Squalene epoxidase (SQLE) exerts anti-ovarian cancer (OC) role, but its mechanistic basis remains to be defined. Through integrated bioinformatic analysis and immunohistochemistry, SQLE protein expression was found highly expressed in OC tissue compared to normal ovarian tissue, however, using the stable/transient SQLE knockdown and overexpression OC cell models, the cell proliferation and metabolism assays revealed SQLE knockdown enhanced, while SQLE overexpression suppressed cell proliferation, total/free cholesterol level, glycolytic flux and hexokinase Ⅱ (HK2) expression. SQLE positively regulated farnesyl-diphosphate farnesyltransferase 1 (FDFT1) expression. These results showed SQLE reprogramed cellular cholesterol homeostasis and aerobic glycolytic metabolism, and exerted tumor-suppressive effects in OC cells, providing a new insight for OC treatment.

Colorectal cancer (CRC) remains a major global health challenge, underscoring the need for reliable biomarkers to improve prognosis and therapeutic stratification. In this study, we comprehensively investigated the expression pattern, clinical significance, molecular functions, and immunological implications of LINGO1 in CRC. Integrative analyses of TCGA and GEO datasets, together with validation in 72 clinical CRC samples, demonstrated that LINGO1 is markedly overexpressed in tumors and strongly associated with advanced clinicopathological features and poor patient outcomes. Functional experiments revealed that both knockdown of LINGO1 in SW480 and LoVo cells and overexpression of LINGO1 in HCT116 cells significantly modulate malignant phenotypes, including proliferation, migration, invasion, and angiogenic capacity. Transcriptome-wide and pathway enrichment analyses further indicated that high LINGO1 expression is linked to epithelial-mesenchymal transition, angiogenesis, Wnt/β-catenin signaling, and other oncogenic pathways. Immunogenomic profiling, supported by multiplex immunofluorescence staining, showed that elevated LINGO1 is associated with an immunosuppressive tumor microenvironment characterized by reduced CD8⁺ T-cell infiltration and diminished GZMB expression, alongside upregulation of multiple immune checkpoint molecules. Collectively, our findings identify LINGO1 as a novel oncogenic driver and immune-modulatory biomarker in colorectal cancer, with potential value for prognosis and therapeutic targeting.

The clinical phenotype and pathogenic mechanism of 46,XY disorders of sex development (DSD) are complex, and several pathogenic variants are identified by next-generation sequencing. However, these variants currently require additional interpretation and validation prior to their application in 46,XY DSD diagnosis and clinical guidance. Here, we identified three genetic variants in two 46,XY DSD patients by whole exome sequencing screening and Sanger sequencing validation. The pathogenicity of three genetic variants was identified by in silico analysis and functional experiments. One patient carrying the reported pathogenic variant (c.319 C > T) of NR5A1 showed a phenotype of 46,XY complete gonadal dysgenesis, which was different from the reported 46,XY partial gonadal dysgenesis. These findings suggested that the variant (c.319 C > T) of NR5A1 contributes to the clinical phenotypic heterogeneity of 46,XY DSD. The other patient carried two genetic variants, among which the c.1252 C > T variant of NR5A1 produced truncated protein and lost the transcriptional activation of NR5A1 to the targeted genes. The other c.769G > A variant of DHX37 had no significant effect on the expression level and cellular localization of DHX37, and the downstream signaling pathway of DHX37. Moreover, the in silico and structural analysis identified the c.769G > A variant of DHX37 as a deleterious variant that may affect DHX37 function. According to the American College of Medical Genetics and Genomics guidelines and relevant literature reports, combined with the patient’s clinical phenotype and pedigreed analysis, it is proposed that the likely pathogenic variant identified in this patient is the c.1252 C > T variant of NR5A1. Nonetheless, the potential pathogenicity of the DHX37 (c.769G > A) variant of this patient also merits further investigation and consideration. Our results have expanded the clinical phenotype spectrum and genetic diagnosis spectrum of 46,XY DSD, which will contribute to the accurate diagnosis and treatment guidance for 46,XY DSD patients and provide evidence-based genetic counseling for 46,XY DSD family fertility.

