Microenvironment-responsive release of Mg2+ from tannic acid decorated and multilevel crosslinked hydrogels accelerates infected wound healing.

The management of chronic infected wounds poses significant challenges due to frequent bacterial infections, high concentrations of reactive oxygen species, abnormal immune regulation, and impaired angiogenesis. This study introduces a novel, microenvironment-responsive, dual dynamic, and covalently bonded hydrogel, termed OHA-P-TA/G/Mg2+. It is derived from the reaction of tannic acid (TA) with phenylboronic acids (PBA), which are grafted onto oxidized hyaluronic acid (OHA-P-TA), combined with GelMA (G) via a Schiff base and chemical bonds, along with the incorporation of Mg2+. This hydrogel exhibits pH and ROS dual-responsiveness, demonstrating effective antibacterial capacity, antioxidant ability, and the anti-inflammatory ability under distinct acidic and oxidative microenvironments. Furthermore, the release of Mg2+ from the TA-Mg2+ network (TA@Mg2+) promotes the transformation of pro-inflammatory M1 phenotype macrophages to anti-inflammatory M2 phenotype, showing a microenvironment-responsive response. Finally, in vivo results indicate that the OHA-P-TA/G/Mg2+ hydrogel enhances epithelial regeneration, collagen deposition, and neovascularization, showing great potential as an effective dressing for infected wound repair.

Injectable Microgels with Hybrid Exosomes of Chondrocyte-Targeted FGF18 Gene-Editing and Self-Renewable Lubrication for Osteoarthritis Therapy.

Abnormal silencing of fibroblast growth factor (FGF) signaling significantly contributes to joint dysplasia and osteoarthritis (OA); However, the clinical translation of FGF18-based protein drugs is hindered by their short half-life, low delivery efficiency and the need for repeated articular injections. This study proposes a CRISPR/Cas9-based approach to effectively activate the FGF18 gene of OA chondrocytes at the genome level in vivo, using chondrocyte-affinity peptide (CAP) incorporated hybrid exosomes (CAP/FGF18-hyEXO) loaded with an FGF18-targeted gene-editing tool. Furthermore, CAP/FGF18-hyEXO are encapsulated in methacrylic anhydride-modified hyaluronic (HAMA) hydrogel microspheres via microfluidics and photopolymerization to create an injectable microgel system (CAP/FGF18-hyEXO@HMs) with self-renewable hydration layers to provide persistent lubrication in response to frictional wear. Together, the injectable CAP/FGF18-hyEXO@HMs, combined with in vivo FGF18 gene editing and continuous lubrication, have demonstrated their capacity to synergistically promote cartilage regeneration, decrease inflammation, and prevent ECM degradation both in vitro and in vivo, holding great potential for clinical translation.

Construction of a Nomogram-Based Prediction Model for the Risk of Diabetic Kidney Disease in T2DM.

Introduction: To investigate the predictors of diabetic kidney disease (DKD) in type 2 diabetes mellitus (T2DM) patients and establish a nomogram model for predicting the risk of DKD. Methods: The clinical data of T2DM patients, admitted to the Endocrinology Department of Chengde Central Hospital from October 2019 to September 2020 and divided into a case group or a control group based on whether they had DKD, were collected. The predictive factors of DKD were screened by univariate and multivariate analysis, and a nomogram prediction model was constructed for the risk of DKD in T2DM. Bootstrapping was used for model validation, receiver operating characteristic (ROC) curve and GiViTI calibration curve were used for evaluating the discrimination and calibration of prediction model, and decision analysis curve (DCA) was used for evaluating the practicality of model. Results: Predictors for DKD are diabetic retinopathy (DR), hypertension, history of gout, smoking history, using insulin, elevation of body mass index (BMI), triglyceride (TG), cystatin C (Cys-C), and reduction of 25 (OH) D. The nomogram prediction model based on the above nine predictors had good representativeness (Bootstrap method: precision: 0.866, Kappa: 0.334), differentiation [the area under curve (AUC) value: 0.868], and accuracy (GiViTI-corrected curved bands, P = 0.836); the DAC curve analysis showed that the prediction model, whose threshold probability was in the range of 0.10 to 0.70, had clinical practical value. Conclusion: The risk of DKD in T2DM could be predicted accurately by DR, hypertension, history of gout, smoking history, using insulin, elevation of BMI, TG, Cys-C, and reduction of 25 (OH) D.

