Impaired TGF-ß signaling via AHNAK family mutations elicits an esophageal cancer subtype with sensitivities to genotoxic therapy and immunotherapy.

BACKGROUND: Genome instability (GI) is a hallmark of esophageal squamous cell carcinoma (ESCC) while factors affecting GI remain unclear. METHODS: Here, we aimed to characterize genomic events representing specific mechanisms of GI based on 201 ESCC samples and validated our findings at the patient, single-cell and cancer cell-line levels, including a newly generated multi-omics dataset of the trial NCT04006041. RESULTS: A two-gene (AHNAK and AHNAK2) mutation signature was identified to define the "AHNAK1/2-mutant" cancer subtype. Single-cell-assisted multi-omics analysis showed that this subtype had a higher neoantigen load, active antigen presentation, and proficient CD8 + T cell infiltrations, which were validated at pan-cancer levels. Mechanistically, AHNAK1/2-mutant ESCC was characterized by impaired response of TGF-ß and the inefficient alternative end-join repair (Alt-EJ) that might promote GI. Knockdown of AHNAK in ESCC cell lines resulted in more Alt-EJ events and increased sensitivities to cisplatin. Furthermore, this two-gene signature accurately predicted better responses to DNA-damaging therapy in various clinical settings (HR ≈ 0.25). The two-gene signature predicted higher pCR rates in ESCCs receiving neoadjuvant immunotherapy-involved treatment. Finally, a molecular classification scheme was built and outperformed established molecular typing models in the prognosis stratification of ESCC patients. CONCLUSION: Our study extended our understanding of the AHNAK family in promoting GI and selecting treatment responders of ESCC.

High-yield porphyrin production through metabolic engineering and biocatalysis.

Porphyrins and their derivatives find extensive applications in medicine, food, energy and materials. In this study, we produced porphyrin compounds by combining Rhodobacter sphaeroides as an efficient cell factory with enzymatic catalysis. Genome-wide CRISPRi-based screening in R. sphaeroides identifies hemN as a target for improved coproporphyrin III (CPIII) production, and exploiting phosphorylation of PrrA further improves the production of bioactive CPIII to 16.5 g L-1 by fed-batch fermentation. Subsequent screening and engineering high-activity metal chelatases and coproheme decarboxylase results in the synthesis of various metalloporphyrins, including heme and the anti-tumor agent zincphyrin. After pilot-scale fermentation (200 L) and setting up the purification process for CPIII (purity >95%), we scaled up the production of heme and zincphyrin through enzymatic catalysis in a 5-L bioreactor, with CPIII achieving respective enzyme conversion rates of 63% and 98% and yielding 10.8 g L-1 and 21.3 g L-1, respectively. Our strategy offers a solution for high-yield bioproduction of heme and other valuable porphyrins with substantial industrial and medical applications.

Nicotine aggravates pancreatic fibrosis in mice with chronic pancreatitis via mitochondrial calcium uniporter.

INTRODUCTION: This study aimed to investigate the effects of nicotine on the activation of pancreatic stellate cells (PSCs) and pancreatic fibrosis in chronic pancreatitis (CP), along with its underlying molecular mechanisms. METHODS: This was an in vivo and in vitro study. In vitro, PSCs were cultured to study the effects of nicotine on their activation and oxidative stress. Transcriptome sequencing was performed to identify potential signaling pathways involved in nicotine action. And the impact of nicotine on mitochondrial Ca2+ levels and Ca2+ transport-related proteins in PSCs was analyzed. The changes in nicotine effects were observed after the knockdown of the mitochondrial calcium uniporter (MCU) in PSCs. In vivo experiments were conducted using a mouse model of CP to assess the effects of nicotine on pancreatic fibrosis and oxidative stress in mice. The alterations in nicotine effects were observed after treatment with the MCU inhibitor Ru360. RESULTS: In vitro experiments demonstrated that nicotine promoted PSCs activation, characterized by increased cell proliferation, elevated α-SMA and collagen expression. Nicotine also increased the production of reactive oxygen species (ROS) and cellular malondialdehyde (MDA), exacerbating oxidative stress damage. Transcriptome sequencing revealed that nicotine may exert its effects through the calcium signaling pathway, and it was verified that nicotine elevated mitochondrial Ca2+ levels and upregulated MCU expression. Knockdown of MCU reversed the effects of nicotine on mitochondrial calcium homeostasis, improved mitochondrial oxidative stress damage and structural dysfunction, thereby alleviating the activation of PSCs. In vivo validation experiments showed that nicotine significantly aggravated pancreatic fibrosis in CP mice, promoted PSCs activation, exacerbated pancreatic tissue oxidative stress, and increased MCU expression. However, treatment with Ru360 significantly mitigated these effects. CONCLUSIONS: This study confirms that nicotine upregulates the expression of MCU, leading to mitochondrial calcium overload and exacerbating oxidative stress in PSCs, and ultimately promoting PSCs activation and exacerbating pancreatic fibrosis in CP.