Microbial synthesis of sabinene from lignocellulosic biomass represents a sustainable and green alternative to traditional production methods. However, achieving high productivity is often hampered by inefficient substrate utilization and significant product toxicity. In this study, Saccharomyces cerevisiae was engineered to efficiently convert xylose and lignocellulosic hydrolysate (LH) to sabinene. Initially, the biosynthetic pathway was established by introducing a heterologous xylose isomerase and a sabinene synthase. We then systematically enhanced sabinene production through combinatorial metabolic engineering, which included optimizing xylose transport, constructing an orthogonal precursor pathway, reinforcing the supply of key precursors (IPP/DMAPP), reducing acetate and xylitol accumulation, dynamically regulating lipid metabolism, and improving key enzyme efficiency as well as optimizing cofactor balance. A critical bottleneck emerged as sabinene accumulation inhibited cell growth. To address this, we employed adaptive laboratory evolution coupled with transcriptomic analysis, which identified FHN1 and VMA3 as novel genetic targets for improving sabinene tolerance. Their coordinated overexpression was shown to restore intracellular pH homeostasis and vacuolar function under sabinene stress, as well as to improve V-ATPase activity, thereby significantly improving cellular robustness. The resulting haploid strain, ZM26, produced 1685.9 mg/L of sabinene. To further enable efficient bioconversion of inhibitory LH, we generated a diploid hybrid (ZM27) by fusing ZM26 with a UV-mutagenized LH-tolerant strain. The final engineered strain ZM27 achieved a highest sabinene titer of 1537.1 mg/L directly from non-detoxified LH. This work not only demonstrates a scalable strategy for sustainable sabinene production but also provides fundamental insights into mechanisms of monoterpene tolerance in yeast.

Engineered Saccharomyces cerevisiae offers a sustainable platform for converting lignocellulosic hydrolysates into high-value chemicals, supporting circular bioeconomy goals. However, multicomponent inhibitors in lignocellulosic hydrolysates often hinder bioconversion efficiency. In this study, strain T1 with enhanced tolerance to corn stover hydrolysate (CSH) was developed by optimizing the xylose metabolic pathway and applying UV mutagenesis. Transcriptomic analysis showed that in strain T1, genes encoding cell cycle regulatory proteins, such as PCL1, were upregulated, thereby contributing to CSH resistance. Physiological analyses showed that improved robustness was associated with stable cell morphology, budding efficiency, and cytoskeletal integrity. Interestingly, strain T1 exhibited superior performance in converting CSH into acetyl-CoA derivatives. Therefore, strain T1 was utilized as a chassis for converting CSH into α-terpineol through engineering modifications, including enhancement of intracellular precursor biosynthesis, optimization of key enzyme copy numbers, and dynamic regulation of ergosterol synthesis. Finally, the engineered strain D22 achieved an α-terpineol titer of 13.6 mg/L from CSH in shake-flask cultivation, representing the first demonstration of α-terpineol biosynthesis directly from CSH. This work offers insights into robust strain design and efficient lignocellulosic biomass valorization, contributing to sustainable biomanufacturing.

Ovarian cancer is often diagnosed at advanced stages and lacks effective biomarkers for prognosis prediction or targeted therapy. The biological role of C11orf86, a previously uncharacterized gene, remains unclear in ovarian cancer. C11orf86 expression and clinical relevance were analyzed using transcriptomic datasets from TCGA, GTEx, and patient tissues. Functional assays, including siRNA knockdown, overexpression, qPCR, Western blotting, flow cytometry, and Transwell assays, were performed in SKOV3 ovarian cancer cells. Pathway enrichment and immune correlation analyses were conducted using publicly available online databases. C11orf86 was significantly upregulated in ovarian cancer and associated with poor prognosis, particularly in the TP53-mutant subgroup. Immunohistochemistry confirmed elevated expression of C11orf86 in primary and metastatic ovarian cancer tissues. Functionally, C11orf86 promoted proliferation, migration, invasion, and cell cycle progression of ovarian cancer cells. It was induced by hypoxia and HIF-1α overexpression, while its silencing was accompanied by reduced STAT3 phosphorylation and HIF-1α levels. C11orf86-correlated genes were enriched in cell cycle, hypoxia, and immune-related pathways. Furthermore, C11orf86 expression showed strong correlation with Th2 infiltration and key Th2 markers including STAT5A. C11orf86 promotes malignant behaviors in ovarian cancer and may be associated with Th2-related immune features. It is linked to the STAT3-HIF-1α axis and may serve as a promising prognostic biomarker and potential therapeutic target.