Cell-Free Osteoarthritis Treatment with Sustained-Release of Chondrocyte-Targeting Exosomes from Umbilical Cord-Derived Mesenchymal Stem Cells to Rejuvenate Aging Chondrocytes.

As chondrocytes from osteoarthritic cartilage usually exhibit aging and senescent characteristics, targeting aging chondrocytes could be a potential therapeutic strategy. In this study, exosomes derived from umbilical cord-derived mesenchymal stem cells (UCMSC-EXOs) combined with the chondrocyte-targeting capacity and controlled-release system were proposed for osteoarthritis (OA) treatment via rejuvenating aging chondrocytes. The essential functional miRNAs within UCMSC-EXOs were investigated, with the p53 signaling pathway identified as the key factor. To improve the therapeutic efficiency and retention time of UCMSC-EXOs in vivo, the exosomes (EXOs) were engineered on membranes with a designed chondrocyte-targeting polymers, and encapsulated within thiolated hyaluronic acid microgels to form a "two-phase" releasing system, which synergistically facilitated the repair of OA cartilage in a rat model. Together, this study highlighted the rejuvenating effects of UCMSC-EXOs on OA chondrocytes and the potential to combine with chondrocyte-targeting and sustained-release strategies toward a future cell-free OA treatment.

Applications of Polyacetylene Derivatives in Gas and Liquid Separation.

As a low energy consumption, simple operation and environmentally friendly separation method, membrane separation has attracted extensive attention. Therefore, researchers have designed and synthesized various types of separation membrane, such as metal organic framework (MOF), covalent organic framework (COF), polymer of intrinsic micro-porosity (PIM) and mixed matrix membranes. Some substituted polyacetylenes have distorted structures and formed micropores due to the existence of rigid main chains and substituted side groups, which can be applied to the field of membrane separation. This article mainly introduces the development and application of substituted polyacetylenes in gas separation and liquid separation based on membrane technology.

Nanostructured 3D-Printed Hybrid Scaffold Accelerates Bone Regeneration by Photointegrating Nanohydroxyapatite.

Nanostructured biomaterials that replicate natural bone architecture are expected to facilitate bone regeneration. Here, nanohydroxyapatite (nHAp) with vinyl surface modification is acquired by silicon-based coupling agent and photointegrated with methacrylic anhydride-modified gelatin to manufacture a chemically integrated 3D-printed hybrid bone scaffold (75.6 wt% solid content). This nanostructured procedure significantly increases its storage modulus by 19.43-fold (79.2 kPa) to construct a more stable mechanical structure. Furthermore, biofunctional hydrogel with biomimetic extracellular matrix is anchored onto the filament of 3D-printed hybrid scaffold (HGel-g-nHAp) by polyphenol-mediated multiple chemical reactions, which contributes to initiate early osteogenesis and angiogenesis by recruiting endogenous stem cells in situ. Significant ectopic mineral deposition is also observed in subcutaneously implanted nude mice with storage modulus enhancement of 25.3-fold after 30 days. Meanwhile, HGel-g-nHAp realizes substantial bone reconstruction in the rabbit cranial defect model, achieving 61.3% breaking load strength and 73.1% bone volume fractions in comparison to natural cranium 15 weeks after implantation. This optical integration strategy of vinyl modified nHAp provides a prospective structural design for regenerative 3D-printed bone scaffold.