13-Oxyingenol-dodecanoate inhibits the growth of non-small cell lung cancer cells by targeting ULK1.

Lung cancer is the leading cause of cancer deaths worldwide. Non-small cell lung cancer (NSCLC) accounts for 80-85% of all lung cancers. Euphorbia kansui yielded 13-oxyingenol-dodecanoate (13OD), an ingenane-type diterpenoid, which had a strong cytotoxic effect on NSCLC cells. The underlying mechanism and potential target, however, remained unknown. The study found that 13OD effectively inhibited the cell proliferation and colony formation of NSCLC cells (A549 and H460 cells), with less toxicity in normal human lung epithelial BEAS-2B cells. Moreover, 13OD can cause mitochondrial dysfunction, and apoptosis in NSCLC cells. Mechanistically, the transcriptomics results showed that differential genes were mainly enriched in the mTOR and AMPK signaling pathways, which are closely related to cellular autophagy, the related indicators were subsequently validated. Additionally, bafilomycin A1 (Baf A1), an autophagy inhibitor, reversed the mitochondrial damage caused by 13OD. Furthermore, the Omics and Text-based Target Enrichment and Ranking (OTTER) method predicted ULK1 as a potential target of 13OD against NSCLC cells. This hypothesis was further confirmed using molecular docking, the cellular thermal shift assay (CETSA), and Western blot analysis. Remarkably, ULK1 siRNA inhibited 13OD's toxic activity in NSCLC cells. In line with these findings, 13OD was potent and non-toxic in the tumor xenograft model. Our findings suggested a possible mechanism for 13OD's role as a tumor suppressor and laid the groundwork for identifying targets for ingenane-type diterpenoids.

13-oxyingenol dodecanoate derivatives induce mitophagy and ferroptosis through targeting TMBIM6 as potential anti-NSCLC agents.

Ingenol diterpenoids continue to attract the attention for their extensive biological activity and novel structural features. To further explore this type of compound as anti-tumor agent, 13-oxyingenol dodecanoate (13-OD) was prepared by a standard chemical transformation from an Euphorbia kansui extract, and 29 derivatives were synthesized through parent 13-OD. Their inhibition activities against different types of cancer were screened and some derivatives showed superior anti-non-small cell lung cancer (NSCLC) cells cytotoxic potencies than oxaliplatin. In addition, TMBIM6 was identified as a crucial cellular target of 13-OD using ABPP target angling technique, and subsequently was verified by pull down, siRNA interference, BLI and CETSA assays. With modulating the function of TMBIM6 protein by 13-OD and its derivatives, Ca2+ release function was affected, causing mitochondrial Ca2+ overload, depolarisation of membrane potential. Remarkably, 13-OD, B6, A2, and A10-2 induced mitophagy and ferroptosis. In summary, our results reveal that 13-OD, B6, A2, and A10-2 holds great potential in developing anti-tumor agents for targeting TMBIM6.

Exploring the mechanism of daphne-type diterpenes against gastric cancer cells.

Gastric cancer is one of the common malignant tumors. It is reported that daphne-type diterpenes have inhibitory effects on gastric cancer cells, but the mechanism is still unknown. To explore the detailed mechanism of the anticancer effect of daphne-type diterpenes, we carried out an integrated network pharmacology prediction study and selected an effective component (yuanhuacine, YHC) for the following validation in silico and in vitro. The result showed that daphne-type diterpenes exerted an anti-tumor effect by targeting proto-oncogene tyrosine-protein kinase SRC as well as regulating the Ras/MAPK signaling pathway, which caused the apoptosis and mitochondrial damage in gastric cancer cells.

Development of Antibacterial Peptides with Membrane Disruption and Folate Pathway Inhibitory Activities against Methicillin-Resistant Staphylococcus aureus.