ABSTRACT Sulfur hexafluoride (SF 6 ) is a potent greenhouse gas widely used in electrical insulation. Although the size difference between SF 6 and N 2 enables separation in principle, achieving high SF 6 selectivity at trace concentrations, large adsorption capacity, and long‐term stability remains a formidable challenge. Herein, we report a family of new zinc‐based metal‐organic frameworks ( Zn‐tcpb , Zn‐tcpb‐bim , Zn‐tppb‐bim ) with systematically tunable pore sizes and electrostatic microenvironments. By integrating a mixed‐ligand strategy (tetracarboxylic acids plus 2,2'‐biimidazole) with pore functionalization, we achieve synergistic control over adsorption and separation properties. Among them, Zn‐tppb‐bim— featuring electron‐withdrawing pyrazine rings—exhibits a remarkable low‐pressure SF 6 uptake of 3.06 mmol/g at 0.1 bar, and an excellent SF 6 /N 2 IAST selectivity of 606 (1:9, 1 bar), achieving a balance between uptake and selectivity. Theoretical calculations reveal that the N‐heterocyclic units in Zn‐tppb‐bim generate a stronger positive framework charge, enhancing C─H···F interactions with SF 6 . Dynamic breakthrough experiments confirm complete separation of SF 6 /N 2 mixtures. Remarkably, the materials retain full separation performance even at 80% relative humidity. This work demonstrates a viable and generalizable design strategy that synergistically optimizes adsorption capacity, selectivity, and humidity resistance, providing a rare example of metal–organic framework that are both highly efficient and stable under practical conditions.

BACKGROUND: Long non-coding RNAs (lncRNAs) have been extensively studied and are recognized for their crucial roles in cancer development. Among them, lncRNA SRRM2-AS1 has emerged as a significant factor, yet its functions in ovarian cancer remain insufficiently understood. MATERIALS AND METHODS: We analyzed SRRM2-AS1 expression and genetic alterations using data from TCGA, GEO, and cBioPortal. Enrichment analyses of differentially expressed genes (DEGs) associated with SRRM2-AS1 were conducted via Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Immune cell infiltrations were assessed with the single-sample Gene Set Enrichment Analysis (ssGSEA) algorithm, while subcellular localization was predicted using the lncATLAS database. We conducted qRT-PCR and fluorescence in situ hybridization (FISH) to examine the expression and localization of SRRM2-AS1. Cellular assays were performed to assess the impact of SRRM2-AS1 inhibition in ovarian cancer. RESULTS: SRRM2-AS1 expression was significantly elevated in ovarian cancer tissues compared to normal tissues, as evidenced by data from TCGA, GTEx, and supported by the GSE18520 and GSE40595 datasets, along with our own samples (14 ovarian cancer tissues and 9 normal tissues). Receiver operating characteristic (ROC) analysis indicated its potential as a diagnostic biomarker with an Area Under the Curve (AUC) of 0.758. We identified 957 DEGs associated with SRRM2-AS1, with GO and KEGG enrichment analyses highlighting their involvement in microtubule-based movement, cilium movement and immune cell interactions. Immune infiltration analyses indicated significant correlations between SRRM2-AS1 expression and various immune cell types, suggesting its role in modulating the tumor microenvironment. Subcellular localization studies using the lncATLAS database, qRT-PCR, and FISH confirmed the nuclear predominance of SRRM2-AS1 in ovarian cancer cells. Functionally, SRRM2-AS1 knockdown inhibited ovarian cancer cell proliferation, migration, and invasion. CONCLUSION: These findings underscore the potential of SRRM2-AS1 as both a biomarker and a therapeutic target in ovarian cancer, highlighting the need for further investigation into its mechanistic roles and clinical applications.

