GPR97 deficiency suppresses Wnt/ß-catenin signaling in hypertensive nephropathy.

Accumulating evidence shows that renal fibrosis plays a key role in the development of hypertensive nephropathy (HTN). Therefore, a better understanding of the underlying mechanism of renal fibrosis regulation in HTN would be critical for designing rational strategies for therapeutic interventions. In this study, we revealed that GPR97, a novel identified adhesion G coupled receptor, plays an important role in the regulation of Wnt/ß-catenin signaling, which is the crucial driver of renal fibrosis in HTN. First, we identified that the expression of GPR97 correlated with the ß-catenin expression in renal biopsy from patients with HTN. Moreover, we found that GPR97 deficiency inhibited Wnt/ß-catenin signaling in mice with HTN, as evidenced by the reduction of ß-catenin expression and downstream target proteins, including MMP7 and Fibronectin. Mechanistically, we found that GPR97 could directly bind with Wnt1 in cultured tubular cells and TGF-ß1 treatment enhanced the binding ability of GPR97 and Wnt1. In addition, the gene silencing of GPR97 could decrease the Wnt1-induced fibrotic phenotype of tubular cells and inflammatory responses, suggesting that the binding of GPR97 and Wnt1 promoted Wnt/ß-catenin signaling. Collectively, our studies reveal that GPR97 is a regulator of Wnt/ß-catenin signaling in HTN, and targeting GPR97 may be a novel therapeutic strategy for HTN treatment.

ITGBL1 promotes anoikis resistance and metastasis in human gastric cancer via the AKT/FBLN2 axis.

The resistance to anoikis plays a critical role in the metastatic progression of various types of malignancies, including gastric cancer (GC). Nevertheless, the precise mechanism behind anoikis resistance is not fully understood. Here, our primary focus was to examine the function and underlying molecular mechanism of Integrin beta-like 1 (ITGBL1) in the modulation of anoikis resistance and metastasis in GC. The findings of our investigation have demonstrated that the overexpression of ITGBL1 significantly augmented the resistance of GC cells to anoikis and promoted their metastatic potential, while knockdown of ITGBL1 had a suppressive effect on both cellular processes in vitro and in vivo. Mechanistically, we proved that ITGBL1 has a role in enhancing the resistance of GC cells to anoikis and promoting metastasis through the AKT/Fibulin-2 (FBLN2) axis. The inhibition of AKT/FBLN2 signalling was able to reverse the impact of ITGBL1 on the resistance of GC cells to anoikis and their metastatic capability. Moreover, the expression levels of ITGBL1 were found to be significantly elevated in the cancerous tissues of patients diagnosed with GC, and there was a strong correlation observed between high expression levels of ITGBL1 and worse prognosis among individuals diagnosed with GC. Significantly, it was revealed that within our cohort of GC patients, individuals exhibiting elevated ITGBL1 expression and diminished FBLN2 expression experienced the worst prognosis. In conclusion, the findings of our study indicate that ITGBL1 may serve as a possible modulator of resistance to anoikis and the metastatic process in GC.

Cardiorespiratory fitness and metabolic risk in Chinese population: evidence from a prospective cohort study.

BACKGROUND: Studies on the association between estimated cardiorespiratory fitness (CRF) and changes in metabolic risk in the Chinese population are limited. This study aims to examine the associations between CRF and changes in metabolic risk. SUBJECTS AND METHODS: We included 4,862 and 2,700 participants recruited from 28 provinces in the China Health and Retirement Longitudinal Study (CHARLS) in the baseline (Wave 1) and follow-up (Wave 4) analyses, respectively. CRF was calculated using sex-specific longitudinal non-exercise equations. Metabolic indicators included systolic blood pressure (SBP), diastolic blood pressure (DBP), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and fasting plasma glucose (FPG) levels. The metabolic score was calculated as the number of changes in the above metabolic indicators above the 75th percentile of the distribution of changes (equal to or below the 25th percentile for HDL-C). RESULTS: In the baseline analysis, CRF was negatively associated with SBP, DBP, TG, and FPG, and positively correlated with HDL-C after adjusting for age, smoking status, and drinking status (all P < 0.0001) in both males and females. In the follow-up analysis, higher baseline CRF was significantly related to a decrease in SBP, DBP, TG, FPG, and metabolic score (all P < 0.0005), and increased HDL-C (P < 0.0001) after further adjustment for corresponding baseline metabolic indicators. The associations remained significant after stratification by sex, except for the changes in HDL-C levels in females. Furthermore, improved CRF was associated with favorable changes in DBP, TG, HDL-C, FPG, and metabolic scores in all populations and males. Significant associations between changes in CRF and DBP, TG, and FPG levels were found in females. CONCLUSION: Higher baseline CRF and improved CRF were associated with favorable changes in metabolic indicators.

