed that 19 metabolites (phosphoethanolamine, carbamoylphosphate, etc.) were upregulated and 109 metabolites (2-aminooctanoic acid, 7-ketocholesterol, etc.) were downregulated in both MCTS cells. Integration pathway analysis revealed altered activity in energy production (glycolysis, citric cycle, fatty acid oxidation), macromolecular synthesis (purine/pyrimidine metabolism, glycerophospholipids metabolism) and redox control (glutathione metabolism). Single-cell RNA sequencing analysis confirmed altered glycolysis, glutathione and glycerophospholipid metabolism in in vivo CSC. We concluded that CSCs are metabolically inactive compared with differentiated cancer cells. Thus, oral CSCs may resist current metabolic-related drugs. Our result may be helpful in developing better therapeutic strategies against CSC.

Lipid metabolism dynamics in cancer stem cells: potential targets for cancers.

Cancer stem cells (CSCs) represent a small subset of heterogeneous cells within tumors that possess the ability to self-renew and initiate tumorigenesis. They serve as potential drivers for tumor initiation, metastasis, recurrence, and drug resistance. Recent research has demonstrated that the stemness preservation of CSCs is heavily reliant on their unique lipid metabolism alterations, enabling them to maintain their own environmental homeostasis through various mechanisms. The primary objectives involve augmenting intracellular fatty acid (FA) content to bolster energy supply, promoting β-oxidation of FA to optimize energy utilization, and elevating the mevalonate (MVA) pathway for efficient cholesterol synthesis. Additionally, lipid droplets (LDs) can serve as alternative energy sources in the presence of glycolysis blockade in CSCs, thereby safeguarding FA from peroxidation. Furthermore, the interplay between autophagy and lipid metabolism facilitates rapid adaptation of CSCs to the harsh microenvironment induced by chemotherapy. In this review, we comprehensively review recent studies pertaining to lipid metabolism in CSCs and provide a concise overview of the indispensable role played by LDs, FA, cholesterol metabolism, and autophagy in maintaining the stemness of CSCs.

Hyperbaric Oxygen Boosts Antitumor Efficacy of Copper-Diethyldithiocarbamate Nanoparticles against Pancreatic Ductal Adenocarcinoma by Regulating Cancer Stem Cell Metabolism.

Cuproptosis-based cancer nanomedicine has received widespread attention recently. However, cuproptosis nanomedicine against pancreatic ductal adenocarcinoma (PDAC) is severely limited by cancer stem cells (CSCs), which reside in the hypoxic stroma and adopt glycolysis metabolism accordingly to resist cuproptosis-induced mitochondria damage. Here, we leverage hyperbaric oxygen (HBO) to regulate CSC metabolism by overcoming tumor hypoxia and to augment CSC elimination efficacy of polydopamine and hydroxyethyl starch stabilized copper-diethyldithiocarbamate nanoparticles (CuET@PH NPs). Mechanistically, while HBO and CuET@PH NPs inhibit glycolysis and oxidative phosphorylation, respectively, the combination of HBO and CuET@PH NPs potently suppresses energy metabolism of CSCs, thereby achieving robust tumor inhibition of PDAC and elongating mice survival importantly. This study reveals novel insights into the effects of cuproptosis nanomedicine on PDAC CSC metabolism and suggests that the combination of HBO with cuproptosis nanomedicine holds significant clinical translation potential for PDAC patients.

Metabolic Profiles of Cancer Stem Cells and Normal Stem Cells and Their Therapeutic Significance.

Cancer stem cells (CSCs) are a rare cancer cell population, responsible for the facilitation, progression, and resistance of tumors to therapeutic interventions. This subset of cancer cells with stemness and tumorigenic properties is organized in niches within the tumor microenvironment (TME) and presents altered regulation in a variety of metabolic pathways, including glycolysis, oxidative phosphorylation (OXPHOS), as well as lipid, amino acid, and iron metabolism. CSCs exhibit similarities as well as differences when comparedto normal stem cells, but also possess the ability of metabolic plasticity. In this review, we summarize the metabolic characteristics of normal, non-cancerous stem cells and CSCs. We also highlight the significance and implications of interventions targeting CSC metabolism to potentially achieve more robust clinical responses in the future.