Aim: To evaluate the therapeutic effects and mechanisms of berberine (BBR) on colon cancer (CC). Methods: Rats were randomly divided into normal, CC, BBR (20, 40, 80 mg/kg), and positive control paclitaxel (Pacl, 5 mg/kg) groups. Except for the normal group, CC was induced using 1,2-dimethylhydrazine (DMH). From the second week of DMH induction, the BBR and Pacl groups received BBR or Pacl daily, while the normal and CC groups received saline for 4 weeks. Observations included body mass, tumor mass and volume, spleen and thymus indices. Serum TNF-α, IL-6, and IL-10 were measured by ELISA, and protein expressions of c-Myc, ki67, cyclin D, cleaved-caspase 3, cleaved-caspase 9, PTEN, Akt, PI3K, and p-Akt were analyzed by western blot. MiR-181a expression was examined by RT-qPCR. Results: In the CC group, body mass, spleen and thymus indices, serum IL-10, and cleaved-caspase 3, cleaved-caspase 9, and PTEN in colon tissue were decreased, while tumor mass, volume, serum TNF-α, IL-6, and c-Myc, ki67, cyclin D, PI3K, p-Akt/Akt, and miR-181a were increased. Compared to CC, the BBR and Pacl groups showed improved body mass, spleen and thymus indices, and increased IL-10, cleaved-caspase 3, cleaved-caspase 9, and PTEN, with reduced tumor mass, volume, TNF-α, IL-6, c-Myc, ki67, cyclin D, PI3K, p-Akt/Akt, and miR-181a (P<0.05). Conclusion: In CC models, BBR exhibits anti-tumor effects, likely through down-regulation of miR-181a, promoting PTEN expression and inhibiting PI3K/Akt pathway activation.

Degradation of microplastics represents a significant global environmental challenge, necessitating the development of bio-inspired catalysts with superior activity and stability, capable of mimicking natural plastic-degrading enzymes. Although nanozymes possess advantages such as low cost, ready availability, and multienzymatic activities, issues of self-consumption often hinder their practical application. Here, motivated by the acceleration of Li+ migration for improving the electrochemical reactivity and cycling stability of lithium iron phosphate (LFP), we engineered LFP by introducing Mn2+ to expand the lattice structure, resulting in Mn-doped LFP (LFMP) that modulates ion migration in nanozymes. Density functional theory (DFT) calculations reveal that Mn2+ doping expands the lattice structure of LFP while narrowing its bandgap, thereby significantly enhancing Li+ migration rates. Leveraging this design, LFMP exhibits enhanced peroxidase-like activity (3 times higher than that of LFP) and cycling stability (80% activity retention after 5 cycles versus 45% for LFP), enabling efficient degradation of microplastics made from polyamide 6, high-density polyethylene, and polypropylene. By exemplifying that the degradation efficiency achieved using LFMP nanozymes significantly exceeds that of traditional methods, we affirm that lattice expansion-driven ion migration may inspire future strategies to circumvent the self-consumption issue while maintaining high catalytic activity in nanozymes.

Tumour progression depends on the bidirectional interactions between cancer and stroma in the heterogeneous tumour microenvironment (TME) partially through extracellular vesicles (EVs). However, the secretary mechanism and biological effect of cancer cell derived EVs on tumour survival under starvation is poorly defined. Here, we identify cancer cells selectively secrete miR-33a with the assistance of aconitase 1 (ACO1), an iron-responsive RNA binding protein, under glucose starvation and lower iron level, which affiliates the binding capability of miR-33a and ACO1. Exosomal miR-33a suppresses putrescine biosynthesis by targeting AGMAT in cancer-associated fibroblasts (CAFs) from tumour core region, where putrescine inhibits the expression of demethylase KDM5C. TIA1 gene, stress granule (SG) marker, is tightly regulated by miR-33a/KDM5C/H3K4me3 axis and exosomal miR-33a diminishes the formation of stromal SGs in CAFs. Collectively, our study reveals tumour selectively secretes miR-33a-5p through EVs to remodel the stromal SG formation and gain survival possibility for cancer cells in tumour core region, highlighting a novel regulatory mechanism of iron and nutrient level on EV secretion and the function of polyamine metabolism in reshaping epigenetic profiles.