Association between diverticular disease and colorectal cancer: a bidirectional mendelian randomization study.

BACKGROUND: Diverticular disease has been inconsistently associated with colorectal cancer risk. We conducted a bidirectional Mendelian randomization study to assess this association. METHODS: Forty-three and seventy single-nucleotide polymorphisms associated with diverticular disease and colorectal cancer at the genome-wide significance level (p < 5 × 10- 8) were selected as instrumental variables from large-scale genome-wide association studies of European descent, respectively. Summary-level data for colon cancer, rectum cancer, and colorectal cancer were obtained from genome-wide association analyses of the FinnGen consortium and the UK Biobank study. Summary-level data for diverticular disease was derived from a genome-wide association study conducted in the UK Biobank population. The random effect inverse-variance weighted Mendelian randomization approach was used as the primary method and MR-Egger, weighted-median, and MR-PRESSO approaches were conducted as sensitivity analyses. RESULTS: Genetically determined diverticular disease was associated with a higher risk of colorectal cancer (beta = 0.441, 95%CI: 0.081-0.801, P = 0.016) in the FinnGen population, but the association was not found in the UK Biobank (beta = 0.208, 95%CI: -0.291,0.532, P = 0.207). The positive association remained consistent direction in the three sensitivity analyses. In the stratified analysis in the FinnGen consortium, an association was found to exist between genetically predicted diverticular disease and colon cancer (beta = 0.489, 95%CI: 0.020-0.959, P = 0.041), rather than rectum cancer (beta = 0.328, 95%CI: -0.119-0.775, P = 0.151). Besides, we found a slight association between colorectal cancer and diverticular disease (beta = 0.007, 95%CI: 0.004-0.010, P < 0.001) when using colorectal cancer as exposome and diverticular disease as outcome. However, there is a large sample overlap in this step of analysis. CONCLUSION: This Mendelian randomization study suggests that diverticular disease may be a possible risk factor for colorectal cancer and colon cancer rather than rectum cancer in the FinnGen population.

GPR97 deficiency ameliorates renal interstitial fibrosis in mouse hypertensive nephropathy.

Hypertensive nephropathy (HTN) ranks as the second-leading cause of end-stage renal disease (ESRD). Accumulating evidence suggests that persistent hypertension injures tubular cells, leading to tubulointerstitial fibrosis (TIF), which is involved in the pathogenesis of HTN. G protein-coupled receptors (GPCRs) are implicated in many important pathological and physiological processes and act as important drug targets. In this study, we explored the intrarenal mechanisms underlying hypertension-associated TIF, and particularly, the potential role of GPR97, a member of the adhesion GPCR subfamily, in TIF. A deoxycorticosterone acetate (DOCA)/salt-induced hypertensive mouse model was used. We revealed a significantly upregulated expression of GPR97 in the kidneys, especially in renal tubules, of the hypertensive mice and 10 patients with biopsy-proven hypertensive kidney injury. GPR97-/- mice showed markedly elevated blood pressure, which was comparable to that of wild-type mice following DOCA/salt treatment, but dramatically ameliorated renal injury and TIF. In NRK-52E cells, we demonstrated that knockdown of GPR97 suppressed the activation of TGF-ß signaling by disturbing small GTPase RhoA-mediated cytoskeletal reorganization, thus inhibiting clathrin-mediated endocytosis of TGF-ß receptors and subsequent Smad activation. Collectively, this study demonstrates that GPR97 contributes to hypertension-associated TIF at least in part by facilitating TGF-ß signaling, suggesting that GPR97 is a pivotal intrarenal factor for TIF progression under hypertensive conditions, and therapeutic strategies targeting GPR97 may improve the outcomes of patients with HTN.

SLC6A14 facilitates epithelial cell ferroptosis via the C/EBPß-PAK6 axis in ulcerative colitis.