Oxamate enhances the efficacy of CAR-T therapy against glioblastoma via suppressing ectonucleotidases and CCR8 lactylation

BackgroundChimeric antigen receptor (CAR)-T immunotherapy fails to treat solid tumors due in part to immunosuppressive microenvironment. Excess lactate produced by tumor glycolysis increases CAR-T immunosuppression. The mechanism of lactate inducing the formation of immunosuppressive microenvironment remains to be further explored.MethodsImmunocyte subpopulations and molecular characteristics were analyzed in the orthotopic xenografts of nude mice using flow cytometry assay and immunohistochemical staining after oxamate, a lactate dehydrogenase A (LDHA) inhibitor, and control T or CAR-T cells injection alone or in combination. RT-qPCR, western blot, flow cytometry, immunofluorescence, luciferase reporter assay, chromatin immunoprecipitation and ELISA were performed to measure the effect of lactate on the regulation of CD39, CD73 and CCR8 in cultured glioma stem cells, CD4 + T cells or macrophages.ResultsOxamate promoted immune activation of tumor-infiltrating CAR-T cells through altering the phenotypes of immune molecules and increasing regulatory T (Treg) cells infiltration in a glioblastoma mouse model. Lactate accumulation within cells upregulated CD39, CD73 and CCR8 expressions in both lactate-treated cells and glioma stem cells-co-cultured CD4 + T cells and macrophages, and intracellular lactate directly elevated the activities of these gene promotors through histone H3K18 lactylation.ConclusionsUtilizing lactate generation inhibitor not only reprogramed glucose metabolism of cancer stem cells, but also alleviated immunosuppression of tumor microenvironment and reduced tumor-infiltrating CAR-Treg cells, which may be a potential strategy to enhance CAR-T function in glioblastoma therapy.

Regulation of iron metabolism and ferroptosis in cancer stem cells.

The ability of cancer stem cells (CSCs) to self-renew, differentiate, and generate new tumors is a significant contributor to drug resistance, relapse, and metastasis. Therefore, the targeting of CSCs for treatment is particularly important. Recent studies have demonstrated that CSCs are more susceptible to ferroptosis than non-CSCs, indicating that this could be an effective strategy for treating tumors. Ferroptosis is a type of programmed cell death that results from the accumulation of lipid peroxides caused by intracellular iron-mediated processes. CSCs exhibit different molecular characteristics related to iron and lipid metabolism. This study reviews the alterations in iron metabolism, lipid peroxidation, and lipid peroxide scavenging in CSCs, their impact on ferroptosis, and the regulatory mechanisms underlying iron metabolism and ferroptosis. Potential treatment strategies and novel compounds targeting CSC by inducing ferroptosis are also discussed.

Eradicating the tumor "seeds": nanomedicines-based therapies against cancer stem cells.

Cancer stem cells (CSCs), a small subpopulation of cells with high tumorigenesis and strong intrinsic drug resistance, exhibit self-renewal and differentiation abilities. CSCs play a crucial role in tumor progression, drug resistance, recurrence and metastasis,and conventional therapy is not enough to eradicate them. Therefore, developing novel therapies targeting CSCs to increase drug sensitivity and preventing relapse is essential. The objective of this review is to present nanotherapies that target and eradicate the tumor "seeds". Evidence was collected and sorted from the literature ranging from 2000 to 2022, using appropriate keywords and key phrases as search terms within scientific databases such as Web of Science, PubMed and Google Scholar. Nanoparticle drug delivery systems have been successfully applied to gain longer circulation time, more precise targeting capability and better stability during cancer treatment. Nanotechnology-based strategies that have been used to target CSCs, include (1) encapsulating small molecular drugs and genes by nanotechnology, (2) targeting CSC signaling pathways, (3) utilizing nanocarriers targeting for specific markers of CSCs, (4) improving photothermal/ photodynamic therapy (PTT/PDT), 5)targeting the metabolism of CSCs and 6) enhancing nanomedicine-aided immunotherapy. This review summarizes the biological hallmarks and markers of CSCs, and the nanotechnology-based therapies to kill them. Nanoparticle drug delivery systems are appropriate means for delivering drugs to tumors through enhanced permeability and retention (EPR) effect. Furthermore, surface modification with special ligands or antibodies improves the recognition and uptake of tumor cells or CSCs. It is expected that this review can offer insights into features of CSCs and the exploration of targeting nanodrug delivery systems.

Anticancer Potential of Apigenin and Isovitexin with Focus on Oncogenic Metabolism in Cancer Stem Cells

It has been demonstrated that cancer stem cells (CSCs) go through metabolic changes that differentiate them from non-CSCs. The altered metabolism of CSCs plays a vital role in tumor initiation, progression, immunosuppression, and resistance to conventional therapy. Therefore, defining the role of CSC metabolism in carcinogenesis has emerged as a main focus in cancer research. Two natural flavonoids, apigenin and isovitexin, have been shown to act synergistically with conventional chemotherapeutic drugs by sensitizing CSCs, ultimately leading to improved therapeutic efficacy. The aim of this study is to present a critical and broad evaluation of the anti-CSC capability of apigenin and isovitexin in different cancers as novel and untapped natural compounds for developing drugs. A thorough review of the included literature supports a strong association between anti-CSC activity and treatment with apigenin or isovitexin. Additionally, it has been shown that apigenin or isovitexin affected CSC metabolism and reduced CSCs through various mechanisms, including the suppression of the Wnt/β-catenin signaling pathway, the inhibition of nuclear factor-κB protein expression, and the downregulation of the cell cycle via upregulation of p21 and cyclin-dependent kinases. The findings of this study demonstrate that apigenin and isovitexin are potent candidates for treating cancer due to their antagonistic effects on CSC metabolism.

