Histone deacetylase 6 as a novel promising target to treat cardiovascular disease.

Histone deacetylase 6 (HDAC6) belongs to a class of epigenetic targets that have been found to be a key protein in the association between tumors and cardiovascular disease. Recent studies have focused on the crucial role of HDAC6 in regulating cardiovascular diseases such as atherosclerosis, myocardial infarction, myocardial hypertrophy, myocardial fibrosis, hypertension, pulmonary hypertension, and arrhythmia. Here, we review the association between HDAC6 and cardiovascular disease, the research progress of HDAC6 inhibitors in the treatment of cardiovascular disease, and discuss the feasibility of combining HDAC6 inhibitors with other therapeutic agents to treat cardiovascular disease.

Notoginsenoside R1 Ameliorate High-Fat-Diet and Vitamin D3-Induced Atherosclerosis via Alleviating Inflammatory Response, Inhibiting Endothelial Dysfunction, and Regulating Gut Microbiota.

Aim: Natural medicines possess significant research and application value in the field of atherosclerosis (AS) treatment. The study was performed to investigate the impacts of a natural drug component, notoginsenoside R1, on the development of atherosclerosis (AS) and the potential mechanisms. Methods: Rats induced with AS by a high-fat-diet and vitamin D3 were treated with notoginsenoside R1 for six weeks. The ameliorative effect of NR1 on AS rats was assessed by detecting pathological changes in the abdominal aorta, biochemical indices in serum and protein expression in the abdominal aorta, as well as by analysing the gut microbiota. Results: The NR1 group exhibited a noticeable reduction in plaque pathology. Notoginsenoside R1 can significantly improve serum lipid profiles, encompassing TG, TC, LDL, ox-LDL, and HDL. Simultaneously, IL-6, IL-33, TNF-α, and IL-1ß levels are decreased by notoginsenoside R1 in lowering inflammatory elements. Notoginsenoside R1 can suppress the secretion of VCAM-1 and ICAM-1, as well as enhance the levels of plasma NO and eNOS. Furthermore, notoginsenoside R1 inhibits the NLRP3/Cleaved Caspase-1/IL-1ß inflammatory pathway and reduces the expression of the JNK2/P38 MAPK/VEGF endothelial damage pathway. Fecal analysis showed that notoginsenoside R1 remodeled the gut microbiota of AS rats by decreasing the count of pathogenic bacteria (such as Firmicutes and Proteobacteria) and increasing the quantity of probiotic bacteria (such as Bacteroidetes). Conclusion: Notoginsenoside R1, due to its unique anti-inflammatory properties, may potentially prevent the progression of atherosclerosis. This mechanism helps protect the vascular endothelium from damage, while also regulating the imbalance of intestinal microbiota, thereby maintaining the overall health of the body.

CircMALAT1 promotes cancer stem-like properties and chemoresistance via regulating Musashi-2/c-Myc axis in esophageal squamous cell carcinoma.

The primary challenge in treating esophageal squamous cell carcinoma (ESCC) is resistance to chemotherapy. Cancer stem cell (CSC) is the root cause of tumor drug resistance. Therefore, targeting CSCs has been considered promising therapeutic strategy for tumor treatment. Here, we report that circMALAT1 was significantly upregulated in ESCC CSC-like cells and primary tumors from ESCC patients. Clinically, there was a positive correlation between circMALAT1 expression and ESCC stage and lymph node metastasis, as well as poor prognosis for ESCC patients. In vitro and in vivo functional studies revealed that circMALAT1 promoted CSC-like cells expansion, tumor growth, lung metastasis and drug resistance of ESCC. Mechanistically, circMALAT1 directly interacted with CSC-functional protein Musashi RNA Binding Protein 2 (MSI2). CircMALAT1 inhibited MSI2 ubiquitination by preventing it from interacting with ß-transducin repeat containing protein (BTRC) E3 ubiquitin ligase. Also, circMALAT1 knockdown inhibited the expression of MSI2-regulating CSC-markers c-Myc in ESCC. Collectively, circMALAT1 modulated the ubiquitination and degradation of the MSI2 protein signaling with ESCC CSCs and accelerated malignant progression of ESCC. CircMALAT1 has the potential to serve as a biomarker for drug resistance and as a target for therapy in CSCs within ESCC.

