Small-diameter vascular grafts (≤ 6 mm) remain a critical unmet need in cardiovascular surgery, as autologous vessels are unavailable in up to 30% of patients requiring coronary or peripheral bypass. Induced pluripotent stem cells (iPSCs) have emerged as a transformative cell source for tissue-engineered vascular grafts (TEVGs), offering unlimited self-renewal, patient-specific or universal donor potential, and the capacity to generate all vascular cell lineages. Recent breakthroughs-including iPSC-derived grafts achieving 100% patency in allogeneic primate models and the first United States Food and Drug Administration (FDA) approval of an acellular tissue-engineered vessel (SYMVESS, December 2024)-signal that clinical translation is accelerating. This review provides a comprehensive synthesis of the iPSC-to-graft pipeline, encompassing vascular cell differentiation protocols, biomaterial scaffold design, immune engineering strategies for universal grafts, bioreactor maturation, preclinical evaluation, and the evolving clinical-regulatory landscape. We critically evaluate how the convergence of clustered regularly interspaced short palindromic repeats (CRISPR)-based immune editing, advanced biomaterials, and scalable manufacturing is reshaping the field toward off-the-shelf vascular grafts. Finally, we identify remaining challenges in long-term patency, thrombogenicity, and manufacturing scalability, and propose a translational roadmap for the next decade.
Intervertebral disc degeneration (IDD) serves as a critical structural basis for chronic low back pain, severely impairing patients' quality of life and imposing a significant socioeconomic burden. Current interventions remain largely limited to symptomatic treatments including pharmacological analgesia and surgical intervention. The recently proposed "gut-disc axis" suggests that the gut microbiome can reshape the endplate-disc microenvironment by influencing intestinal barrier integrity, microbial metabolite profiles, and host immune-metabolic status. Existing evidence indicates that dysbiosis-related increases in endotoxin load, dysregulated metabolism of short-chain fatty acids, tryptophan, and bile acids, systemic low-grade inflammation, and shifts in immune cell lineages may collectively promote nucleus pulposus cell senescence and apoptosis, matrix degradation, and endplate pathology. Mendelian randomization studies have also suggested potential causal links between certain gut microbiota and disc diseases. However, the determination of whether "microbial signals" detected within the intervertebral disc represent true colonization is currently hindered by methodological limitations, particularly low-biomass contamination. This review focuses on mechanisms through which gut microbiota influence the endplate-disc microenvironment via immune-metabolic pathways, including the LPS/TLR4/NF-κB axis, SCFAs-AhR axis, and lipid/iron metabolism, while only briefly addressing studies related to mechanical injury and surgery. Building on these insights, we integrate advances from clinical cohorts, animal models, and multiomics studies, summarize key actionable intervention nodes, and propose a preliminary patient stratification framework and validation pathway based on gut-immune-metabolic typing, providing a theoretical foundation for developing microbiome-guided disease-modifying interventions.
The adenylyl cyclase (ADCY) family comprises key signal transduction enzymes that catalyze the conversion of ATP to the second messenger cyclic adenosine monophosphate (cAMP). Through the downstream cAMP-protein kinase A (PKA) signaling pathway, this family exerts central regulatory effects on glucose and lipid homeostasis. In mammals, the ADCY family consists of nine transmembrane isoforms (ADCY1-9) and one soluble isoform (ADCY10), all of which exhibit tissue‑specific distribution, distinct regulatory mechanisms, and non‑redundant functions in core metabolic organs. Compelling evidence from gene‑edited animal models, functional validation studies, and multi‑ethnic genetic association analyses has demonstrated that dysfunction of specific ADCY isoforms is closely linked to the pathogenesis of obesity, type 2 diabetes mellitus (T2DM), metabolic dysfunction‑associated steatotic liver disease (MASLD), and other metabolic disorders. This review systematically summarizes the classification, structural characteristics, and multilayered regulatory mechanisms of the ADCY family, with a particular focus on the physiological and pathological roles of its isoforms in glucose metabolism, lipid metabolism, and feeding regulation. It also discusses recent advances in ADCY‑targeted agents and highlights unresolved challenges and future directions. Particular emphasis is given to recent structural biology breakthroughs, genetic evidence from diverse populations, and isoform‑specific therapeutic strategies, with the aim of providing a theoretical basis for mechanistic research and the development of targeted therapeutics for metabolic diseases.
