Repeated implantation failure (RIF) remains a formidable challenge in in vitro fertilization-embryo transfer (IVF-ET). The etiology of RIF is multifactorial, involving complex interactions between embryo quality, the endometrium, and the maternal microenvironment. Adequate energy metabolism is pivotal for successful embryo implantation, supporting both embryonic development and the establishment of endometrial receptivity. Conversely, metabolic dysregulation contributes to RIF by arresting embryonic development, impairing endometrial receptivity, and disrupting the essential crosstalk between the embryo and the endometrium. Embryos and endometrial tissues from patients with RIF frequently exhibit distinct metabolomic abnormalities, including glycolysis utilization disorders, lipid metabolism disorders, and mitochondrial dysfunction. Clinical evidence suggests that therapeutic interventions involving antioxidants and specific metabolic modulators can enhance pregnancy rates in this population. This article reviews the critical role of energy metabolism in embryonic development and implantation, elucidates the pathological mechanisms linking metabolic dysfunction to RIF, and explores potential therapeutic strategies. We highlight that a comprehensive management strategy integrating diet, exercise, and targeted nutritional and antioxidant supplementation is expected to restore metabolic homeostasis in RIF patients and improve reproductive outcomes.

Insulin resistance (IR) is the core pathological basis of type 2 diabetes mellitus (T2DM). This study aimed to identify core lipid metabolism-ubiquitination-related feature genes in IR. Integrative transcriptomic and functional analysis screened differential genes via multiple machine learning models. Gene set enrichment analysis (GSEA), regulatory network prediction, and immune infiltration analysis were performed. C2C12 IR models were constructed, and ATG5 was knocked down to detect glucose-lipid metabolism, inflammation, and insulin signaling. Results showed that four feature genes were identified: Good genes Ankyrin Repeat And SOCS Box Containing 4 (ASB4)/ Low Density Lipoprotein Receptor (LDLR) and Bad genes ATG5/ CD36 molecule (CD36 blood group) (CD36). They were enriched in metabolism/inflammation pathways consistent with IR phenotypes. Regulatory network analysis predicted potential upstream microRNAs (miRNAs) and transcription factors (TFs) modulating these feature genes. IR/diabetes groups had lower ImmuneScores vs. insulin-sensitive groups. ATG5 was upregulated in IR models. Its knockdown inhibited autophagy, improved glucose and lipid metabolism, decreased inflammatory cytokines, and exerted no influence on cell viability. In conclusion, ASB4, LDLR, ATG5, and CD36 are potential IR biomarkers. ATG5 regulates IR via autophagy, insulin signaling, and metabolism, serving as a therapeutic target for metabolic diseases.

Inflammatory bowel disease (IBD) is an idiopathic inflammatory disorder of intestine and a high risk for colorectal cancer; however, its precise etiology and pathogenesis remain poorly understood. Interleukin (IL)-37, a member of IL-1 family, exerts anti-inflammatory effects in various inflammatory diseases and cancers, and is generated by several epithelial cells and immune cells. Mechanistically, IL-37 mediates its anti-inflammatory either by translocating into nucleus in complex with small mother against decapentaplegic homolog 3 or binding to extracellular interleukin-18 receptor and IL-1 receptor-related receptor 8 (IL-1R8), which is abundantly expressed in the gastrointestinal tract. Recently, accumulating evidence has demonstrated that IL-37 expression is upregulated and plays protective roles in IBD and colitis-associated cancer (CAC). This review summarizes the recent advances regarding the expression, biological functions, molecular mechanism, and therapeutic potential of IL-37 in IBD and CAC, aiming to provide novel insights into its underlying mechanism and clinical application.

Glioblastoma (GBM) is defined by extreme lethality and transcriptomic plasticity, but the signatures driving the most aggressive tumors remain incompletely defined. In this exploratory in silico study, TCGA-GBM patients were stratified using a strict 1-year overall survival threshold. We integrated differential expression analysis, WGCNA, single-cell RNA-seq, spatial transcriptomics, and virtual knockout simulations. A high-risk signature centered on CCL2 and TIMP1 was identified. Single-cell and spatial mapping linked these genes to an inflammatory, macrophage-enriched microenvironment. The signature inversely correlated with neuronal synapse mimicry scores, suggesting that extreme aggressiveness involves a macroscopic shift from differentiated neuronal states toward an undifferentiated inflammatory phenotype. Virtual perturbation modeling confirmed CCL2 and TIMP1 as highly interconnected network hubs. Despite limitations inherent to computational and retrospective cohorts, our rigorous multi-omics validation identifies the CCL2/TIMP1 axis as a driver of potential prognostic indicator. These findings generate the hypothesis that these mediators reflect a critical inflammatory, mesenchymal-like tumor microenvironment shift, warranting independent cohort validation and experimental investigation.