NRSN2 is a Prognostic Biomarker in Gastric Cancer and Facilitates the Growth and Migration of Gastric Cancer Cells.

BACKGROUND: Neurensin-2 (NRSN2) is reported to be associated with the progression of many tumors. This work aimed at investigating the biological function and prognostic significance of NRSN2 in gastric cancer (GC). METHODS: NRSN2 expression in various cancer tissue was analyzed by the TIMER database. NRSN2 expression in GC tissue samples of different groups was analyzed by the UALCAN database. The survival analysis was performed with the Kaplan-Meier database. NRSN2 expression in GC tissues and cell lines was measured by qRT-PCR and Western blot. CCK-8, Transwell and scratch healing assays were conducted to detect the proliferative, migrative and invasive capabilities of GC cells, respectively. The LinkedOmics database and StarBase database were utilized to analyze the related genes with NRSN2 in GC. The association of NRSN2 expression with tumor immune infiltrating cells and molecular markers of immune cells was investigated with the TIMER database. RESULTS: NRSN2 expression was up-regulated in GC tissues, which was correlated with GC tumor grade, lymph node metastasis, and TP53 mutation. The prognosis of GC patients with high NRSN2 expression was worse than those of the patients with low NRSN2 expression. NRSN2 expression was also associated with the TNM stage, and Lauren subtype of GC patients. NRSN2 overexpression promoted the growth, migration and invasion of GC cells lines; knocking down NRSN2 worked oppositely. NRSN2 expression in GC was associated with Wnt, p53, and NOD-like receptor signaling pathways. NRSN2 expression was also significantly associated with the infiltration of CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells in the GC microenvironment. CONCLUSION: NRSN2 expression in GC tissues is up-regulated, which correlates with a poor prognosis and immune cell infiltration of GC patients. NRSN2 facilitates the growth and aggressiveness of GC cells, implying that it may be a diagnostic biomarker and therapy target for GC.

Covalently Grafted Biomimetic Matrix Reconstructs the Regenerative Microenvironment of the Porous Gradient Polycaprolactone Scaffold to Accelerate Bone Remodeling.

Integrating a biomimetic extracellular matrix to improve the microenvironment of 3D printing scaffolds is an emerging strategy for bone substitute design. Here, a "soft-hard" bone implant (BM-g-DPCL) consisting of a bioactive matrix chemically integrated on a polydopamine (PDA)-coated porous gradient scaffold by polyphenol groups is constructed. The PDA-coated "hard" scaffolds promoted Ca2+ chelation and mineral deposition; the "soft" bioactive matrix is beneficial to the migration, proliferation, and osteogenic differentiation of stem cells in vitro, accelerated endogenous stem cell recruitment, and initiated rapid angiogenesis in vivo. The results of the rabbit cranial defect model (Φ = 10 mm) confirmed that BM-g-DPCL promoted the integration between bone tissue and implant and induced the deposition of bone matrix. Proteomics confirmed that cytokine adhesion, biomineralization, rapid vascularization, and extracellular matrix formation are major factors that accelerate bone defect healing. This strategy of highly chemically bonded soft-hard components guided the construction of the bioactive regenerative scaffold.

KCNE4 expression is correlated with the pathological characteristics of colorectal cancer patients and associated with the radioresistance of cancer cells.