Microgravity brings various pathological changes to astronauts, which may be related to the senescence of adult stem cells. However, how microgravity affects the senescence of stem cells remains barely known. In this study, it was found that microgravity simulated by Rotating Flat Chamber induced MSC senescence and promoted the expression of cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING), and C176, a STING inhibitor, alleviated the rotating culture-induced MSC senescence. Rotating culture also promoted the cytosolic leakage of mitochondrial DNA (mtDNA), while the depletion of mtDNA inhibited cGAS-STING activation and reversed MSC senescence. Knockdown of either BAK or BAX, proteins forming pores on the mitochondrial outer membrane, suppressed mtDNA leakage, cGAS-STING activation, and MSC senescence, suggesting that BAK/BAX mediates the activation of mtDNA-cGAS-STING axis and the associated MSC senescence. Recovering mitochondrial function by Mito TEMPO inhibited the activation of mtDNA-cGAS-STING axis and reversed MSC senescence. In vivo, using rat hindlimb unloading (HU) model to simulate microgravity, it was found that inhibition of STING ameliorated MSC senescence induced by HU. Together, our study demonstrated that simulated microgravity induces MSC senescence by the activation of cytosolic mtDNA-cGAS-STING axis and indicated cGAS-STING pathway as a therapeutic target of MSC senescence under microgravity.
Cancer-associated fibroblasts (CAFs) are key drivers of tumor progression. This study examined how three-dimensional (3D) culture, hypoxia, and cancer-derived soluble factors influence the transformation of human mesenchymal stem cells (hMSCs) into inflammatory CAFs (iCAFs). hMSCs from bone marrow, placenta, and chorion were cultured in 2D, in Matrigel-based 3D systems, under hypoxia, and with soluble factors from colon cancer cells (HT29, HCT116). 3D culture strongly induced iCAF markers (IL1α, CSF3, IL6) while reducing myofibroblastic CAF markers (CCN2, MYL9, TAGLN). Hypoxia and cancer factors further enhanced this phenotype, promoting IL1α/IL6 secretion and shifting their influence from suppressing to stimulating cancer cell growth and angiogenesis. Mechanistically, these changes were associated with YAP/TAZ down-regulation, and genetic depletion of YAP/TAZ alone was sufficient to convert hMSCs into iCAFs even in 2D culture. These findings highlight YAP/TAZ as critical regulators of hMSC-to-CAF transformation, with implications for therapeutic strategies targeting tumor stroma.
Arginine methylation is a common post-translational modification that exists in three distinct forms-monomethylation, asymmetric dimethylation, and symmetric dimethylation-through which it regulates precursor RNA splicing and maintains cellular homeostasis. Dysregulation of the writing, reading, or erasure of arginine methylation promotes cancer development. Recent studies have identified PRMTs as key regulators of alternative splicing, and aberrant PRMT-driven splicing directly impacts multiple biological processes, including tumor proliferation, apoptosis resistance, metastasis, and immune evasion. This review focuses on the molecular mechanisms by which PRMTs regulate alternative splicing, their connections to oncogenic processes, and the therapeutic implications and challenges of targeting the PRMT-splicing axis in cancer.
Zhenwu Decoction (ZWD) is a traditional Chinese medicine prescription with well-documented renoprotective effects, though its precise mechanism of action against renal fibrosis remains to be elucidated. This study aimed to explore whether ZWD mitigates renal fibrosis by modulating the loop of transforming growth factor-β (TGF-β)/Smad and Notch signaling pathways. In vivo and in vitro experiments were conducted using unilateral ureteral obstruction (UUO) rat models and TGF-β1-stimulated NRK-49F fibroblast cells, respectively. The study's findings revealed that ZWD significantly improved renal function, mitigated pathological damage, and decreased extracellular matrix deposition in UUO rats. Treatment with ZWD led to a marked downregulation of TGF-β1, Notch1, and Jagged1 expression, as well as a reduction in Smad2/3 phosphorylation, both in vivo and in vitro. Gain- and loss-of-function experiments demonstrated that overexpression of TGF-β1 enhanced Notch signaling, whereas TGF-β1 knockdown inhibited it. Similarly, Notch1 overexpression increased TGF-β/Smad signaling, while Notch1 silencing suppressed TGF-β/Smad activity, thus confirming the existence of a positive bidirectional feedback loop in the context of renal fibrosis. Importantly, Notch1 overexpression directly induced a fibrotic phenotype in NRK 49F cells. In summary, the TGF-β/Smad and Notch pathways constitute a bidirectional positive feedback loop that promotes renal fibrosis. ZWD alleviates renal fibrosis by disrupting this crosstalk, highlighting its potential as a therapeutic strategy for chronic kidney disease (CKD).