Emerging evidence suggests that ferroptosis is involved in the pathogenesis of ulcerative colitis (UC). However, the key regulator of this process remains uncertain. In this study, we aimed to explore the roles of solute carrier (SLC) family 6 member 14 (SLC6A14) in regulating ferroptosis in UC. The expression of SLC6A14 was significantly increased and positively associated with that of prostaglandin-endoperoxide synthase 2 (PTGS2) in tissue samples from patients with UC. Moreover, a series of in vitro and in vivo experiments showed that SLC6A14 knockdown markedly suppressed ferroptosis. RNA sequencing revealed that SLC6A14 inhibited the expression of P21 (RAC1)-activated kinase 6 (PAK6) and that PAK6 knockdown abolished the effects of SLC6A14 on RAS-selective lethal 3 (RSL3)-induced ferroptosis in Caco-2 cells. Furthermore, chromatin immunoprecipitation (ChIP) and Western blot analysis demonstrated that SLC6A14 negatively regulated PAK6 expression in a CCAAT enhancer binding protein beta (C/EBPß)-dependent manner. Collectively, these findings indicate that SLC6A14 facilitates ferroptosis in UC by promoting C/EBPß expression and binding activity to inhibit PAK6 expression, suggesting that targeting SLC6A14-C/EBPß-PAK6 axis-mediated ferroptosis may be a promising therapeutic alternative for UC.

Estimated cardiorespiratory fitness and incident risk of cardiovascular disease in China.

BACKGROUND: Limited evidence is available on the association between estimated cardiorespiratory fitness (e-CRF) and incidence of cardiovascular disease (CVD) in Chinese population. METHODS: A total of 10,507 adults including 5084 men (48.4%) and 5423 (51.6%) women with a median age of 56.0 (25% quantile: 49, 75% quantile 63) years from the China Health and Retirement Longitudinal Study (CHARLS) was recruited in 2011 as baseline. The CVD incident events were followed-up until 2018. e-CRF was calculated from sex-specific longitudinal non-exercise equations and further grouped into quartiles. Cox proportional models were used to calculate hazard ratio (HR) and 95% confidence interval (CI) for incidence risks of CVD, heart disease and stroke. RESULTS: During a median follow-up of 7 years, a total of 1862 CVD, 1409 heart disease and 612 stroke events occurred. In fully adjusted models, each one MET increment of e-CRF was associated with lower risk of CVD (HR = 0.91, 95%CI = 0.85-0.96 for males, HR = 0.87, 95%CI = 0.81-0.94 for females). Compared with the Quartile (Q)1 group, the HRs (95%CI) of the Q2, Q3 and Q4 groups were 0.84 (0.63-1.03), 0.72 (0.57-0.91) and 0.66 (0.51-0.87) for CVD in males. Females had HRs of 0.79 (0.66-0.96) in Q2, 0.71 (0.57-0.88) in Q3 and 0.58 (0.45-0.75) in Q4 for CVD. The associations between e-CRF and heart disease and stroke were slightly weaker than that for CVD in both males and females. CONCLUSIONS: Higher e-CRF decreases the incident risk of CVD, heart disease and stroke.

Gastric cancer-derived exosomal miR-135b-5p impairs the function of Vγ9Vδ2 T cells by targeting specificity protein 1.

Recent studies have shown that tumor-derived exosomes participate in the communication between tumor cells and their microenvironment and mediate malignant biological behaviors including immune escape. In this study, we found that gastric cancer (GC) cell-derived exosomes could be effectively uptaken by Vγ9Vδ2 T cells, decrease the cell viability of Vγ9Vδ2 T cells, induce apoptosis, and reduce the production of cytotoxic cytokines IFN-γ and TNF-α. Furthermore, we demonstrated that exosomal miR-135b-5p was delivered into Vγ9Vδ2 T cells. Exosomal miR-135b-5p impaired the function of Vγ9Vδ2 T cells by targeting specificity protein 1 (SP1). More importantly, blocking the SP1 function by Plicamycin, an SP1 inhibitor, abolished the effect of stable miR-135b-5p knockdown GC cell-derived exosomes on Vγ9Vδ2 T cell function. Collectively, our results suggest that GC cell-derived exosomes impair the function of Vγ9Vδ2 T cells via miR-135b-5p/SP1 pathway, and targeting exosomal miR-135b-5p/SP1 axis may improve the efficiency of GC immunotherapy based on Vγ9Vδ2 T cells.

pH-Responsive Nanoparticle Superlattices with Tunable DNA Bonds.