Circular RNAs (circRNAs), a class of non-coding RNAs, are critical regulators of liver injury repair. In this study, using a CCl4-induced mouse liver injury model, we conducted high-throughput sequencing to identify circRNAs enriched in the cell cycle pathway. Four circRNAs (circ_0000604, circ_0001350, circ_0001829, and circ_0001830) were significantly upregulated in early liver injury, with dynamic expression patterns closely linked to repair. Of these, circ_0001829 was selected for functional validation. Circ_0001829 overexpression promoted FL83B cell proliferation and alleviated G2/M phase arrest, whereas its knockdown inhibited these effects. This pro-proliferative effect was confirmed in Hepa1-6 cells. Mechanistically, circ_0001829 functions as a molecular sponge for miR-3095-3p, attenuating its repression of the target gene CDC7 and forming a novel competitive endogenous RNA (ceRNA) axis: circ_0001829/miR-3095-3p/CDC7. To the best of our knowledge, this is the first study to demonstrate that circ_0001829 facilitates liver injury repair by promoting cell proliferation and mitigating cell cycle arrest via a ceRNA mechanism. These results offer valuable insights for the development of ncRNA-based therapeutics for liver injury.

Vascular endothelial dysfunction plays a critical role in the development of atherosclerosis; however, the mechanisms by which endothelial cells contribute to plaque instability remain incompletely understood. In this study, we performed an integrated analysis of single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq data to characterize endothelial cell heterogeneity associated with carotid plaque instability. Clustering analysis, gene set variation analysis (GSVA), differential gene expression analysis, and KEGG pathway enrichment were conducted to identify key endothelial cell subsets and their functional characteristics. We identified three endothelial cell subsets (subsets 9, 10, and 11) that were significantly enriched in unstable plaques and exhibited upregulation of multiple pro-inflammatory cytokines. Pathway analysis revealed that these subsets were associated with activation of the PI3K - Akt signaling pathway and other inflammation-related pathways. Furthermore, findings were validated in an apolipoprotein E-deficient (ApoE-/-) mouse model, where increased expression of placental growth factor (PGF) and a higher proportion of PGF-positive endothelial cells were observed in atherosclerotic lesions. In conclusion, this study reveals the heterogeneity of endothelial cells in atherosclerotic plaques and identifies pro-inflammatory endothelial subsets potentially associated with plaque instability, providing new insights into the pathogenesis of atherosclerosis.Trial registration: This study was approved by the Experimental Animal Ethics Committee of Guizhou University of Chinese Medicine (approval number: 2,024,010).

This study aimed to investigate the effects of bone marrow mesenchymal stem cell-derived exosomes (BMSCs-EXOs) on postmenopausal osteoporosis (PMOP). Bilateral ovariectomy (OVX) surgery was performed to establish mouse PMOP models. Histological analysis was conducted using hematoxylin and eosin staining. Gene expression was detected using immunohistochemistry and Western blot. miRNA and mRNA were detected using quantitative reverse transcriptase PCR. Cell functions were analyzed using oil red O, alizarin red, and alkaline phosphatase (ALP) staining, and flow cytometry. The interaction between miR-196a-5p and R-spondin 2 (Rspo2) was verified by luciferase and RNA immunoprecipitation assays. We found that BMSCs-EXOs promoted osteogenesis and macrophage M2 polarization. BMSCs-derived exosomal miR-196a-5p enhanced the effects of BMSCs-EXOs on mediating osteogenesis and M2 polarization. Mechanistically, miR-196a-5p targeted Rspo2, activating Wnt/β-Catenin signaling. BMSCs-derived exosomal miR-196a-5p alleviated the effects of M1 macrophages and promoted the osteogenesis of BMSCs, which was reversed by Rspo2. Furthermore, BMSCs-derived exosomal miR-196a-5p promoted the osteogenesis in vivo. However, miR-196a-5p inhibitor exerted the opposite effects, which was reversed by recombinant IL-10. Taken together, BMSCs-derived exosomal miR-196a-5p protects against PMOP by driving macrophage M2 polarization though regulating Rspo2/Wnt/β-Catenin signaling. Therefore, targeting cell-cell communication in the microenvironment of bone lesions may be a promising strategy for PMOP.