The adaptive capacity of chondrocytes to fluctuating oxygen levels during the process of osteoarthritis remains poorly understood. This study aimed to investigate the role and underlying mechanisms of the Mt1-Ca2+-mitochondrial metabolic axis in chondrocyte function and cartilage homeostasis. Primary rat condylar chondrocytes were cultured under physiological low oxygen (5% O2) and hypoxia (<1% O2) with Mt1 knockdown or overexpression. The role of Mt1 in chondrocyte functions were investigated. Transcriptomic analysis identified intracellular Ca2+ and metabolism-related pathways regulated by Mt1. Mitochondrial respiration and glycolytic capacity were evaluated by Seahorse XF assays, while intracellular Ca2+ concentration was quantified by Calcium Assay Kit. The effects of extracellular Ca2+ supplementation were analyzed to clarify the Mt1-Ca2+ interaction in metabolic regulation. In vivo, a rat model with intra-articular Mt1 knockdown and chronic sleep deprivation-induced hypoxia was established to verify the role of Mt1 in condylar cartilage homeostasis. Mt1 expression was significantly upregulated under hypoxia and positively correlated with chondrocyte viability, migration, and extracellular matrix synthesis. RNA-seq and enrichment analyses revealed that Mt1 regulates genes associated with mitochondrial respiration and Ca2+ binding. Mt1 knockdown significantly downregulated intracellular Ca2+, which were restored by extracellular Ca2+ supplementation. Seahorse analysis demonstrated that Mt1 knockdown significantly suppressed mitochondrial respiration and glycolytic capacity, whereas extracellular Ca2+ supplementation restored these deficits. In vivo, Mt1 knockdown aggravated condylar cartilage degeneration, which was further exacerbated under chronic sleep deprivation-induced hypoxia, as evidenced by surface erosion, matrix loss, and histological disorganization. Mt1 preserves TMJ condylar chondrocyte homeostasis under low oxygen and hypoxic conditions by coordinating mitochondrial and glycolytic metabolism through Ca2+ regulation. The Mt1-Ca2+-mitochondrial metabolic axis serves as a key adaptive mechanism sustaining cellular energy homeostasis and represents a potential therapeutic target for preventing temporomandibular joint osteoarthritis.
Sepsis induces profound metabolic and mitochondrial dysfunction, contributing to multiple organ injury and mortality. Lipocalin-2 (Lcn2), an acute-phase protein, regulates iron homeostasis and oxidative stress, but its impact on mitochondrial resilience remains poorly understood. Here, we investigated the role of Lcn2 in modulating mitochondrial function and hepatic stress responses in C57BL/6 J (BL6) and BALB/c mice in LPS-induced endotoxemia. Lcn2-deficient (Lcn2KO) mice exhibited reduced basal respiration, maximal respiration, and spare respiratory capacity, indicating impaired mitochondrial oxidative phosphorylation. Administration of recombinant Lcn2 (rLcn2) restored mitochondrial respiration in both mouse strains under basal conditions; however, during LPS challenge, only BL6 mice partially preserved mitochondrial function, whereas BALB/c mice remained compromised. To explore underlying mechanisms, we assessed hepatic gene expression by qRT-PCR. LPS induced Acyl-CoA synthetase long-chain family member 4 (ACSL4) and suppressed lysophosphatidylcholine acyltransferase 3 (LPCAT3), markers associated with lipid remodeling, as well as altered antioxidant genes glutathione peroxidase 4 (GPX4) and superoxide dismutase 2 (SOD2) in both strains. rLcn2 treatment in BL6 mice normalized ACSL4 and LPCAT3 expression and enhanced antioxidant gene transcription, whereas BALB/c mice showed minimal recovery. In BL6 mice, Lcn2 supports oxidative phosphorylation while simultaneously modulating lipid metabolism and antioxidant defenses, highlighting its integrated role in cellular adaptation to endotoxemia. Our results reveal that differential Lcn2 responsiveness contributes to inter-strain variation in susceptibility to sepsis-induced mitochondrial dysfunction and identify Lcn2 as a potential therapeutic target for enhancing metabolic resilience during sepsis.