Stimuli-responsive nanomaterials with reconfigurable structures and properties have garnered significant interest in the fields of optics, electronics, magnetics, and therapeutics. DNA is a powerful and versatile building material that provides programmable structural and dynamic properties, and indeed, sequence-dependent changes in DNA have already been exploited in creating switchable DNA-based architectures. However, rather than designing a new DNA input sequence for each intended dynamic change, it would be useful to have one simple, generalized stimulus design that could provide multiple different structural outputs. In pursuit of this goal, we have designed, synthesized, and characterized pH-dependent, switchable nanoparticle superlattices by utilizing i-motif DNA structures as pH-sensitive DNA bonds. When the pH of the solution containing such superlattices is changed, the superlattices reversibly undergo: (i) a lattice expansion or contraction, a consequence of the pH-induced change in DNA length, or (ii) a change in crystal symmetry, a consequence of both pH-induced DNA "bond breaking" and "bond forming" processes. The introduction of i-motifs in DNA colloidal crystal engineering marks a significant step toward being able to dynamically modulate crystalline architectures and propagate local molecular motion into global structural change via exogenous stimuli.

The Structural Fate of Individual Multicomponent Metal-Oxide Nanoparticles in Polymer Nanoreactors.

Multicomponent nanoparticles can be synthesized with either homogeneous or phase-segregated architectures depending on the synthesis conditions and elements incorporated. To understand the parameters that determine their structural fate, multicomponent metal-oxide nanoparticles consisting of combinations of Co, Ni, and Cu were synthesized by using scanning probe block copolymer lithography and characterized using correlated electron microscopy. These studies revealed that the miscibility, ratio of the metallic components, and the synthesis temperature determine the crystal structure and architecture of the nanoparticles. A Co-Ni-O system forms a rock salt structure largely owing to the miscibility of CoO and NiO, while Cu-Ni-O, which has large miscibility gaps, forms either homogeneous oxides, heterojunctions, or alloys depending on the annealing temperature and composition. Moreover, a higher-ordered structure, Co-Ni-Cu-O, was found to follow the behavior of lower ordered systems.

Three-dimensional nitrogen-doped graphene nanoribbons aerogel as a highly efficient catalyst for the oxygen reduction reaction.

A highly conductive, ultralight, neat and versatile nitrogen-doped GNRs aerogel has been fabricated by a new hydrothermal method for the first time. The newly developed aerogel shows a very promising performance when used as a novel ORR catalyst in both alkaline and acidic solutions.

Nitrogen-Doped Carbon Nanotube Aerogels for High-Performance ORR Catalysts.

By utilizing the dual roles of the erasable promoter (pyrrole), "clean", highly conductive, and nitrogen-doped CNT aerogels are derived from a promoter-assisted hydrothermal reaction (HTR) coupling with pyrolysis. The resulting materials show an excellent performance towards oxygen reduction reaction (ORR).

Functional magnetic nanoparticles for non-viral gene delivery and MR imaging.

Gene therapy is becoming a promising strategy to treat various kinds of genetic and acquired diseases. However, the development of safe, efficient, and targetable gene delivery systems remains a major challenge in gene therapy. The unique material characteristics of magnetic nanoparticles (MNPs), including high surface area, facile surface modification, controllable size, and excellent magnetic properties, make them promising candidates for gene delivery. The engineered MNPs with modifiable functional surfaces and bioactive cores can result in several advantageous diagnostic and therapeutic properties including enhanced magnetic resonance imaging (MRI) signal intensity, long permeation and retention in the circulatory system, specific delivery of therapeutic genes to target sites. In this review, the updated research on the preparation and surface modification of MNPs for gene delivery is summarized.

Building nanocomposite magnets by coating a hard magnetic core with a soft magnetic shell.

Controlling exchange coupling between hard magnetic and soft magnetic phases is the key to the fabrication of advanced magnets with tunable magnetism and high energy density. Using FePt as an example, control over the magnetism in exchange-coupled nanocomposites of hard magnetic face-centered tetragonal (fct) FePt and soft magnetic Co (or Ni, Fe2C) is shown. The dispersible hard magnetic fct-FePt nanoparticles are first prepared with their coercivity (Hc) reaching 33 kOe. Then core/shell fct-FePt/Co (or Ni, Fe2C) nanoparticles are synthesized by reductive thermal decomposition of the proper metal precursors in the presence of fct-FePt nanoparticles. These core/shell nanoparticles are strongly coupled by exchange interactions and their magnetic properties can be rationally tuned by the shell thickness of the soft phase. This work provides an ideal model system for the study of exchange coupling at the nanoscale, which will be essential for building superstrong magnets for various permanent magnet applications in the future.