Understanding molecular pathways in prostate cancer (PCa) is essential. This study demonstrates that miR-6833-3p plays a key role in prostate tumorigenesis via multi-omics integration and functional validation. Expression levels of miR-6833-3p, NUMB, and NOTCH1 were measured in PCa cell lines. The direct regulation of NUMB by miR-6833-3p was confirmed via dual-luciferase reporter assays with mutagenesis. Functional effects were examined using NUMB plasmids or miR-6833-3p mimics. Cell function assays and xenograft models in nude mice were employed, with tissues analyzed via HE staining, qRT-PCR, and Western blot. miR-6833-3p and NOTCH1 were upregulated in PCa, while NUMB was downregulated. miR-6833-3p mimics promoted proliferation, migration, and stemness but inhibited apoptosis and the NUMB/NOTCH1 pathway. NUMB overexpression reversed these effects. In vivo, miR-6833-3p accelerated tumor growth and suppressed NUMB/NOTCH1. miR-6833-3p promotes PCa progression and stemness by inhibiting the NUMB-NOTCH pathway, highlighting its potential as a biomarker for detection and targeted therapy.

Acute myeloid leukemia (AML) is a highly aggressive malignancy with frequent therapeutic resistance, necessitating the identification of novel molecular targets. This study aims to elucidate the role of the deubiquitinase OTUD5 in AML progression by regulating SLC7A11 to suppress ferroptosis. We analyzed OTUD5 expression in AML patient samples and cell lines using RNA sequencing and quantitative PCR. Functional roles were assessed through OTUD5 silencing and overexpression in AML cell lines (THP-1, HL-60), followed by proliferation, colony formation, and ferroptosis assays (ROS, labile Fe2 +, GSH, MDA). Co-immunoprecipitation and ubiquitination assays confirmed OTUD5-SLC7A11 interactions, while in vivo xenograft models validated findings. Molecular docking and transmission electron microscopy further elucidated mechanisms. OTUD5 was significantly upregulated in AML, correlating with ferroptosis suppression. OTUD5 directly interacted with and deubiquitinated SLC7A11, enhancing its stability and promoting AML cell survival. OTUD5 silencing induced ferroptosis, marked by increased labile iron, ROS, and mitochondrial damage, which was reversed by SLC7A11 overexpression or GSH supplementation. In vivo, OTUD5 knockdown reduced tumor growth, an effect mitigated by SLC7A11 overexpression or GSH. The OTUD5-SLC7A11 axis drives AML progression by suppressing ferroptosis, offering a novel therapeutic target to exploit ferroptosis sensitivity and overcome treatment resistance in AML.

Melanoma remains one of the most aggressive cancers, and although immune checkpoint blockade and MAPK-targeted therapies have transformed clinical management, durable responses occur in only a subset of patients. Converging evidence identifies microphthalmia-associated transcription factor (MITF) - dependent phenotype switching as a central, non-genetic mechanism enabling melanoma cells to escape therapy. Dynamic fluctuations in MITF activity permit transitions between differentiated, proliferative states and invasive, drug-resistant phenotypes. This review synthesizes emerging insights into the tumor microenvironmental, mechanical, and metabolic cues that regulate MITF states. These include cytokine-driven inflammatory signaling, hypoxia, cancer-associated fibroblasts, extracellular matrix remodeling, integrin - YAP/TAZ - mediated mechanotransduction, and metabolic reprogramming involving glycolysis - OXPHOS switching, lipid-regulated MITF control, and nutrient-stress responses. By integrating these pathways, MITF-dependent plasticity shapes melanoma adaptation and persistence under therapeutic pressure. Understanding this interconnected network provides a foundation for developing strategies to target phenotype switching and overcome treatment resistance.