Antimicrobial peptides (AMPs) offer an opportunity to overcome multidrug resistance. Here, novel peptides were designed based on AMP fragments derived from sea cucumber hemolytic lectin to enhance anti-methicillin-resistant Staphylococcus aureus (MRSA) activity with less side effects. Two designed peptides, CGS19 (LARVARRVIRFIRRAW-NH2) and CGS20 (RRRLARRLIFFIRRAW-NH2), exhibited strong antibacterial activities against clinically isolated MRSA with MICs of 3-6 µM, but no obvious cytotoxicity was observed. Consistently, CGS19 and CGS20 exerted rapid bactericidal activity and effectively induced 5.9 and 5.8 log reduction of MRSA counts in mouse subeschar, respectively. Further, CGS19 and CGS20 kill bacteria not only through disturbing membrane integrity but also by binding formate-tetrahydrofolate ligase, a key enzyme in the folate metabolism pathway, thereby inhibiting the folate pathway of MRSA. CGS19 and CGS20 are promising lead candidates for drug development against MRSA infection. The dual mechanisms on the identical peptide sequence or scaffold might be an underappreciated manner of treating life-threatening pathogens.

Tetrahydropalmatine promotes random skin flap survival in rats via the PI3K/AKT signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Flap necrosis is the most common complication after flap transplantation, but its prevention remains challenging. Tetrahydropalmatine (THP) is the main bioactive component of the traditional Chinese medicine Corydalis yanhusuo, with effects that include the activation of blood circulation, the promotion of qi, and pain relief. Although THP is widely used to treat various pain conditions, its impact on flap survival is unknown. AIM OF THE STUDY: To explore the effect and mechanism of THP on skin flap survival. MATERIALS AND METHODS: In this study, we established a modified McFarlane flap model, and the flap survival rate was calculated after 7 days of THP treatment. Angiogenesis and blood perfusion were evaluated using lead oxide/gelatin angiography and laser Doppler, respectively. Flap tissue obtained from zone II was evaluated histopathologically, by hematoxylin and eosin staining, and in assays for malondialdehyde content and superoxide dismutase activity. Immunofluorescence was performed to detect interleukin (IL)-6, tumor necrosis factor (TNF)-α, hypoxia-inducible factor (HIF)-1α, Bcl-2, Bax, caspase-3, caspase-9, SQSTM1/P62, Beclin-1, and LC3 expression, and Western blot to assess PI3K/AKT signaling pathway activation and Vascular endothelial growth factor (VEGF) expression. The role played by the autophagy pathway in flap necrosis was examined using rapamycin, a specific inhibitor of mTOR. RESULTS: Experimentally, THP improved the survival rate of skin flaps, promoted angiogenesis, and improved blood perfusion. THP administration reduced the inflammatory response, oxidative stress, and apoptosis in addition to inhibiting autophagy via the PI3K/AKT/mTOR pathway. Rapamycin partially reversed these effects. CONCLUSION: THP promotes skin flap survival via the PI3K/AKT signaling pathway.

L-Borneol promotes skin flap survival by regulating HIF-1α/NF-κB pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: The clinical application of skin flaps in surgical reconstruction is frequently impeded by the occurrence of distant necrosis. L-Borneol exhibits myogenic properties in traditional Chinese medicine and is used in clinical settings to promote wound healing and conditions such as stroke. Nevertheless, the precise mechanism by which borneol exerts its protective effects on skin flap survival remains unclear. AIM OF THE STUDY: To explore the potential of L-borneol to promote skin flap survival and elucidate the underlying mechanisms. MATERIALS AND METHODS: Thirty-six male Sprague-Dawley rats were randomly divided into three groups: a high-dose (200 mg/kg L-borneol per day), a low-dose (50 mg/kg/day), and control group (same volume of solvent). In each rat, a modified rectangular McFarlane flap model measuring 3 × 9 cm was constructed. Daily intragastric administration of L-borneol or solvent was performed. The flap was divided into three square sections of equal size, namely Zone I (the proximal zone), Zone II (the intermediate zone), and Zone III (the distal zone). The survival rate was quantified, and the histological state of each flap was evaluated on the seventh day following the surgical procedure. The assessment of angiogenesis was conducted using lead oxide/gelatin angiography, whereas the evaluation of blood flow in the free flap was performed using laser Doppler flow imaging. Superoxide dismutase activity was detected using the water-soluble tetrazolium salt-8 method. The quantities of vascular endothelial growth factor, interleukin (IL)-1ß, IL-6, and tumour necrosis factor-α were determined using immunohistochemistry. The levels of nuclear transcription factor-κB, hypoxia-inducible factor-1, B-cell lymphoma-2 (BCL-2), and BCL-2-associated X (BAX) were determined by Western blotting technique. RESULTS: Flap survival rate significantly improved and neutrophil recruitment and release were enhanced after treatment with the compound. Angiogenesis was promoted. L-borneol protected against oxidative stress by increasing superoxide dismutase activity and decreasing malondialdehyde content. It downregulated the hypoxia-inducible factor nuclear transcription factor-κB pathway, leading to the inhibition of several inflammatory factors. Simultaneously, it facilitated the expression of vascular endothelial growth factor and BCL-2. CONCLUSION: The study shows that L-borneol may promote skin flap survival by inhibiting HIF-1α/NF-κB pathway.