NR4A1 depletion inhibits colorectal cancer progression by promoting necroptosis via the RIG-I-like receptor pathway.

Necroptosis is a regulated necrotic cell death mechanism and plays a crucial role in the progression of cancers. However, the potential role and mechanism of necroptosis in colorectal cancer (CRC) has not been fully elucidated. In this study, we found that nuclear receptor subfamily 4 group A member 1 (NR4A1) was highly expressed in CRC cells treated with TNF-α, Smac mimetic, and z-VAD-FMK (TSZ). The depletion of NR4A1 significantly enhanced the sensitivity of CRC cells to TSZ-induced necroptosis, while NR4A1 overexpression suppressed these effects, as evidenced by the LDH assay, flow cytometry analysis of cell death, PI staining, and expression analysis of necrosome complexes (RIPK1, RIPK3, and MLKL). Moreover, NR4A1 deficiency made HT29 xenograft tumors sensitive to necroptotic cell death in vivo. Mechanistically, NR4A1 depletion promoted necroptosis activation in CRC through the RIG-I-like receptor pathway by interacting with DDX3. Importantly, the RIG-I pathway agonist poly(I:C) or inhibitor cFP abolished the effects of NR4A1 overexpression or suppression on necroptosis in CRC cells. Moreover, we observed that NR4A1 was highly expressed in CRC tissues and was associated with a poor prognosis. In conclusion, our results suggest that NR4A1 plays a critical role in modulating necroptosis in CRC cells and provide a new therapeutic target for CRC.

HOOK3 suppresses proliferation and metastasis in gastric cancer via the SP1/VEGFA axis.

HOOK3, a member of the human hook microtubule-tethering protein family, has been implicated in the progression of cancer. However, the role of HOOK3 in the pathogenesis of gastric cancer (GC) remains incompletely understood. In this study, we investigated the expression of HOOK3 protein in GC tissues using immunohistochemistry (IHC). The findings of our study indicate that the expression levels of HOOK3 in GC tissues were relatively low. Furthermore, a significant negative association was seen between HOOK3 expression and the prognosis of patients with GC. The suppression of HOOK3 resulted in a notable increase in the proliferation, migration, invasion, and survival of GC cells. Conversely, the overexpression of HOOK3 had the opposite impact, reducing these cellular processes. Moreover, in vivo tests have shown evidence that the overexpression of HOOK3 significantly inhibited the formation of tumors and the spread of GC cells to the lungs. In a mechanistic manner, the analysis of RNA-seq data demonstrated that the knockdown of HOOK3 resulted in a notable increase in the expression of vascular endothelial growth factor A (VEGFA) in GC cells. Furthermore, the upregulation of VEGFA counteracted the impacts of HOOK3 upregulation on the proliferation, migration, invasion, and survival of GC cells. Furthermore, it was revealed that specificity protein 1 (SP1) exhibited the ability to bind to the promoter region of VEGFA. Moreover, the overexpression of SP1 successfully counteracted the inhibitory impact of HOOK3 overexpression on the expression of VEGFA in GC cells. In summary, the results of our study indicate that HOOK3 has a role in inhibiting the growth, migration, invasion, and survival of GC cells by modulating the SP1/VEGFA pathway. These findings contribute significant knowledge to our understanding of the underlying mechanisms involved in the development of GC.

Metabolic health and adiposity transitions and risks of type 2 diabetes and cardiovascular diseases: a systematic review and meta-analysis.

BACKGROUND: Metabolic health status and levels of adiposity are prone to change over time. Mixed results have been reported regarding the extent by which changes in metabolic health and weight affect cardiometabolic risks. This systematic review and meta-analysis aims to examine the association between transitions in metabolic health and adiposity status on risk of incident type 2 diabetes (T2DM) and cardiovascular disease (CVD) events. METHODS: A systematic literature search was conducted on MEDLINE and EMBASE through August 2022 for prospective cohort studies examining transitions in metabolic health and adiposity status and risk of incident T2DM and CVDs without restrictions on language or publication status. Meta-analysis was performed to summarize hazard ratios for T2DM and composite CVD events separately using random-effects model. RESULTS: A total of 17 studies were included. Compared to stable metabolically healthy status, transition to metabolically unhealthy status significantly increased the risk of incident T2DM and composite CVD events among individuals with normal weight and individuals with overweight/obesity. Compared to stable metabolically unhealthy status, transition to metabolically healthy status significantly lowered the risk among individuals with normal weight and individuals with overweight/obesity. When metabolic health status remained unchanged, progression from normal weight to overweight/obesity significantly increased risk of CVDs but not risk of T2DM. CONCLUSION: The impact of change in metabolic health on the risks of T2DM and CVD is more prominent than that of change to body mass index category. Obesity treatment should consider prioritizing improvement in metabolic health parameters over focusing on the extent of weight loss only.