High-Pressure-Field Induced Synthesis of Ultrafine-Sized High-Entropy Compounds with Excellent Sodium-Ion Storage.

Emerging high entropy compounds (HECs) have attracted huge attention in electrochemical energy-related applications. The features of ultrafine size and carbon incorporation show great potential to boost the ion-storage kinetics of HECs. However, they are rarely reported because high-temperature calcination tends to result in larger crystallites, phase separation, and carbon reduction. Herein, using the NaCl self-assembly template method, by introducing a high-pressure field in the calcination process, the atom diffusion and phase separation are inhibited for the general formation of HECs, and the HEC aggregation is inhibited for obtaining ultrafine size. The general preparation of ultrafine-sized (<10 nm) HECs (nitrides, oxides, sulfides, and phosphates) anchored on porous carbon composites is realized. They are demonstrated by combining advanced characterization technologies with theoretical computations. Ultrafine-sized high entropy sulfides-MnFeCoCuSnMo/porous carbon (HES-MnFeCoCuSnMo/PC) as representative anodes exhibit excellent sodium-ion storage kinetics and capacities (a high rating capacity of 278 mAh g-1 at 10 A g-1 for full cell and a high cycling capacity of 281 mAh g-1 at 20 A g-1 after 6000 cycles for half cell) due to the combining advantages of high entropy effect, ultrafine size, and PC incorporation. Our work provides a new opportunity for designing and fabricating ultrafine-sized HECs.

Improving Anti-HIV activity and pharmacokinetics of enfuvirtide (T20) by modification with oligomannose.

Dendritic cells (DCs) play a pivotal role in controlling HIV-1 infections of CD4+ T cells. DC-SIGN, which is expressed on the surface of DCs, efficiently captures HIV-1 virions by binding to the highly mannosylated membrane protein, gp120, and then the DCs transport the virus to target T cells in lymphoid organs. This study explored the modification of T20, a peptide inhibitor of HIV-1 fusion, by conjugation of the N-terminus with varying sizes of oligomannose, which are DC-SIGN-specific carbohydrates, aiming to create dual-targeting HIV inhibitors. Mechanistic studies indicated the dual-target binding of the conjugates. Antiviral assays demonstrated that N-terminal mannosylation of T20 resulted in increased inhibition of the viral infection of TZM-b1 cells (EC50 = 0.3-0.8 vs. 1.4 nM). Pentamannosylated T20 (M5-T20) exhibited a stronger inhibitory effect on virus entry into DC-SIGN+ 293T cells compared with T20 (67% vs. 50% inhibition at 500 µM). M5-T20 displayed an extended half-life in rats relative to T20 (T1/2: 8.56 vs. 1.64 h, respectively). These conjugates represent a potential new treatment for HIV infections with improved antiviral activity and pharmacokinetics, and this strategy may prove useful in developing dual-target inhibitors for other pathogens that require DC-SIGN involvement for infection.

Glycan-Modified Peptides for Dual Inhibition of Human Immunodeficiency Virus Entry into Dendritic Cells and T Cells.

Dendritic cells (DCs) play a crucial role in HIV-1 infection of CD4+ T cells. DC-SIGN, a lectin expressed on the surface of DCs, binds to the highly mannosylated viral membrane protein gp120 to capture HIV-1 virions and then transport them to target T cells. In this study, we modified peptide C34, an HIV-1 fusion inhibitor, at different sites using different sizes of the DC-SIGN-specific carbohydrates to provide dual-targeted HIV inhibition. The dual-target binding was confirmed by mechanistic studies. Pentamannose-modified C34 inhibited virus entry into both DC-SIGN+ 293T cells (52%-71% inhibition at 500 µM) and CD4+ TZM-b1 cells (EC50 = 0.7-1.7 nM). One conjugate, NC-M5, showed an extended half-life relative to C34 in rats (T1/2: 7.8 vs 1.02 h). These improvements in antiviral activity and pharmacokinetics have potential for HIV treatment and the development of dual-target inhibitors for pathogens that require the involvement of DC-SIGN for infection.