Non-muscle myosin IIA (NMIIA), a motor protein plays a critical role in regulating cell morphology, adhesion, migration, contractility, and mechanotransduction across various tissues, including the ocular lens. S100A4, a known NMIIA-interacting protein, is abundantly expressed and exhibits a discrete spatial distribution in lens fibers. Loss of S100A4 has previously been shown to associate with late-onset lens opacification in mice. However, its role in regulating NMIIA activity, assembly, and actin cytoskeletal organization in the lens remains unclear. Using S100A4-null mice, this study reveals that S100A4 co-immunoprecipitates with NMIIA and that its absence leads to decreased NMIIA (Ser1943) phosphorylation, impaired NMIIA filament assembly, and disruption in actin cytoskeletal organization and polymerization in the lens. Quantitative proteomic analysis further identified decreased levels of CLIC5 and RNA binding protein-SERBP1 in cytoskeletal- and membrane-enriched fractions from S100A4-null versus wild-type lenses. Moreover, treatment of wild-type mouse lenses in ex-vivo with trifluoperazine, a known S100A4 inhibitor, induced lens opacification in association with increased insolubilization of S100A4, NMIIA and actin. Collectively, these findings demonstrate that S100A4 plays a critical role in regulating NMIIA activity and assembly, and maintaining actin cytoskeletal organization in the ocular lens, thereby contributing to lens transparency and homeostasis.
Preeclampsia (PE) is a major cause of maternal and fetal morbidity and mortality during pregnancy. PE is characterized by widespread endothelial dysfunction in mothers and fetuses. The etiology of PE remains elusive, but the dysregulation of microRNAs (miRNAs) in endothelial cells may contribute to the pathogenesis of PE. We have reported that PE downregulates expression of two miRNAs, miR-29a-3p and miR-29c-3p (miR-29a/c-3p), and knockdown of miR-29a/c-3p impairs functions of human umbilical vein endothelial cells (HUVECs). Herein, we tested the hypothesis that knockdown of miR-29a/c-3p sex-specifically impairs cellular responses to vascular endothelial growth factor-A (VEGFA) and fibroblast growth factor 2 (FGF2) via disrupting the transcriptome in HUVECs. MiR-29a/c-3p were knocked down using miR-29c-3p inhibitors in male and female HUVECs. Chemotactic and proliferative responses to VEGFA and FGF2 were assessed. RNA-seq was performed to identify miR-29a/c-3p regulated genes and pathways. Knockdown analysis demonstrated that miR-29c-3p inhibitors decreased miR-29a/c-3p levels by over 95% in male and female HUVECs. Functionally, miR-29c-3p inhibitors suppressed VEGFA-, but not FGF2-stimulated chemotaxis by 26% in male, but not female HUVECs. RNA-seq revealed that miR-29a/c-3p inhibitors dysregulated 47 and 118 genes in male and female HUVECs, respectively. Bioinformatics analyses showed that miR-29a/c-3p-regulated genes were differently associated with hypertension, heart, angiogenesis, and immunology in male and female HUVECs. These data demonstrate that knockdown of miR-29a/c-3p sex-specifically affects cellular responses to VEGFA and FGF2 in HUVECs, possibly via disrupting the transcriptome and relevant pathways. These miR-29a/c-3p-regulated genes might represent promising sex-specific therapeutic targets for PE-associated endothelial dysfunction pending further in vivo and clinical verification.