BACKGROUND: Colorectal cancer (CRC) is a common malignancy, and radioresistance limits the effectiveness of radiotherapy for rectal cancer. This study is performed to investigate the role and regulatory mechanism of Potassium Voltage-Gated Channel Subfamily E Regulatory Subunit 4 (KCNE4) in the radioresistance of CRC cells. METHODS: Immunohistochemical staining results of KCNE4 in normal tissues and CRC tissues were obtained from the Human Protein Atlas (HPA) database. The UALCAN database was used for analyzing KCNE4 mRNA expression in normal tissue samples and CRC tissue samples and its relationship with tumor stage. The relationship of KCNE4 expression with prognosis was analyzed utilizing the data of GEPIA database. LinkedOmics database was searched to analyze the co-expressed gene sets of KCNE4 in CRC, and to analyze the signaling pathways related with KCNE4 in CRC. GO and KEGG enrichment analyses were carried out on the co-expressed genes of KCNE4 with DAVID database. Ionizing radiation (IR)-resistant cell lines (HCT116/IR and HT29/IR) were established; cell viability was assessed via cell counting kit-8 (CCK-8) and EdU assays, and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay was performed for detecting cell apoptosis. Western blotting was carried out to detect the expressions of p-p85 and p-AKT. RESULTS: KCNE4 was highly expressed in CRC tissues and linked to advanced tumor stage, lymph node metastasis and poor prognosis of CRC patients. KCNE4 overexpression promoted HCT116/IR cell proliferation and inhibited the apoptosis, while KCNE4 knockdown suppressed HT29/IR cell proliferation and facilitated the apoptosis. Furthermore, high KCNE4 expression was associated with the activation of the PI3K/AKT signal pathway. CONCLUSION: KCNE4 is associated with the clinicopathological characteristics of CRC patients, and its high expression level contributes to the radioresistance of cancer cells via activating the PI3K/AKT signal pathway.

Tailorable 3DP Flexible Scaffolds with Porosification of Filaments Facilitate Cell Ingrowth and Biomineralized Deposition.

Facilitating cell ingrowth and biomineralized deposition inside filaments of 3DP scaffolds are an ideal bone repair strategy. Here, 3D printed PLGA/HA scaffolds with hydroxyapatite content of 50% (P5H5) and 70% (P3H7) were prepared by optimizing 3D printing inks, which exhibited good tailorability and foldability to meet clinical maneuverability. The supercritical CO2 foaming technology further endowed the filaments of P5H5 with a richer interconnected pore structure (P5H5-C). The finite element and computational fluid dynamics simulation analysis indicated that the porosification could effectively reduce the stress concentration at the filament junction and improved the overall permeability of the scaffold. The results of in vitro experiments confirmed that P5H5-C promoted the adsorption of proteins on the surface and inside of filaments, accelerated the release of Ca and P ions, and significantly upregulated osteogenesis (Col I, ALP, and OPN)- and angiogenesis (VEGF)-related gene expression. Subcutaneous ectopic osteogenesis experiments in nude mice further verified that P5H5-C facilitated cell growth inside filaments and biomineralized deposition, as well as significantly upregulated the expression of osteogenesis- and angiogenesis-related genes (Col I, ALP, OCN, and VEGF) and protein secretion (ALP, RUNX2, and VEGF). The porosification of filaments by supercritical CO2 foaming provided a new strategy for accelerating osteogenesis of 3DP implants.

An instantly fixable and self-adaptive scaffold for skull regeneration by autologous stem cell recruitment and angiogenesis.

Limited stem cells, poor stretchability and mismatched interface fusion have plagued the reconstruction of cranial defects by cell-free scaffolds. Here, we designed an instantly fixable and self-adaptive scaffold by dopamine-modified hyaluronic acid chelating Ca2+ of the microhydroxyapatite surface and bonding type I collagen to highly simulate the natural bony matrix. It presents a good mechanical match and interface integration by appropriate calcium chelation, and responds to external stress by flexible deformation. Meanwhile, the appropriate matrix microenvironment regulates macrophage M2 polarization and recruits endogenous stem cells. This scaffold promotes the proliferation and osteogenic differentiation of BMSCs in vitro, as well as significant ectopic mineralization and angiogenesis. Transcriptome analysis confirmed the upregulation of relevant genes and signalling pathways was associated with M2 macrophage activation, endogenous stem cell recruitment, angiogenesis and osteogenesis. Together, the scaffold realized 97 and 72% bone cover areas after 12 weeks in cranial defect models of rabbit (Φ = 9 mm) and beagle dog (Φ = 15 mm), respectively.