Combining photodynamic therapy and cascade chemotherapy for enhanced tumor cytotoxicity: the role of CTT2P@B nanoparticles.

The mitochondria act as the main producers of reactive oxygen species (ROS) within cells. Elevated levels of ROS can activate the mitochondrial apoptotic pathway, leading to cell apoptosis. In this study, we devised a molecular prodrug named CTT2P, demonstrating notable efficacy in facilitating mitochondrial apoptosis. To develop nanomedicine, we enveloped CTT2P within bovine serum albumin (BSA), resulting in the formulation known as CTT2P@B. The molecular prodrug CTT2P is achieved by covalently conjugating mitochondrial targeting triphenylphosphine (PPh3), photosensitizer TPPOH2, ROS-sensitive thioketal (TK), and chemotherapeutic drug camptothecin (CPT). The prodrug, which is chemically bonded, prevents the escape of drugs while they circulate throughout the body, guaranteeing the coordinated dispersion of both medications inside the organism. Additionally, the concurrent integration of targeted photodynamic therapy and cascade chemotherapy synergistically enhances the therapeutic efficacy of pharmaceutical agents. Experimental results indicated that the covalently attached prodrug significantly mitigated CPT cytotoxicity under dark conditions. In contrast, TPPOH2, CTT2, CTT2P, and CTT2P@B nanoparticles exhibited increasing tumor cell-killing effects and suppressed tumor growth when exposed to light at 660 nm with an intensity of 280 mW cm-2. Consequently, this laser-triggered, mitochondria-targeted, combined photodynamic therapy and chemotherapy nano drug delivery system, adept at efficiently promoting mitochondrial apoptosis, presents a promising and innovative approach to cancer treatment.

Novel exosomal circEGFR facilitates triple negative breast cancer autophagy via promoting TFEB nuclear trafficking and modulating miR-224-5p/ATG13/ULK1 feedback loop.

Triple-negative breast cancer (TNBC) cells are in a more hypoxic and starved state than non-TNBC cells, which makes TNBC cells always maintain high autophagy levels. Emerging evidence has demonstrated that circular RNAs (circRNAs) are involved in the progress of tumorigenesis. However, the regulation and functions of autophagy-induced circRNAs in TNBC remain unclear. In our study, autophagy-responsive circRNA candidates in TNBC cells under amino acid starved were identified by RNA sequencing. The results showed that circEGFR expression was significantly upregulated in autophagic cells. Knockdown of circEGFR inhibited autophagy in TNBC cells, and circEGFR derived from exosomes induced autophagy in recipient cells in the tumor microenvironment. In vitro and in vivo functional assays identified circEGFR as an oncogenic circRNA in TNBC. Clinically, circEGFR was significantly upregulated in TNBC and was positively associated with lymph node metastasis. CircEGFR in plasma-derived exosomes was upregulated in breast cancer patients compared with healthy people. Mechanistically, circEGFR facilitated the translocation of Annexin A2 (ANXA2) toward the plasma membrane in TNBC cells, which led to the release of Transcription Factor EB (a transcription factor of autophagy-related proteins, TFEB) from ANXA2-TFEB complex, causing nuclear translocation of TFEB, thereby promoting autophagy in TNBC cells. Meanwhile, circEGFR acted as ceRNA by directly binding to miR-224-5p and inhibited the expression of miR-224-5p, which weakened the suppressive role of miR-224-5p/ATG13/ULK1 axis on autophagy. Overall, our study demonstrates the key role of circEGFR in autophagy, malignant progression, and metastasis of TNBC. These indicate circEGFR is a potential diagnosis biomarker and therapeutic target for TNBC.