BACKGROUND:Ovarian cancer is associated with a high mortality rate. Oxidative Phosphorylation (OXPHOS) is an active metabolic pathway in cancer; nevertheless, its role in ovarian cancer continues to be ambiguous. Therefore, the objective of this study was to identify the prognostic value of OXPHOS-related genes and the immune landscape in ovarian cancer. METHODS:We obtained public ovarian cancer-related datasets from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases and recognized OXPHOS-related genes from the GeneCards database and literature. Cox regression analyses were conducted to identify prognostic OXPHOS-related genes and develop a prognostic nomogram based on the OXPHOS score and clinicopathological features of patients. Functional enrichment analyses were employed to identify related processes. RESULTS:A 12-gene signature was identified to classify the ovarian cancer patients into high- and low-risk groups. The Immunophenoscore (IPS) was higher in the OXPHOS score-high group than in the OXPHOS score-low group, suggesting a better response to immune checkpoint inhibitors. Functional enrichment analyses unveiled that OXPHOS-related genes were considerably abundant in a series of immune processes. The calibration curves of the constructed prognostic nomograms at 1, 2, and 3 years exhibited strong concordance between the anticipated and observed survival probabilities of ovarian cancer patients. CONCLUSION:We have constructed a prognostic model containing 12 OXPHOS-related genes and demonstrated its strong predictive value in ovarian cancer patients. OXPHOS has been found to be closely linked to immune infiltration and the reaction to immunotherapy, which may contribute to improving individualized treatment and prognostic evaluation in ovarian cancer.

OBJECTIVE:To investigate the synergistic effect and its mechanism of ginsenoside-Rg5 in combination with imatinib in inhibiting proliferation of chronic myeloid leukemia K562 cells. METHODS:K562 cells were treated with ginsenoside-Rg5 and imatinib. Cell survival was detected by CCK-8 assay, and IC50 were calculated separately for each drug. Based on the value of IC50 of ginsenoside-Rg5 and imatinib, an appropriate concentration gradient was selected for the combination. The synergistic effect of the two drug was analyzed using the online software synergy finder. The effects of single or combination therapy on apoptosis rate and the cell cycle distribution of K562 cells were analyzed by flow cytometry. Western blot was used to detect the expression of PI3K/AKT/mTOR signaling pathway related proteins and apoptosis related proteins in K562 cells after single or combination therapy. RESULTS:Ginsenoside-Rg5 and imatinib were able to inhibit the proliferative activity of K562 cells in a dosedependent manner(r =-0.991， r =-0.942). The synergy score ZIP >10 was measured by Synergy Finder online software, indicating that ginsenoside-Rg5 and imatinib act synergistically on K562 cells. The apoptotic rates of K562 cells after single treatments with ginsenoside-Rg5 and imatinib were 11.96% and 8.13%, respectively, while the rate increased to 21.35% with the combination of two drugs, the apoptosis rate in the combination group was higher than that in the single-drug group ( P <0.05). The proportion of K562 cells in the G0/G1 phase was significantly increased with the combined treatment of two drugs( P <0.05). The protein expression levels of p-PI3K, p-AKT, p-mTOR in K562 cells treated with the combination were significantly decreased, with noticeable downregulation of BCL-2 and upregulation of BAX, leading to a decreased Bcl-2/BAX ratio, while no significant changes were observed in the non-phosphorylated forms of PI3K, AKT, and mTOR proteins. CONCLUSION:The combination of ginsenoside-Rg5 and imatinib can inhibit the proliferation of CML cells and induce apoptosis, and the mechanism may act through PI3K/AKT/mTOR signaling pathways.