Glutamine Metabolism in Cancer Stem Cells: A Complex Liaison in the Tumor Microenvironment.

In this review we focus on the role of glutamine in control of cancer stem cell (CSC) fate. We first provide an overview of glutamine metabolism, and then summarize relevant studies investigating how glutamine metabolism modulates the CSC compartment, concentrating on solid tumors. We schematically describe how glutamine in CSC contributes to several metabolic pathways, such as redox metabolic pathways, ATP production, non-essential aminoacids and nucleotides biosynthesis, and ammonia production. Furthermore, we show that glutamine metabolism is a key regulator of epigenetic modifications in CSC. Finally, we briefly discuss how cancer-associated fibroblasts, adipocytes, and senescent cells in the tumor microenvironment may indirectly influence CSC fate by modulating glutamine availability. We aim to highlight the complexity of glutamine's role in CSC, which supports our knowledge about metabolic heterogeneity within the CSC population.

Metabolism in Cancer Stem Cells: Targets for Clinical Treatment.

Cancer stem cells (CSCs) have high tumorigenicity, high metastasis and high resistance to treatment. They are the key factors for the growth, metastasis and drug resistance of malignant tumors, and are also the important reason for the occurrence and recurrence of tumors. Metabolic reprogramming refers to the metabolic changes that occur when tumor cells provide sufficient energy and nutrients for themselves. Metabolic reprogramming plays an important role in regulating the growth and activity of cancer cells and cancer stem cells. In addition, the immune cells or stromal cells in the tumor microenvironment (TME) will change due to the metabolic reprogramming of cancer cells. Summarizing the characteristics and molecular mechanisms of metabolic reprogramming of cancer stem cells will provide new ideas for the comprehensive treatment of malignant tumors. In this review, we summarized the changes of the main metabolic pathways in cancer cells and cancer stem cells.

Targeted Anti-Mitochondrial Therapy: The Future of Oncology.

Like living organisms, cancer cells require energy to survive and interact with their environment. Mitochondria are the main organelles for energy production and cellular metabolism. Recently, investigators demonstrated that cancer cells can hijack mitochondria from immune cells. This behavior sheds light on a pivotal piece in the cancer puzzle, the dependence on the normal cells. This article illustrates the benefits of new functional mitochondria for cancer cells that urge them to hijack mitochondria. It describes how functional mitochondria help cancer cells’ survival in the harsh tumor microenvironment, immune evasion, progression, and treatment resistance. Recent evidence has put forward the pivotal role of mitochondria in the metabolism of cancer stem cells (CSCs), the tumor components responsible for cancer recurrence and metastasis. This theory highlights the mitochondria in cancer biology and explains how targeting mitochondria may improve oncological outcomes.

Impairment of Glucose Metabolism and Suppression of Stemness in MCF-7/SC Human Breast Cancer Stem Cells by Nootkatone.

Targeting cancer stem cell metabolism has emerged as a promising therapeutic strategy for cancer treatment. Breast cancer stem cells (BCSCs) exert distinct metabolism machinery, which plays a major role in radiation and multidrug resistance. Therefore, exploring the mechanisms involved in energy utilization of BCSCs could improve the effectiveness of therapeutic strategies aimed at their elimination. This study was conducted to clarify the glucose metabolism machinery and the function of nootkatone, a bioactive component of grapefruit, in regulating glucose metabolism and stemness characteristics in human breast carcinoma MCF-7 stem cells (MCF-7SCs). In vivo experiments, transcriptomic analysis, seahorse XF analysis, MTT assay, Western blotting, mammosphere formation, wound healing, invasion assay, flow cytometric analysis, reverse transcription-quantitative polymerase chain reaction, and in silico docking experiments were performed. MCF-7SCs showed a greater tumorigenic capacity and distinct gene profile with enrichment of the genes involved in stemness and glycolysis signaling pathways compared to parental MCF-7 cells, indicating that MCF-7SCs use glycolysis rather than oxidative phosphorylation (OXPHOS) for their energy supply. Nootkatone impaired glucose metabolism through AMPK activation and reduced the stemness characteristics of MCF-7SCs. In silico docking analysis demonstrated that nootkatone efficiently bound to the active site of AMPK. Therefore, this study indicates that regulation of glucose metabolism through AMPK activation could be an attractive target for BCSCs.