Spectroscopic Study of a New Electronic Band System 33Δg-a3Πu of C2.

As one of the most important diatomic molecules in the universe, the spectroscopic characterizations of C2 have attracted wide attention in various fields, such as interstellar chemistry, planetary atmospheric chemistry, and combustion. In recent years, a systematic spectroscopic study of C2 in the vacuum ultraviolet (VUV) region has been carried out in our laboratory by using the (1VUV+1'UV) resonance-enhanced multiphoton ionization method based on the combination of a tunable VUV laser source and a time-of-flight mass spectrometer. Two new electronic transition band systems have been reported, following the pioneering work of Herzberg and co-workers in 1969. In the current study, a total of 18 vibronic transition bands of C2 from the lower a3Πu state are experimentally observed in the VUV photon energy range 72000-81000 cm-1, and 6 new upper vibronic levels of 3Δg symmetry are identified, which are assigned as the v' = 0-5 vibrational levels of the 33Δg state of C2. The term energy Te of the 33Δg state is determined to be in the range of 78425-78475 cm-1 (9.724-9.730 eV) with respect to the ground X1Σg+ state, and the molecular constants such as vibrational and rotational constants are also determined, which are in reasonable agreement with those predicted by high-level ab initio theoretical calculations. Irregular vibrational energy level spacings in the 33Δg state are observed, which is tentatively attributed to the strong perturbations between the 33Δg and 23Δg states, as previously predicted by theory.

Incidence of low-level viremia and its impact on virologic failure among people living with HIV who started an integrase strand transfer inhibitors: a longitudinal cohort study.

BACKGROUND: Low-level viremia (LLV) has been identified as a potential precursor to virologic failure (VF), yet its clinical implications, particularly within the context of Integrase Strand Transfer Inhibitors (INSTIs)-based regimens, remain insufficiently explored. The study aimed to investigate the relationship between LLV and VF within ART-naïve patients on INSTIs-based regimens in China. METHODS: A longitudinal cohort study was conducted with ART-naïve patients aged ≥ 18 years at Beijing Ditan Hospital, under the Chinese National Free Antiretroviral Treatment Program (NFATP). The LLV was defined as a viral load (VL) ranging from 50 to 199 copies/mL after six months of ART initiation, and VF as a VL ≥ 200 copies/mL. Sensitive analyses were also performed, defining LLV as 50-999 copies/mL and VF as exceeding 1000 copies/mL. Multivariate logistic regression, Kaplan-Meier (KM) curve, and Generalized Estimating Equation (GEE) models were used to evaluate the risk factors associated with LLV and VF events. RESULTS: The study involved 830 ART-naïve patients, comprising 600 in the INSTIs group and 230 in the protease inhibitors (PIs) group. LLV events were observed in 10.4% of patients on PIs-based regimens and and 3.2% on INSTIs-based regimens (P < 0.001). INSTIs-based regimens demonstrated a protective effect against LLV events (aHR = 0.27, 95% CI 0.137-0.532). VF events occurred in 10.9% of patients on PIs-based regimens and 2.0% on INSTIs-based regimens, respectively (P < 0.001). The occurrence of LLV events significantly increased the risk of VF by 123.5% (95% CI 7.5%-364.4%), while the integrase inhibitors were associated with a 76.9% (95% CI 59.1%-86.9%) reduction in VF risk. CONCLUSION: Our findings indicate that INSTIs-based regimens are critical protective factors against LLV and subsequent VF. These results underscore the importance of HIV viral load monitoring to ensuring effective treatment outcomes, highlighting the necessity for prompt and precise monitoring to refine HIV treatment methodologies.

Transcriptome Analysis Reveals Novel Insights into the Hyperaccumulator Phytolacca acinosa Roxb. Responses to Cadmium Stress.