FCGR2B, the only inhibitory receptor in the Fcγ receptor family, plays a crucial role in both innate and adaptive immunity. In this study, we observed high FCGR2B expression in tumor-associated macrophages (TAMs) induced by B16 melanoma cells. Knockdown of Fcgr2b in these TAMs suppressed their M2 polarization, as evidenced by decreased expression of immunosuppressive factors, including Arg-1, IL-10, and Fizz1. Furthermore,Fcgr2b knockdown enhanced the phagocytic and antigen-presenting capacities of TAMs, promoted ROS production, and improved their ability to kill melanoma cells in vitro. Transcriptomic analysis revealed thatFcgr2b knockdown predominantly affected key metabolic and signaling pathways, including the JAK-STAT and PPAR-γ pathways. Using classic pharmacological inhibitors (2-DG and C75), we confirmed that FCGR2B interference remodels glycolipid metabolism in TAMs, which is characterized primarily by attenuated fatty acid metabolism, accompanied by increased glycolysis and intracellular free fatty acid accumulation. Moreover, FCGR2B interference downregulated the fatty acid oxidation key enzyme CPT1a by inhibiting the JAK/STAT6/PPAR-γ signaling axis, thereby reducing fatty acid oxidation. Concomitantly, it alleviated endoplasmic reticulum stress via the IRE1/XBP1 pathway, ultimately attenuating the tumor-promoting phenotype of TAMs. Our findings delineate a mechanism by which FCGR2B integrates metabolic and signaling pathways to regulate TAM function, providing a mechanistic basis for targeting FCGR2B in cancer immunotherapy.

Multiple myeloma (MM) is an incurable malignancy of bone marrow plasma cells. Tumor-associated macrophages (TAMs) are the predominant immune cells in the bone marrow microenvironment of MM and play important roles in MM. The effect of RBMS1 on MM has not yet been reported. This study aimed to investigate the function of RBMS1 in MM. Through the analysis of GSE datasets, we identified RBMS1 as a potential pathogenic factor in MM. We further investigated the effects of RBMS1 on the proliferation of MM cells (RPMI8226, MM1S, and KMS11) and its regulation of TAM polarization. An animal model was established by intravenous injection of MM cells into 6-week-old male NOG mice. Bioinformatics analyses, including RRA, WGCNA, and GO enrichment, screened for potential pathogenic genes in MM. Kaplan - Meier survival identified RBMS1 as a prognostic marker associated with poor outcomes in MM. Functionally, RBMS1 enhanced MM cell proliferation, colony formation, and cell cycle. Moreover, RBMS1 promoted M2 polarization of macrophages, as evidenced by elevated levels of M2 macrophage markers, as well as increased CCL2 secretion. Consistently, in a male NOD/Shi-scid IL-2 Rγnull mouse xenograft model, RBMS1 accelerated tumor growth and enhanced M2 macrophage polarization. Mechanistically, RBMS1 bound to the 3'UTR of PDPK1 mRNA, enhancing its stability and activating the pro-tumorigenic β-catenin signaling pathway, thereby promoting tumor growth. Collectively, this study is the first to report the functional role of RBMS1 in MM and highlights the importance of the RBMS1/PDPK1/β-catenin signaling axis in MM, providing new insights for basic research on MM.

Melanoma-associated antigen D4 (MAGED4) belongs to the melanoma-associated antigen family and is upregulated in various cancer types. However, the functional role and molecular mechanisms of MAGED4 in hepatocellular carcinoma (HCC) remain largely unknown. In this study, we observed that MAGED4 expression levels were significantly higher in HCC tissues than in non-cancerous tissues and elevated expression was associated with poor patient outcomes. Functional assays demonstrated that MAGED4 promoted proliferation and migration of HCC. We found that MAGED4 can activate the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway. Mass spectrometry and co-immunoprecipitation assays revealed an interaction between MAGED4 and tripartite motif-containing 21 (TRIM21). Confocal microscopy experiments confirmed the colocalization of MAGED4 with TRIM21. Mechanistically, MAGED4 can regulate the stability of TRIM21 by preventing its ubiquitination and degradation. Furthermore, MAGED4 contributes to the downregulation of suppressor of cytokine signaling 3 (SOCS3) via TRIM21, and this effect can be partially reversed by si-TRIM21 in MAGED4-overexpressing cells. These findings indicate that MAGED4 promotes HCC progression through the activation of the JAK2/STAT3 pathway by stabilizing TRIM21, suggesting that targeting MAGED4 may provide new insights into HCC treatment strategies.