Objectives Renal fibrosis (RF) is a critical pathway in the progression of chronic kidney disease (CKD) to end-stage kidney diseases. This study aimed to investigate the role of miR-101-3p in the progression of fibrosis in renal tubular epithelial cells (RTECs) and to elucidate the underlying molecular mechanisms.Methods An RF cell model was established by induction with transforming growth factor-beta 1 (TGF-beta 1). The expression levels of miR-101-3p and fibrosis-associated proteins were measured using quantitative real-time reverse transcription polymerase chain reaction. Cell migration ability was detected by Transwell assay. The potential target genes of miR-101-3p were predicted through bioinformatic analysis. The interaction between miR-101-3p and EZH2 was verified using the luciferase assay and RNA immunoprecipitation (RIP) assay.Results HK-2 cells treated with TGF-beta 1 showed downregulated expression of miR-101-3p. Overexpression of miR-101-3p reduced cell migration and decreased the production of fibronectin, collagen IV and alpha-smooth muscle actin (alpha-SMA). EZH2 was identified as a downstream target gene of miR-101-3p. The interaction between miR-101-3p and EZH2 was confirmed by luciferase assay and RIP assay. EZH2 was upregulated in TGF-beta 1-induced cells. Upregulation of EZH2 partially reversed the anti-fibrotic effects caused by miR-101-3p overexpression.Conclusions miR-101-3p alleviates TGF-beta 1-induced fibrosis in RTECs by inhibiting EZH2. This study provides new insights into the molecular mechanisms of RF and suggests potential therapeutic targets for CKD.

The growing demand for energy‐efficient natural gas purification necessitates advanced porous adsorbents that enable molecular precision in separating higher hydrocarbons C 2 H 6 /C 3 H 8 from CH ₄ while maintaining methane purity. Through rational π ‐electron engineering of the framework structure, a microporous Co‐MOF is reported, constructed from pyridine carboxylic acid‐based aromatic ligands that achieve a benchmark C₂H₆/CH₄ selectivity of 83.8, ranking among the highest reported for MOF materials. The framework also demonstrates an exceptional IAST selectivity of 715.6 for C 2 H 6 /C 3 H 8 (5/5) mixtures, coupled with high uptake capacities of 65.5 cm 3 ·g⁻¹ for C₂H₆ and 65.8 cm 3 ·g⁻¹ for C₃H₈ at 298 K and 100 kPa. This remarkable separation performance stems from the strategic incorporation of π ‐electron aromatic ligands, which enhance the C‐H··· π interactions with hydrocarbon molecules. Breakthrough experiments demonstrate practical viability, achieving 99.97% methane purity in the effluent stream. Molecular simulations confirm that the selective adsorption originates from optimized C‐H··· π interactions and van der Waals forces between the framework and guest molecules, validating the rational design approach for high‐performance MOFs in industrial gas separation.

WD repeat-containing protein 5 (WDR5) is a highly conserved chromatin-associated scaffold protein that recognizes short, arginine-containing WDR5 interacting (WIN) motifs in various partners to assemble transcriptional complexes. Although the WIN motif has been considered strictly arginine-dependent, our previous binding assays showed that the MBD3C_R43K variant retained binding to WDR5 (KD = 1.31 μM), though the underlying mechanism remained unclear. Here, we report the crystal structure of WDR5 in complex with MBD3C40-51 (R43K) peptide at 1.9 Å resolution, revealing that lysine can also insert into the WIN pocket. Structural analysis shows that the lysine side chain mimics the canonical arginine interactions, forming hydrogen bonds with Ser91and engaging in hydrophobic contacts with Ser49, Phe133, Cys261, and Ile305 within the conserved WIN-binding site of WDR5. Interestingly, this experimentally determined structure contrasts with AlphaFold3 predictions, which incorrectly placed Arg45 into the WIN pocket rather than Lys43, underscoring the limitations of current predictive models for protein-peptide complexes involving mutations. Overall, our findings redefine the WIN motif consensus to include an alternative "AK" motif and highlight the contributions of residues at positions +2, +3, and +4 in stabilizing WDR5 binding. This work broadens the understanding of WDR5 substrate recognition and offers a structural framework for designing WIN-site inhibitors that target lysine-mediated interactions.