Bioinspired Hydrogel Anchoring 3DP GelMA/HAp Scaffolds Accelerates Bone Reconstruction.

Seeking high biological activity and osteoinductive ability has always been an urgent problem for three-dimensional-printed (3DP) bony implants. Here, a 3DP methacrylic anhydride-modified gelatin (GelMA)/hydroxyapatite (HAp) scaffold with a high solid content of 82.5% was prepared and anchored by a functionalized polyphenol hydrogel. The scaffold and hydrogel were organically integrated into a bioinspired bony implant (HGH) by phenolic hydroxyl of hyaluronan derivatives conjugating amino groups of collagen I and GelMA and further chelating calcium ions of HAp. Compared with a simplex 3DP scaffold, this freeze-dried HGH presented better water retention, delayed degradation, and mechanical stability. It could promote migration, proliferation, and osteogenic differentiation of bone marrow stem cells in vitro. One week of implantation showed that it promoted directional migration of endogenous stem cells and early osteogenesis and angiogenesis. After 15 week surgery of rabbit skull defects, the BV/TV value of HGH returned to 73% of the normal group level. This strategy provided a new research idea for bone regeneration.

Biomaterials-assisted exosomes therapy in osteoarthritis.

Due to the avascular characteristic of articular cartilage, its self-repair capacity is limited. When cartilage is damaged or forms osteoarthritis (OA), clinical treatment is necessary. However, conventional treatments, including joint replacement, microfracture, cell and drug therapies, have certain limits. Lately, the exosomes derived from mesenchymal stem cells (MSCs-EXO), which consist of complex transcription factors, proteins and targeting ligand components, have shown great therapeutic potentials. With recent advancements in various biomaterials to extend MSCs-EXO's retention time and control the release propertiesin vivo, biomaterials-assisted exosomes therapy has been soon becoming a practically powerful tool in treating OA. This review analyzes the effects of MSCs-EXO on OA inflammation, metabolism, ageing and apoptosis, and introduces the combinational systems of MSCs-EXO with biomaterials to enhance the repair, anti-inflammatory, and homeostasis regulation functions. Moreover, different types of natural or synthetic biomaterials and their applications with MSCs-EXO were also described and discussed. And finally, we presage the future perspective in the development of biomaterial-assisted exosome therapies, as well as the potential to incorporate with other treatments to enhance their therapeutic effects in OA.

Copolymers of 4-Trimethylsilyl Diphenyl Acetylene and 1-Trimethylsilyl-1-Propyne: Polymer Synthesis and Luminescent Property Adjustment.

Poly(4-trimethylsilyl diphenyl acetylene) (PTMSDPA) has strong fluorescence emission, but its application is limited by the effect of aggregation-caused quenching (ACQ). Copolymerization is a commonly used method to adjust the properties of polymers. Through the copolymerization of 4-trimethylsilyl diphenyl acetylene and 1-trimethylsilyl-1-propyne (TMSP), we successfully realized the conversion of PTMSDPA from ACQ to aggregation-induced emission (AIE) and aggregation-induced emission enhancement (AEE). By controlling the monomer feeding ratio and with the increase of the content of TMSDPA inserted into the copolymer, the emission peak was red-shifted, and a series of copolymers of poly(TMSDPA-co-TMSP) that emit blue-purple to orange-red light was obtained, and the feasibility of the application in explosive detection was verified. With picric acid (PA) as a model explosive, a super-quenching process has been observed, and the quenching constant (KSV) calculated from the Stern-Volmer equation is 24,000 M-1, which means that the polymer is potentially used for explosive detection.

Childhood Cartilage ECM Enhances the Chondrogenesis of Endogenous Cells and Subchondral Bone Repair of the Unidirectional Collagen-dECM Scaffolds in Combination with Microfracture.