Ovarian cancer peritoneal metastasis remains a major cause of recurrence and death despite advances in cytoreductive surgery, platinum-based chemotherapy, PARP inhibition, and immune checkpoint blockade. The limited activity of immunotherapy in this setting reflects layered immune resistance shaped by impaired antigen visibility, redundant inhibitory receptor networks, suppressive myeloid and regulatory circuits, and metabolic-epigenetic constraints within ascites and multicellular spheroids. These compartment-specific features distinguish peritoneal disease from anatomically confined tumors and help explain why systemic immune reinvigoration alone rarely produces durable benefit. Here, we synthesize current evidence on the mechanisms that govern immune escape in ovarian cancer peritoneal dissemination, with emphasis on antigen presentation defects, checkpoint-driven T-cell exhaustion, anti-phagocytic signaling, soluble suppressive mediators, and metabolic remodeling of the ascites microenvironment. We further examine how DNA damage response states intersect with innate immune sensing and discuss the translational implications of homologous recombination deficiency for combination treatment design. Finally, we propose a biomarker-guided framework that links antigen-presentation competence, immune engagement, dominant suppressive axes, and ascites-specific biology to rational therapeutic matching. This mechanism-centered view supports more precise trial design and provides a roadmap for combination immunotherapy in advanced ovarian cancer.
Presbycusis is caused by multiple factors, the mechanisms of which are not fully understood. This study investigated mitochondria-related genes in presbycusis, a condition with multifactorial and incompletely understood mechanisms, by combining Mendelian randomization analysis and functional validation. Genetically predicted higher ABHD10 expression was identified as a protective factor against presbycusis and was regulated by methylation sites such as cg15684481, whereas methylation at other sites inhibited ABHD10 expression and alleviated the condition. In contrast, ABHD10 was upregulated in d-galactose-induced HEI-OC1 cells and aged mouse cochlear hair cells, where it promoted senescence. Silencing ABHD10 in senescent cells reduced P21 and P16 protein levels, decreased reactive oxygen species levels, improved mitochondrial membrane potential, and lowered lipid droplet formation along with triglycerides and fatty acids. Co-immunoprecipitation experiments showed that ABHD10 interacts with KCMF1, indicating that the complex may regulate cellular metabolism and stress responses through signaling pathways. This was supported by GO and KEGG analyses linking ABHD10 to aging-related processes such as energy metabolism and oxidative stress. Overall, ABHD10 functions as a context-dependent mitochondrial regulator, with the ABHD10-KCMF1 axis integrating mitochondrial quality control, lipid homeostasis, and redox balance, thereby offering a potential druggable target for presbycusis.
Advanced maternal age is associated with increased oocyte aneuploidy and early miscarriage. Serum- and glucocorticoid-regulated kinase 1 (SGK1), a member of the serine/threonine kinase family, is downregulated in oocytes from aged mice. However, the mechanisms by which SGK1 controls oocyte maturation remain unclear. Here, we show that SGK1 localizes predominantly to spindle poles during oocyte maturation. Knockdown of SGK1 via siRNA or pharmacological inhibition disrupts spindle assembly and impairs kinetochore-microtubule attachments in mouse oocytes. This disruption leads to sustained activation of the spindle assembly checkpoint, failure of Cyclin B1 and Securin degradation, impaired metaphase I-anaphase transition, and defective first polar body extrusion. Mechanistically, we identify RanBP1 as a potential mediator of SGK1 function during meiotic progression. In porcine oocytes, SGK1 inhibition similarly compromises maturation and Cyclin B1 degradation, suggesting a conserved role across mammalian species. Together, our findings establish SGK1 as a critical regulator of spindle assembly and meiotic progression in mammalian oocytes.
Epithelial-mesenchymal transition (EMT) refers to a process in which epithelial cells shed their polarity and intercellular adhesion while adopting mesenchymal traits. Emerging evidence indicates that EMT is critically involved in the pathogenesis of several oral inflammatory diseases, including periodontitis, drug-induced gingival overgrowth, and Sjögren's syndrome. A thorough understanding of the molecular mechanisms governing EMT may help elucidate the pathogenesis of these diseases and provide new diagnostic and therapeutic strategies for clinical practice. This review will focus on the recent research progress regarding the role of EMT in the above three oral inflammatory diseases, with the aim of offering insights for related research and clinical applications.