Biochemical and Structural Characterization of OvoATh2: A Mononuclear Nonheme Iron Enzyme from Hydrogenimonas thermophila for Ovothiol Biosynthesis.

Ovothiol A and ergothioneine are thiol-histidine derivatives with sulfur substitutions at the δ-carbon or ε-carbon of the l-histidine imidazole ring, respectively. Both ovothiol A and ergothioneine have protective effects on many aging-related diseases, and the sulfur substitution plays a key role in determining their chemical and biological properties, while factors governing sulfur incorporation regioselectivities in ovothiol and ergothioneine biosynthesis in the corresponding enzymes (OvoA, Egt1, or EgtB) are not yet known. In this study, we have successfully obtained the first OvoA crystal structure, which provides critical information to explain their C-S bond formation regioselectivity. Furthermore, OvoATh2 exhibits several additional activities: (1) ergothioneine sulfoxide synthase activity akin to Egt1 in ergothioneine biosynthesis; (2) cysteine dioxygenase activity using l-cysteine and l-histidine analogues as substrates; (3) cysteine dioxygenase activity upon mutation of an active site tyrosine residue (Y406). The structural insights and diverse chemistries demonstrated by OvoATh2 pave the way for future comprehensive structure-function correlation studies.

Clinical value of station 4R node dissection in esophageal squamous cell carcinoma.

BACKGROUND: Many controversies still exist concerning the optimal extent of lymphadenectomy during esophagectomy in esophageal squamous cell carcinoma (ESCC). The objective of this study was to explore the characteristics of 4R metastasis and evaluate the clinical value of 4R node dissection in ESCC. METHODS: A total of 736 ESCC patients who underwent radical esophagectomy between 2005 and 2013 were retrospectively collected, among which 393 ones underwent 4R dissection. Propensity score matching (PSM) method was applied to reduce the effects of confounding variables between the 4R dissection and non-dissection groups to analyze overall survival. RESULTS: Patients showed a low 4R metastasis rate of 5.1% (20/393) (5.2%, 5.8%, and 1.8% for upper, middle, and lower tumors, respectively). Correlation analyses identified that 4R metastasis was significantly associated with station 2R metastasis (p < 0.001) and pathologic tumor-node-metastasis (pTNM) stage (p < 0.001). All 4R metastases were observed in stages IIIB and IVA. Moreover, patients with station 4R dissection failed to achieve significantly improved overall survival compared with those without 4R dissection, regardless of tumor stage (overall: p = 0.696; stage 0-IIIA: p = 0.317; stage IIIB-IVA: p = 0.619). CONCLUSION: 4R metastasis is likely to be associated with more aggressive disease, and routine 4R node dissection might not be necessary for ESCC patients.

Integrin ß4 promotes DNA damage-related drug resistance in triple-negative breast cancer via TNFAIP2/IQGAP1/RAC1.

Anti-tumor drug resistance is a challenge for human triple-negative breast cancer (TNBC) treatment. Our previous work demonstrated that TNFAIP2 activates RAC1 to promote TNBC cell proliferation and migration. However, the mechanism by which TNFAIP2 activates RAC1 is unknown. In this study, we found that TNFAIP2 interacts with IQGAP1 and Integrin ß4. Integrin ß4 activates RAC1 through TNFAIP2 and IQGAP1 and confers DNA damage-related drug resistance in TNBC. These results indicate that the Integrin ß4/TNFAIP2/IQGAP1/RAC1 axis provides potential therapeutic targets to overcome DNA damage-related drug resistance in TNBC.

SGCE promotes breast cancer stemness by promoting the transcription of FGF-BP1 by Sp1.