Despite the formation of mechanically inferior fibrocartilage, microfracture (MF) still remains the gold standard to repair the articular cartilage defects in clinical settings. To date, although many tissue-engineering scaffolds have been developed to enhance the MF outcome, the clinical outcomes remain inconsistent. Decellularized extracellular matrix (dECM) is among the most promising scaffold for cartilage repair due to its inheritance of the natural cartilage components. However, the impact of dECM from different developmental stages on cellular chondrogenesis and therapeutic effect remains elusive, as the development of native cartilage involves the distinct temporal dependency of the ECM components and various growth factors. Herein, we hypothesized that the immature cartilage dECM at various developmental stages was inherently different, and would consequently impact the chondrogenic potential BMSCs. In this study, we fabricated three different unidirectional collagen-dECM scaffolds sourced from neonatal, childhood, and adolescent rabbit cartilage tissues, and identified the age-dependent biological variations, including DNA, cartilage-specific proteins, and growth factors; along with the mechanical and degradation differences. Consequently, the different local cellular microenvironments provided by these scaffolds led to the distinctive cell morphology, circularity, proliferation, chondrogenic genes expression, and chondrogenesis of BMSCs in vitro, and the different gross morphology, cartilage-specific protein production, and subchondral bone repair when in combination with microfracture in vivo. Together, this work highlights the immature cartilage dECM at different developmental stages that would result in the diversified effects to BMSCs, and childhood cartilage would be considered the optimal dECM source for the further development of dECM-based tissue engineering scaffolds in articular cartilage repair.

Integrated Analysis of the Transcriptome and Metabolome Reveals Genes Involved in Terpenoid and Flavonoid Biosynthesis in the Loblolly Pine (Pinus taeda L.).

Loblolly pine (Pinus taeda L.) is an important tree for afforestation with substantial economic and ecological value. Many metabolites with pharmacological activities are present in the tissues of P. taeda. However, the biosynthesis regulatory mechanisms of these metabolites are poorly understood. In the present study, transcriptome and metabolome analyses were performed on five tissues of P. taeda. A total of 40.4 million clean reads were obtained and assembled into 108,663 unigenes. These were compared with five databases, revealing 39,576 annotated unigenes. A total of 13,491 differentially expressed genes (DEGs) were observed in 10 comparison groups. Of these, 487 unigenes exhibited significantly different expressions in specific tissues of P. taeda. The DEGs were explored using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes metabolic pathway analysis. We identified 343 and 173 candidate unigenes related to the biosynthesis of terpenoids and flavonoids, respectively. These included 62 R2R3-MYB, 30 MYB, 15 WRKY, seven bHLH, seven ERF, six ZIP, five AP2, and one WD40 genes that acted as regulators in flavonoid and/or terpenoid biosynthesis. Additionally, metabolomics analysis detected 528 metabolites, among which 168 were flavonoids. A total of 493 differentially accumulated metabolites (DAMs) were obtained in 10 comparison groups. The 3,7-Di-O-methyl quercetin was differentially accumulated in all the comparison groups. The combined transcriptome and metabolome analyses revealed 219 DEGs that were significantly correlated with 45 DAMs. Our study provides valuable genomic and metabolome information for understanding P. taeda at the molecular level, providing a foundation for the further development of P. taeda-related pharmaceutical industry.

[Research Progress in Promotion of Tissue Regeneration and Reconstruction with Exosomes Derived from Mesenchymal Stem Cells].

In regenerative medicine, stem cell therapy is an effective strategy for tissue regeneration and has a positive therapeutic effect on the regeneration and repair of defective tissues. In recent years, a series of studies have shown that the positive effects of stem cell therapy are mediated by exosomes released by the paracrine action of mesenchymal stem cells. Researchers have thus proposed a novel treatment strategy to use stem-cell-derived exosomes alone for tissue regeneration and repair, and affirmed through studies that the effects achieved were comparable to those of stem-cell-based therapies. Therefore, as a promising treatment strategy, exosome-based tissue regeneration treatment measures have been extensively studied. In this review, we discussed the latest knowledge of exosomes and the research progress in the regeneration and repair of related connective tissues, including the regeneration of bones, cartilage, skin, spinal cord and tendons, and briefly discussed the corresponding mechanisms. In addition, the challenges and prospects of tissue regeneration and repair based on mesenchymal stem cell exosomes were discussed.