Intestinal senescence is an important factor in systemic aging and age-related diseases; however, detailed studies have been limited due to the lack of robust experimental models. In this study, we established cellular senescence models of human small intestinal organoids using two senescence-inducing agents: butyrate (an endogenous microbial metabolite) and cisplatin (an exogenous chemotherapeutic agent). Both molecules induced senescence-associated features, including increased p16INK4a, CDKN1A, IL8, and TNF expression, as well as SA-β-Gal activity. RNA-sequencing revealed that cisplatin, but not butyrate, activated the p53 signaling pathway, whereas both downregulated various nutrient absorption and metabolism-related pathways. These models exhibited reduced nutrient transporter expression, diminished glucose uptake, and decreased vitamin D responsiveness, thus recapitulating the features of aged or damaged intestinal tissue. In cisplatin-treated organoids, epithelial to mesenchymal transition (EMT)-related gene ontologies were enriched based on RNA-sequencing. The induction of EMT through cisplatin-induced senescence was further confirmed by EMT marker gene expression, which decreased following the inhibition of TGF-β signaling, a canonical EMT-inducing pathway. Notably, TGF-β signaling inhibition attenuated senescence-induced inflammation and nutrient dysfunction, which suggests the importance of EMT as a target for preventing intestinal senescence. Our models provide a novel platform for examining the intestine-specific molecular mechanisms of senescence associated with distinct senescence-inducing mechanisms and for developing strategies to prevent age-related intestinal dysfunction.
5-fluorouracil (5FU)-induced intestinal mucositis significantly limits its clinical utility and compromises patient outcomes. Building on our previous finding that a specific probiotic formulation, consisting of Limosilactobacillus reuteri BCRC 80379 and Clostridium butyricum MIYAIRI 588 (collectively referred to as LCs), mitigated cisplatin-induced mucositis, this study evaluated the prophylactic efficacy and underlying mechanisms of LCs against 5FU-induced mucositis in Wistar rats. Rats were divided into control, 5FU-only, and 5FU+LCs groups. LCs was orally administered daily for 21 days before and throughout the 5FU treatment (50 mg/kg/day for 5 days). Intestinal tissues were analyzed using histological, molecular, and microbiological approaches. Pretreatment with LCs significantly attenuated 5FU-induced small intestinal damage, as evidenced by improved mucosal structure (e.g., increased villus height, crypt depth, and goblet cell density), along with reduced inflammatory cell infiltration. Moreover, LCs reinforced the intestinal barrier by upregulating genes associated with the mucus layer (Muc2) and tight junctions (Ocln, Tjp1, and Cldn1). LCs also suppressed the TLR4/MyD88/NF-κB pathway, leading to reduced levels of pro-inflammatory mediators (e.g., TNF-α, IL-1β, and MPO) while elevating key regulatory mediators such as IL-10 and secretory IgA (sIgA). Furthermore, microbial profiling revealed that LCs beneficially reshaped gut microbiota composition by reducing opportunistic pathogens (e.g., Escherichia-Shigella and Enterobacter). These microbial changes were accompanied by a favorable immune modulation, including decreased pro-inflammatory markers and increased homeostatic mediators. Collectively, these findings suggest that LCs mitigates 5FU-induced mucositis through coordinated regulation of intestinal barrier integrity, immune responses, and gut microbiota, highlighting its potential as a probiotic-based approach for managing chemotherapy-induced intestinal injury.
Erythropoiesis is a meticulously regulated process influenced by a multitude of factors. Prior research has demonstrated that hypoxic conditions (5% O2) facilitate erythroid differentiation. Nevertheless, although our preliminary data indicate the involvement of VEGF/VEGFR2 in this process, the precise regulatory mechanism in erythropoiesis under hypoxia remains inadequately understood. In this study, an in vitro model of inhibited erythroid differentiation was developed using CD34+ hematopoietic stem cells treated with a VEGFR2-neutralizing antibody. Additionally, the signaling axis was modulated under hypoxia conditions employing the mTOR inhibitor rapamycin and TTI1-siRNA. The findings revealed that hypoxia significantly upregulated VEGF/VEGFR2 expression and promoted erythroid differentiation. Conversely, VEGFR2 inhibition resulted in a substantial decrease in erythroid surface markers and hemoglobin synthesis. Proteomics analysis suggested that TTI1 and mTOR are pivotal components of this signaling axis, with their suppression effectively impeding erythropoiesis. Under hypoxic conditions, VEGFR2 may regulate erythroid differentiation of CD34+ cells through a mechanism involving the TTI1-mTORC1 signaling pathway.