Cadmium (Cd) is a highly toxic heavy metal that causes serious damage to plant and human health. Phytolacca acinosa Roxb. has a large amount of aboveground biomass and a rapid growth rate, and it has been identified as a novel type of Cd hyperaccumulator that can be harnessed for phytoremediation. However, the molecular mechanisms underlying the response of P. acinosa to Cd2+ stress remain largely unclear. In this study, the phenotype, biochemical, and physiological traits of P. acinosa seeds and seedlings were analyzed under different concentrations of Cd2+ treatments. The results showed higher Cd2+ tolerance of P. acinosa compared to common plants. Meanwhile, the Cd2+ content in shoots reached 449 mg/kg under 10 mg/L Cd2+ treatment, which was obviously higher than the threshold for Cd hyperaccumulators. To investigate the molecular mechanism underlying the adaptability of P. acinosa to Cd stress, RNA-Seq was used to examine transcriptional responses of P. acinosa to Cd stress. Transcriptome analysis found that 61 genes encoding TFs, 48 cell wall-related genes, 35 secondary metabolism-related genes, 133 membrane proteins and ion transporters, and 96 defense system-related genes were differentially expressed under Cd2+ stress, indicating that a series of genes were involved in Cd2+ stress, forming a complex signaling regulatory mechanism. These results provide new scientific evidence for elucidating the regulatory mechanisms of P. acinosa response to Cd2+ stress and new clues for the molecular breeding of heavy metal phytoremediation.

Novel porphyrin derivative containing cations as new photodynamic antimicrobial agent with high efficiency.

Bacterial infections from chronic wounds affect about 175 million people each year and are a significant clinical problem. Through the integration of photodynamic therapy (PDT) and chemotherapy, a new photosensitizer consisting of ammonium salt N,N-bis-(2-hydroxyethyl)-N-(6-(4-(10,15,20-trimesitylporphyrin-5-yl) phenoxy) hexane)-N-methanaminium bromide, TMP(+) was successfully synthesized with a total reaction yield of 10%. The novel photosensitizer consists of two parts, a porphyrin photosensitizer part and a quaternary ammonium salt part, to achieve the synergistic effect of photodynamic and chemical antibacterial activity. With the increase of TMP(+) concentration, the diameter of the PCT fiber membranes (POL/COL/TMP(+); POL, polycaprolactone; COL, collagen) gradually increased, which was caused by the charge of the quaternary ammonium salt. At the same time, the antibacterial properties were gradually improved. We finally selected the PCT 0.5% group for the antibacterial experiment, with excellent performance in fiber uniformity, hydrophobicity and biosafety. The antibacterial experiment showed that the modified porphyrin TMP(+) had a better antibacterial effect than others. In vivo chronic wound healing experiments proved that the antibacterial and anti-inflammatory effect of the PCTL group was the best, further confirmed by H&E histological analysis, immunofluorescence and immunohistochemistry mechanism experiments. This research lays the foundation for the manufacture of novel molecules that combine chemical and photodynamic strategies.

The m6A reader IGF2BP2 promotes the progression of esophageal squamous cell carcinoma cells by increasing the stability of OCT4 mRNA.

Esophageal squamous cell carcinoma (ESCC) is a common malignancy with high morbidity and mortality. Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) serves as a reader of RNA m6A (N6 methyladenosine) modification to regulate gene expression at the post-transcriptional level. Emerging evidence suggests that IGF2BP2 plays critical roles in tumorigenesis and malignant development. However, the biological function and molecular mechanism of IGF2BP2 in ESCC are not well understood. Here, we found that IGF2BP2 expression was upregulated in esophageal cancer tissues and ESCC cells, and IGF2BP2 overexpression enhanced proliferation, migration, invasion, and stem cell-like properties of ESCC cells. Conversely, the knockdown of IGF2BP2 expression inhibited malignant phenotype of ESCC cells. Mechanistically, IGF2BP2 upregulated octomer-binding transcription factor 4 (OCT4) mRNA expression, and RNA immunoprecipitation (RIP) assay proved that IGF2BP2 could interact with OCT4 mRNA. Moreover, OCT4 was modified at m6A confirmed by methylated m6A RNA immunoprecipitation (Me-RIP)-qPCR assay, and IGF2BP2 knockdown reduced OCT4 mRNA stability. These results suggested that IGF2BP2 served as a reader for m6A-modified OCT4, thus increased OCT4 mRNA expression by regulating its stability. Furthermore, the knockdown of OCT4 could reverse the effects of IGF2BP2 on ESCC cells. In conclusion, these data indicate that IGF2BP2, as a reader for m6A, plays an oncogenic role by regulating OCT4 expression in ESCC, which provides new insights into targeting IGF2BP2/OCT4 axis for the therapy of ESCC.