The effect of LyPRP/collagen composite hydrogel on osteogenic differentiation of rBMSCs.

Although platelet-rich plasma (PRP) plays a significant role in the orthopedic clinical application, it still faces two major problems, namely, uncontrollable factors release, frequent preparation and extraction processes as well as the inconvenient form of usage. To overcome these shortcomings, freeze-dried PRP (LyPRP) was encapsulated into bioactive Col I hydrogel to induce osteogenic differentiation of rabbit bone marrow mesenchymal stem cells (rBMSCs). And PRP/Col І composite hydrogel was prepared as a control. Compared with Col І hydrogel, the introduction of platelets significantly improved the mechanical properties of hydrogels. Meanwhile, platelets were evenly distributed in the composite hydrogels network. The sustainable release of related factors in the composite hydrogels could last for more than 14 days to maintain its long-term biological activity. Further cell experiments confirmed that PRP and LyPRP could effectively alleviate the contraction of collagen hydrogel in vitro, and promote the adhesion, proliferation and osteogenesis differentiation of rBMSCs. The results of osteogenic gene expression indicated that the 10% LyPRP/Col І composite hydrogel could facilitate the early expression of BMP-2 and late osteogenic associated protein formation with higher expression of alkaline phosphatase and Osteocalcin (OCN). These results might provide new insights for the clinical application of 10% LyPRP/Col І composite hydrogel as practical bone repair injection.

SPT6 recruits SND1 to co-activate human telomerase reverse transcriptase to promote colon cancer progression.

Human telomerase reverse transcriptase (hTERT) plays an extremely important role in cancer initiation and development, including colorectal cancer (CRC). However, the precise upstream regulatory mechanisms of hTERT in different cancer types remain poorly understood. Here, we uncovered the candidate transcriptional factor of hTERT in CRC and explored its role and the corresponding molecular mechanisms in regulating hTERT expression and CRC survival with an aim of developing mechanism-based combinational targeting therapy. The possible binding proteins at the hTERT promoter were uncovered using pull-down/mass spectrometry analysis. The regulation of SPT6 on hTERT expression and CRC survival was evaluated in human CRC cell lines and mouse models. Mechanistic studies focusing on the synergy between SPT6 and staphylococcal nuclease and Tudor domain containing 1 (SND1) in controlling hTERT expression and CRC progression were conducted also in the above two levels. The expression correlation and clinical significance of SPT6, SND1, and hTERT were investigated in tumor tissues from murine models and patients with CRC in situ. SPT6 was identified as a possible transcriptional factor to bind to the hTERT promoter. SPT6 knockdown decreased the activity of hTERT promoter, downregulated the protein expression level of hTERT, suppressed proliferation, invasion, and stem-like properties, promoted apoptosis induction, and enhanced chemotherapeutic drug sensitivity in vitro. SPT6 silencing also led to the delay of tumor growth and metastasis in mice carrying xenografts of human-derived colon cancer cells. Mechanistically, SND1 interacted with SPT6 to co-control hTERT expression and CRC cell proliferation, stemness, and growth in vitro and in vivo. SPT6, SND1, and hTERT were highly expressed simultaneously in CRC tissues, both from the murine model and patients with CRC in situ, and pairwise expression among these three factors showed a significant positive correlation. In brief, our research demonstrated that SPT6 synergized with SND1 to promote CRC development by targeting hTERT and put forward that inhibiting the SPT6-SND1-hTERT axis may create a therapeutic vulnerability in CRC.