Breast cancer stem cells are mainly responsible for poor prognosis, especially in triple-negative breast cancer (TNBC). In a previous study, we demonstrated that ε-Sarcoglycan (SGCE), a type Ⅰ single-transmembrane protein, is a potential oncogene that promotes TNBC stemness by stabilizing EGFR. Here, we further found that SGCE depletion reduces breast cancer stem cells, partially through inhibiting the transcription of FGF-BP1, a secreted oncoprotein. Mechanistically, we demonstrate that SGCE could interact with the specific protein 1 transcription factor and translocate into the nucleus, which leads to an increase in the transcription of FGF-BP1, and the secreted FBF-BP1 activates FGF-FGFR signaling to promote cancer cell stemness. The novel SGCE-Sp1-FGF-BP1 axis provides novel potential candidate diagnostic markers and therapeutic targets for TNBC.

Experimental study on adsorption of PbCl2 and CdCl2 on kaolin modified by leachates from municipal solid waste incineration power plant.

Six kinds of waste liquids produced in the treatment process of leachate in a waste incineration plant were used to improve the adsorption effect of raw kaolin on heavy metal chloride. The capture performances of these modified kaolin on PbCl2 and CdCl2 vapor were investigated in a two-stage fixed bed combustor. The results indicated that the adsorption effects of raw kaolin on PbCl2 and CdCl2 were improved in some experimental groups, main effective component was Na+ in the leachate, but the influences did not change regularly with the increase in the concentration of Na + introduced into kaolin. The adsorbents formed by modifying 10 g kaolin with 21.25 ml leachate 2 were the best adsorbents for PbCl2 and CdCl2. The capture efficiencies of PbCl2 and CdCl2 can reach 95% and 63.88%, with the increase of 36% and 53%, respectively. Using leachate as modifying agent had the same effect as directly using Na+. Adsorptions of PbCl2 and CdCl2 were still mainly chemical adsorptions. After adsorption of PbCl2, the modified kaolin not only generated PbA12Si2O8, but also produced other chemical compounds. The adsorption of CdCl2 by modified kaolin did not generate CdAl2Si2O8, but other chemical reactions occurred to generate CdAl2O4 and Pb8Cd (Si2O7)3.

Ingenane-type diterpenoids inhibit non-small cell lung cancer cells by regulating SRC/PI3K/Akt pathway.

Ingenane-type diterpenoids (ITDs) are distinct components of plants belonging to the genus Euphorbia. These compounds have significant cytotoxic effects on non-small cell lung cancer (NSCLC) cells. However, the underlying molecular mechanism has yet to be reported. To explore the mechanism of the anticancer effect of ITDs, we carried out a network pharmacology prediction study. PPI network suggested that SRC and PI3K had high levels of interaction. In addition, KEGG analysis revealed that these common targets were significantly enriched in the PI3K/Akt signalling pathway. 13-oxyingenol-dodecanoate (13OD) was used for validation after the biological evaluation of some ITDs against NSCLC cells. It demonstrated that 13OD could significantly inhibit the growth of NSCLC cells by inducing apoptosis. The results from molecular docking and Western blotting showed that 13OD interacted with SRC and PI3K and down-regulated the SRC/PI3K/Akt signalling pathway in NSCLC cells. This study provided the underlying mechanism of ITDs against NSCLC.

Targeted Degradation of PD-L1 and Activation of the STING Pathway by Carbon-Dot-Based PROTACs for Cancer Immunotherapy.

Proteolysis targeting chimeras (PROTACs) technology is an emerging approach to degrade disease-associated proteins. Here, we report carbon-dot (CD)-based PROTACs (CDTACs) that degrade membrane proteins via the ubiquitin-proteasome system. CDTACs can bind to programmed cell death ligand 1 (PD-L1), recruit cereblon (CRBN) to induce PD-L1 ubiquitination, and degrade them with proteasomes. Fasting-mimicking diet (FMD) is also used to enhance the cellular uptake and proteasome activity. More than 99 % or 90 % of PD-L1 in CT26 or B16-F10 tumor cells can be degraded by CDTACs, respectively. Furthermore, CDTACs can activate the stimulator of interferon genes (STING) pathway to trigger immune responses. Thus, CDTACs with FMD treatment effectively inhibit the growth of CT26 and B16-F10 tumors. Compared with small-molecule-based PROTACs, CDTACs offer several advantages, such as efficient membrane protein degradation, targeted tumor accumulation, immune system activation, and in vivo detection.