Lysine demethylase 5B (KDM5B): A key regulator of cancer drug resistance.

Chemoresistance, a roadblock in the chemotherapy process, has been impeding its effective treatment. KDM5B, a member of the histone demethylase family, has been crucial in the emergence and growth of malignancies. More significantly, KDM5B has recently been linked closely to cancer's resistance to chemotherapy. In this review, we explain the biological properties of KDM5B, its function in the emergence and evolution of cancer treatment resistance, and our hopes for future drug resistance-busting combinations involving KDM5B and related targets or medications.

Alkaloid diversity expansion of a talent fungus Penicillium raistrichii through OSMAC-based cultivation.

Introduction: Alkaloidal natural products are attractive for their broad spectrum of pharmaceutical bioactivities. In the present work, the highly productive saline soil derived fungus, Penicillium raistrichii, was subjected to the strategy of OSMAC (one strain many compounds) with changes of cultivation status. Then, the work-flow led to the expansion of the alkaloid chemical diversity and subsequently induced the accumulation of four undescribed alkaloids, named raistrimides A-D (1-4), including three ß-carbolines (1-3), one 2-quinolinone (4), and one new natural product, 2-quinolinone (5), along with five known alkaloid chemicals (6-10). Methods: A set of NMR techniques including 1H, 13C, HSQC and HMBC, along with other spectroscopic data of UV-Vis, IR and HRESIMS, were introduced to assign the plain structures of compounds 1-10. The absolute configuration of 1-3 were elucidated by means of X-ray crystallography or spectroscopic analyses on optical rotation values and experimental electronic circular dichroism (ECD) data. In addition, it was the first report on the confirmation of structures of 6, 7 and 9 by X-ray crystallography data. The micro-broth dilution method was applied to evaluate antimicrobial effect of all compounds towards Staphylococcus aureus, Escherichia coli, and Candida albicans. Results and discussion: The results indicated compounds 1, 3 and 4 to be bioactive, which may be potential for further development of anti-antimicrobial agents. The finding in this work implied that OSMAC strategy was a powerful and effective tool for promotion of new chemical entities from P. raistrichii.

Phenotypic variability in two female siblings with oocyte maturation arrest due to a TUBB8 variant.

Tubulin beta-8 (TUBB8) is expressed exclusively in the oocyte and early embryo, encoding a beta-tubulin polypeptide that participates in the assembly of microtubules. TUBB8 was first attributed to being responsible for oocyte MI arrest. Further studies have demonstrated that patients with different pathogenic variants have variable phenotypes. We report a TUBB8 variant (c.10 A > C) in two siblings who presented different clinical features of primary infertility. The younger sister showed severe oocyte maturation arrest with abnormal morphology, whereas a few mature oocytes and zygotes could be retrieved from the older sister, but no embryo was available for transfer. This variant was previously reported without in vitro functional assays. In the present study, RT‒qPCR and western blot analyses revealed that c.10 A > C reduces TUBB8 mRNA and protein levels; however, immunofluorescence demonstrated that this variant does not change the localization of the protein. These findings confirm the pathogenicity of the c.10 A > C variant and support the relationship between the variant and phenotype in the patients.

A Universal Cross-Synthetic Strategy for Sub-10 nm Metal-Based Composites with Excellent Ion Storage Kinetics.