Gastric cancer derived exosomal THBS1 enhanced Vγ9Vδ2 T-cell function through activating RIG-I-like receptor signaling pathway in a N6-methyladenosine methylation dependent manner.

Gamma delta (γδ) T-cell-based immunotherapy has shown favorable safety and clinical response in patients with multiple types of cancer. However, its efficiency in treating patients with solid tumors remains limited. In the current study, we investigated the function and molecular mechanism underlying gastric cancer (GC) cell-derived exosomal THBS1 in the regulation of Vγ9Vδ2 T cells. We found that GC cell-derived exosomal THBS1 markedly enhanced the cytotoxicity of Vγ9Vδ2 T cells against GC cells and the production of IFN-γ, TNF-α, perforin and granzyme B in vitro and elevated the killing effects of Vγ9Vδ2 T cells on GC cells in vivo. Mechanistically, exosomal THBS1 could regulate METTL3-or IGF2BP2-mediated m6A modification, further activating the RIG-I-like receptor signaling pathway in Vγ9Vδ2 T cells. Moreover, blocking the RIG-I-like receptor signaling pathway reversed the effects of exosomal THBS1 on the function of Vγ9Vδ2 T cells. In addition, THBS1 was expressed at low levels in GC tissues and was associated with an unfavorable prognosis in GC patients. In sum, our findings indicate that exosomal THBS1 derived from GC cells enhanced the function of Vγ9Vδ2 T cells by activating the RIG-I-like signaling pathway in a m6A methylation-dependent manner. Targeting the exosomal THBS1/m6A/RIG-I axis may have important implications for GC immunotherapy based on Vγ9Vδ2 T cells.

Integrated multi-dimensional analysis highlights DHCR7 mutations involving in cholesterol biosynthesis and contributing therapy of gastric cancer.

BACKGROUND: Genetic background plays an important role in the occurrence and development of gastric cancer (GC). With the application of genome-wide association study (GWAS), an increasing number of tumor susceptibility genes in gastric cancer have been discovered. While little of them can be further applicated in clinical diagnosis and treatment due to the lack of in-depth analysis. METHODS: A GWAS of peripheral blood leukocytes from GC patients was performed to identify and obtain genetic background data. In combination with a clinical investigation, key SNP mutations and mutated genes were screened. Via in vitro and in vivo experiments, the function of the mutated gene was verified in GC. Via a combination of molecular function studies and amino acid network analysis, co-mutations were discovered and further identified as potential therapeutic targets. RESULTS: At the genetic level, the G allele of rs104886038 in DHCR7 was a protective factor identified by the GWAS. Clinical investigation showed that patients with the rs104886038 A/G genotype, age ≥ 60, smoking ≥ 10 cigarettes/day, heavy drinking and H. pylori infection were independent risk factors for GC, with odds ratios of 12.33 (95% CI, 2.10 ~ 72.54), 20.42 (95% CI, 2.46 ~ 169.83), and 11.39 (95% CI, 1.82 ~ 71.21), respectively. Then molecular function studies indicated that DHCR7 regulated cell proliferation, migration, and invasion as well as apoptosis resistance via cellular cholesterol biosynthesis pathway. Further amino acid network analysis based on the predicted structure of DHCR7 and experimental verification indicated that rs104886035 and rs104886038 co-mutation reduced the stability of DHCR7 and induced its degradation. DHCR7 mutation suppressed the malignant behaviour of GC cells and induced apoptosis via inhibition on cell cholesterol biosynthesis. CONCLUSION: In this work, we provided a comprehensive multi-dimensional analysis strategy which can be applied to in-depth exploration of GWAS data. DHCR7 and its mutation sites identified by this strategy are potential theratic targets of GC via inhibition of cholesterol biosynthesis.