Chlorogenic acid alleviates hypoxic-ischemic brain injury in neonatal mice.

Recent studies have shown that chlorogenic acid (CGA), which is present in coffee, has protective effects on the nervous system. However, its role in neonatal hypoxic-ischemic brain injury remains unclear. In this study, we established a newborn mouse model of hypoxic-ischemic brain injury using a modified Rice-Vannucci method and performed intraperitoneal injection of CGA. We found that CGA intervention effectively reduced the volume of cerebral infarct, alleviated cerebral edema, restored brain tissue structure after injury, and promoted axon growth in injured brain tissue. Moreover, CGA pretreatment alleviated oxygen-glucose deprivation damage of primary neurons and promoted neuron survival. In addition, changes in ferroptosis-related proteins caused by hypoxic-ischemic brain injury were partially reversed by CGA. Furthermore, CGA intervention upregulated the expression of the key ferroptosis factor glutathione peroxidase 4 and its upstream glutamate/cystine antiporter related factors SLC7A11 and SLC3A2. In summary, our findings reveal that CGA alleviates hypoxic-ischemic brain injury in neonatal mice by reducing ferroptosis, providing new ideas for the treatment of neonatal hypoxic-ischemic brain injury.

Sesquiterpene lactones from Elephantopus scaber exhibit cytotoxic effects on glioma cells by targeting GSTP1.

Sesquiterpene lactones possess excellent anti-tumor activity in multiple cancer cell lines, including glioma, the most common type of malignant brain tumor with high mortality. However, the detailed mechanism of this type of constituent, especially the potential target for anti-glioma effect, is still unclear. Here, we collected 52 sesquiterpene lactones from Elephantopus scaber Linn. for network pharmacology analysis. The results demonstrated that the targets of the active components were markedly enriched on the pathways in cancer, which were closely related to cell proliferation regulation. Next, the Gene Expression Omnibus (GEO) and DisGeNET were analyzed by bioinformatics, and 429 glioma-related targets were obtained. Furtherly, 34 common targets of compounds and glioma were revealed, and they were significantly enriched in MAPK signaling pathway. Subsequently, we constructed a common target-compound network, and glutathione S-transferase Pi 1 (GSTP1) had the highest degree value, which explained its significance in the network. Therefore, we speculated that the compounds might exert an anti-glioma effect by targeting GSTP1. To verify the above results, we obtained part of sesquiterpene lactones isolated from E. scaber in our laboratory and evaluated their activities against glioma U87 cells. Among these sesquiterpene lactones (1-27), compounds 1 (elephantopinolide A), 2 (cis-scabertopin) and 3 (elephantopinolide F) exhibited the strongest inhibitory effect, and the IC50 values were 4.22 ± 0.14 µM, 4.28 ± 0.21 µM and 1.79 ± 0.24 µM, respectively. The results from molecular docking, cellular thermal shift assay (CETSA), as well as RT-PCR and Western blot analysis suggested that the compounds exerted an inhibitory effect by targeting GSTP1. Meanwhile, the compounds also activated JNK/STAT3 signaling pathway. Furthermore, we found that 1, 2 and 3 could suppress cell proliferation and also induce mitochondrial dysfunction as well as oxidative stress, eventually leading to cellular apoptosis. Taken together, this study revealed that sesquiterpene lactones from E. scaber could be a promising therapeutic strategy for the treatment of glioma by targeting GSTP1.

An Epigenetic Role of Mitochondria in Cancer.

Mitochondria are not only the main energy supplier but are also the cell metabolic center regulating multiple key metaborates that play pivotal roles in epigenetics regulation. These metabolites include acetyl-CoA, α-ketoglutarate (α-KG), S-adenosyl methionine (SAM), NAD+, and O-linked beta-N-acetylglucosamine (O-GlcNAc), which are the main substrates for DNA methylation and histone post-translation modifications, essential for gene transcriptional regulation and cell fate determination. Tumorigenesis is attributed to many factors, including gene mutations and tumor microenvironment. Mitochondria and epigenetics play essential roles in tumor initiation, evolution, metastasis, and recurrence. Targeting mitochondrial metabolism and epigenetics are promising therapeutic strategies for tumor treatment. In this review, we summarize the roles of mitochondria in key metabolites required for epigenetics modification and in cell fate regulation and discuss the current strategy in cancer therapies via targeting epigenetic modifiers and related enzymes in metabolic regulation. This review is an important contribution to the understanding of the current metabolic-epigenetic-tumorigenesis concept.