The sub-10 nm metal-based nanomaterials (SMNs) show great potential for the electrochemical energy storage field. However, their ion storage capacity and stability suffer from severe agglomeration and interface problems. Herein, a universal strategy is reported to synthesize a wide range of SMNs (e.g., metal, nitride, oxide, and sulfides) embedded in free-standing carbon foam (SMN/FC-F) composite electrodes by crossing the interfacial confinement of NaCl self-assembly with the thermal-mechanical coupling of powder metallurgy. The pressure-enhanced NaCl self-assembly interfacial confinement is greatly beneficial to preventing SMN agglomeration and promoting SMNs embedded in FC-F which originate from the welding of carbon nanosheets. They are confirmed via a series of advanced characterizations including X-ray photoelectron spectroscopy, and spherical aberration-corrected scanning transmission electron microscopy, with theoretical computations. Benefiting from the unique structure, SMNs/FC-F delivers ultrafast and stable ion-storage kinetics. As a proof-of-concept demonstration, the MoS2 /FC-F shows excellent ion storage kinetics and superior long-term cycling performance for ion storage (e.g., Na3 V2 (PO4 )2 O2 F/C//MoS2 /FC-F sodium-ion batteries exhibit a high reversible capacity of 185 mAh g-1 at 0.5 A g-1 with a decay rate of 0.05% per cycle.). This work provides a new opportunity to design and fabricate promising SMN-based free-standing working electrodes for electrochemical energy storage and conversion applications.

Hypoxia-induced TMTC3 expression in esophageal squamous cell carcinoma potentiates tumor angiogenesis through Rho GTPase/STAT3/VEGFA pathway.

BACKGROUND: Hypoxia is one of most typical features in the tumor microenvironment of solid tumor and an inducer of endoplasmic reticulum (ER) stress, and HIF-1α functions as a key transcription factor regulator to promote tumor angiogenesis in the adaptive response to hypoxia. Increasing evidence has suggested that hypoxia plays an important regulatory role of ER homeostasis. We previously identified TMTC3 as an ER stress mediator under nutrient-deficiency condition in esophageal squamous cell carcinoma (ESCC), but the molecular mechanism in hypoxia is still unclear. METHODS: RNA sequencing data of TMTC3 knockdown cells and TCGA database were analyzed to determine the association of TMTC3 and hypoxia. Moreover, ChIP assay and dual-luciferase reporter assay were performed to detect the interaction of HIF-1α and TMTC3 promoter. In vitro and in vivo assays were used to investigate the function of TMTC3 in tumor angiogenesis. The molecular mechanism was determined using co-immunoprecipitation assays, immunofluorescence assays and western blot. The TMTC3 inhibitor was identified by high-throughput screening of FDA-approved drugs. The combination of TMTC3 inhibitor and cisplatin was conducted to confirm the efficiency in vitro and in vivo. RESULTS: The expression of TMTC3 was remarkably increased under hypoxia and regulated by HIF-1α. Knockdown of TMTC3 inhibited the capability of tumor angiogenesis and ROS production in ESCC. Mechanistically, TMTC3 promoted the production of GTP through interacting with IMPDH2 Bateman domain. The activity of Rho GTPase/STAT3, regulated by cellular GTP levels, decreased in TMTC3 knockdown cells, whereas reversed by IMPDH2 overexpression. Additionally, TMTC3 regulated the expression of VEGFA through Rho GTPase/STAT3 pathway. Allopurinol inhibited the expression of TMTC3 and further reduced the phosphorylation and activation of STAT3 signaling pathway in a dose-dependent manner in ESCC. Additionally, the combination of allopurinol and cisplatin significantly inhibited the cell viability in vitro and tumor growth in vivo, comparing with single drug treatment, respectively. CONCLUSIONS: Collectively, our study clarified the molecular mechanism of TMTC3 in regulating tumor angiogenesis and highlighted the potential therapeutic combination of TMTC3 inhibitor and cisplatin, which proposed a promising strategy for the treatment of ESCC.