Ginsenoside 20(S)-Rg3 exhibits the anti-ovarian cancer activity by modulating aerobic glycolysis, but its role in reprogramming sterol metabolism remains unclear. This research utilized transcriptomic and lipidomic to identify the key metabolic pathways and targets influenced by 20(S)-Rg3. 20(S)-Rg3 altered 175 mRNAs and 64 metabolites in ovarian cancer cells, and cluster analysis found that the differentially expressed genes and metabolites were highly associated with the steroid biosynthesis. Multi-omics analysis revealed squalene epoxidase (SQLE), a rate-limiting enzyme in steroid biosynthesis, was upregulated by 20(S)-Rg3. Silencing of SQLE attenuated the inhibitory effects of 20(S)-Rg3 on ovarian cancer cell proliferation in vitro and in vivo, as well as cell migration, invasion, and cholesterol synthesis. 20(S)-Rg3 enhanced SQLE expression by downregulating HIF-1α. Co-immunoprecipitation confirmed the interaction between SQLE and farnesyl-diphosphate farnesyltransferase 1 (FDFT1), another rate-limiting enzyme in cholesterol metabolism. These findings suggest that 20(S)-Rg3 exerts anti-ovarian cancer effects by HIF-1α/SQLE/FDFT1 to reprogram cholesterol metabolism.

Dioscin is a natural, bioactive steroid saponin that has the antiarthritic activity. Circular RNAs (circRNAs) are stable noncoding RNAs involving in the pathogenesis of rheumatoid arthritis (RA). Here, this study aimed to probe the role and mechanism of dioscin and circ_0008267 in RA progression. Cell proliferation, apoptosis, invasive, and migratory abilities, as well as inflammatory response were evaluated by CCK-8 assay, EdU assay, flow cytometery, transwell assay, wound healing assay, and ELISA analysis, respectively. Levels of genes and protein were tested by qRT-PCR and western blotting. The interaction between miR-942-5p and circ_0008267 or FK506-binding protein 5 (FKBP5) was confirmed using dual-luciferase reporter and RNA pull-down assays. Dioscin treatment was demonstrated to suppress RA-FLS proliferation, invasion, migration, and inflammatory response, but induced cell apoptosis. Circ_0008267 is a stable circRNA, and was increased in RA samples. Moreover, its expression was reduced by dioscin in RA-FLS, overexpression of circ_0008267 reversed the effects of dioscin on RA-FLS. Mechanistically, circ_0008267 acted as a sponge for miR-942-5p, which targeted FKBP5. Dioscin reduced FKBP5 expression, but elevated miR-942-5p level in RA-FLS. MiR-942-5p inhibition or FKBP5 upregulation abolished the inhibitory effects of dioscin on RA-FLS dysfunction. Moreover, circ_0008267 deficiency impaired RA-FLS proliferation, invasion, migration, and inflammation through regulating FKBP5. Dioscin suppressed the proliferation, invasion, migration, and inflammatory response in RA-FLS via circ_0008267/miR-942-5p/FKBP5 axis, providing new insights for RA prevention.

IntroductionBreast cancer (BC) remains a widespread malignancy and ranks as the second leading cause of cancer-related mortality among women worldwide. Hypoxia, epithelial-mesenchymal transition (EMT), and immune-related processes have been increasingly recognized as critical contributors to BC pathogenesis. However, a prognostic model integrating hypoxia-, EMT-, and immune-related genes (HEMTIRGs) to predict BC outcomes has not yet been established.MethodsGene expression datasets of BC patients were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Prognostic genes were identified using Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression analysis. A prognostic model was developed based on these genes. Immune infiltration was assessed using CIBERSORT and ssGSEA analyses. Immunotherapy response was predicted using the tumor immune dysfunction and exclusion (TIDE) algorithm. Functional roles of HEMTIRGs in BC malignancy were validated through in vitro experiments.ResultsIn this study, four HEMTIRGs (PAX7, DCD, CRISP3, and FGG) were identified and used to develop a prognostic model. Patients were stratified into high- and low-risk groups based on median risk scores. A nomogram based on this model accurately predicted overall survival (OS), consistent with the observed outcomes. Notably, patients in the high-risk group exhibited increased immune cell infiltration but a lower predicted response to immunotherapy. Immunohistochemistry (IHC) further confirmed that HEMTIRGs expression levels were strongly associated with breast cancer, with CRISP3 showing the most pronounced upregulation. In vitro functional assays demonstrated that CRISP3 promoted malignant phenotypes of breast cancer cells under hypoxic conditions through activation of the IL-17/AKT signaling pathway.ConclusionThis study establishes a novel HEMTIRGs-based prognostic model for BC, offering a robust tool for predicting patient prognosis and immunotherapy efficacy. Additionally, our findings provide new insights into BC pathogenesis, highlighting potential therapeutic targets.