Respiratory chain complex I is related to oxidative phosphorylation in gastric cancer stem cells

Background: Cancer stem cells (CSCs) are the main cause of resistance to anti-cancer drug therapy and distant metastasis of tumors, including gastric cancer. The metabolism of CSCs is an important factor in the maintenance of its stemness. This study is intended to explore the role of oxidative phosphorylation in gastric CSCs.
 Methods: EpCAM+CD44+ gastric CSCs were sorted from the SGC-7901 cell line. The oxidative phosphorylation and glycolysis were determined by Seahorse experiment, and the oxygen consumption of cells was determined by Clark’s oxygen electrodes. Gene expression and protein levels of mitochondrial proteins belonging to five respiratory chain complexes were checked. Phenformin and siRNA-NDUFB8 were used to inhibit respiratory chain complex I to explore the biological effect of enhanced oxidation phosphorylation in gastric CSCs. Cell migration capacity, proliferation ability, and vascular endothelial growth factor (VEGF) levels were also evaluated.
 Results: Compared with control cells, the oxidation phosphorylation in mitochondria increased in EpCAM+CD44+ gastric CSCs, although the respiration level remained the same, and no significant changes were observed in glycolysis. Moreover, mRNA and protein expression levels of NDUFB8 in complex I were significantly increased. However, oxidative phosphorylation decreased in EpCAM+CD44+ cells after the treatment of phenformin and siRNA-NDUFB8 compared to the untreated cells. siRNA for NDFUB8 and phenformin inhibition also decreased the ability of cell migration, cell proliferation, as well as the VEGF secretion of gastric CSCs.
 Conclusion: These results suggest that the increased oxidative phosphorylation was related to respiratory chain complex I and NDUFB8 in gastric CSCs.

Molecular Radiotherapy with 177Lu-Immunoliposomes Induces Cytotoxicity in Mesothelioma Cancer Stem Cells In Vitro.

Malignant mesothelioma (MM) is a lethal tumor originating in the mesothelium with high chemotherapeutic resistance. Cancer stem cells (CSCs) persist in tumors and are critical targets responsible for tumor resistance and recurrence. The identification and characterization of CSCs may help develop effective treatment for MM. The objective of this study was to evaluate the therapeutic effect of molecular targeted radiotherapy by 177Lu-labeled immunoliposomes (177Lu-ILs) on CSCs of mesothelioma. MM CSCs were sorted based on CD26/CD24 expression level and their functional significances were established by small interference RNA. CSC potential of MM was evaluated for drug resistance, cell invasion, and cell growth rate in vitro. CSC metabolism was evaluated with the uptake of 18F-FDG. Therapeutic effects of 177Lu-labeled immunoliposomes targeting CD26 and CD24 were evaluated in vitro through proliferation and apoptotic assays. CSCs sorted from H28 cells exhibited significant drug resistance and enhanced proliferative activity as well as increased metabolism indicated by higher 18F-FDG uptake. Treatment with 177Lu-ILs, compared with 177Lu-CL and ILs, showed enhanced therapeutic effects on inhibition of proliferation, up-regulation of apoptosis, and suppression of CD26 and CD24 expression. Thus, our results suggest that molecular radiotherapy targeting both CD26 and CD24 could be a promising approach for CSC-targeting therapy for MM.

Lipid metabolism of cancer stem cells.

Cancer stem cells (CSCs), also termed cancer-initiating cells, are a special subset of cells with high self-replicating and self-renewing abilities that can differentiate into various cell types under certain conditions. A number of studies have demonstrated that CSCs have distinct metabolic properties. The reprogramming of energy metabolism enables CSCs to meet the needs of self-renewal and stemness maintenance. Increasing evidence supports the view that alterations in lipid metabolism, including an increase in fatty acid (FA) uptake, de novo lipogenesis, formation of lipid droplets and mitochondrial FA oxidation, are involved in CSC regulation. In the present review, the metabolic characteristics of CSCs, particularly in lipid metabolism, were summarized. In addition, the potential mechanisms of CSC lipid metabolism in treatment resistance were discussed. Given their significance in cancer biology, targeting CSC metabolism may serve an important role in future cancer treatment.

Targeting the metabolism of cancer stem cells by energy disruptor molecules

Cancer stem cells (CSCs) have been identified in various tumor types. CSCs are believed to contribute to tumor metastasis and resistance to conventional therapy. So targeting these cells could be an effective strategy to eliminate tumors and a promising new type of cancer treatment. Alterations in metabolism play an essential role in CSC biology and their resistance to treatment. The metabolic properties pathways in CSCs are different from normal cells, and to some extent, are different from regular tumor cells. Interestingly, CSCs can use other nutrients for their metabolism and growth. The different metabolism causes increased sensitivity of CSCs to agents that disrupt cellular homeostasis. Compounds that interfere with the central metabolic pathways are known as energy disruptors and can reduce CSC survival. This review highlights the differences between regular cancer cells and CSC metabolism and discusses the action mechanisms of energy disruptors at the cellular and molecular levels.