Programmed cell death participates in diverse physiological and pathological processes. The identification of disulfidptosis reveals that disulfide stress-induced cytoskeletal disintegration constitutes a targetable biological process mediated through pathways such as SLC7A11-dependent cystine metabolism, offering potential therapeutic avenues for disease intervention. Disulfidptosis involves activation of specific molecular pathways, including SLC7A11-mediated cystine uptake, NADPH depletion, aberrant intracellular disulfide accumulation, filamentous actin collapse, and dysregulation of the antioxidant system, ultimately leading to cell death and contributing to disease progression. Furthermore, comparison between disulfidptosis and other established cell death modalities, such as apoptosis, necroptosis, pyroptosis, ferroptosis, and cuproptosis, further underscores its unique biological characteristics and research significance, enabling intervention in disease progression. By targeting these pathways, we systematically integrated pharmacological agonists and inhibitors of key targets, such as SLC7A11-dependent cystine metabolism, to promote or inhibit disulfidptosis, thereby restoring cellular homeostasis disrupted by diseases including cancer, neurodegeneration, ischemia/reperfusion injury, autoimmune diseases, metabolic syndrome, and sepsis. This highlights the potential of disulfidptosis as a therapeutic target. We identified that therapeutic strategies targeting disulfidptosis converge on the core pathogenic axis of “redox imbalance, disulfide stress, actin cytoskeleton collapse.” These strategies exhibit disease-dependent bidirectionality—inducing disulfidptosis to selectively eliminate cancer cells in neoplastic diseases while suppressing this process to protect functional cells in non-neoplastic conditions. This review explores the current understanding of the molecular mechanisms and key regulatory nodes of disulfidptosis, deepening our comprehension of the role of disulfidptosis in human health and disease while revealing actionable targets and future research directions. Significance Statement The discovery of disulfidptosis enriches understanding of programmed cell death, providing a foundation for targeting SLC7A11-mediated cystine metabolism and other key pathways to treat various diseases and offering new approaches for managing pathological processes previously considered intractable. As molecular mechanistic understanding advances, these emerging therapeutic strategies may open new research avenues, although clinical translation and efficacy require further validation.

BACKGROUND:Cardiovascular and cerebrovascular diseases (CCVDs) have surpassed cancer as a significant global health challenge. As essential responders of the immune system, macrophages play a critical role in maintaining and remodeling CCVD homeostasis. They are involved in various functions, including the clearance of apoptotic cells, regulation of inflammatory responses, enhancement of electrical conduction, and facilitation of tissue development and repair. Ion channels not only participate in the electrophysiological activities of macrophages but also directly influence tissue immune responses and inflammatory processes. The regulatory role of ion channels in macrophage function in CCVDs has attracted considerable attention. AIM:of Review: This review aims to systematically elucidate the specific expression and functional regulation of macrophage ion channels within the cardiovascular and cerebrovascular systems and analyzes the functional heterogeneity of these channels across distinct tissue-specific macrophage subsets. It further explores their mechanistic roles in the progression and repair of CCVDs. Key Scientific Concepts of Review: This review elucidates the fundamental functions and electrophysiological basis of macrophages in the heart, vasculature, and brain, including parenchymal resident macrophages (microglia) of the brain. It further discusses the variation in ion channel expression across macrophages of different tissue origins and polarization states and how this heterogeneity dictates their specific functional roles. Additionally, this review summarizes the pathophysiological contributions of macrophage ion channels to major cardiovascular and cerebrovascular disorders, as well as the underlying molecular mechanisms. Furthermore, it provides an in-depth analysis of the functional mechanisms of key ion channels, critically discusses existing controversies and limitations in current research, and offers our perspectives along with feasible solutions. Finally, this review explores future research directions and emerging trends in this field, along with the clinical potential of targeting macrophage ion channels as a novel therapeutic strategy for CCVDs.

Prolonged survival of patients with cancer has increased the need to address chemotherapy‑related cardiovascular complications. Doxorubicin (DOX), a widely used anthracycline, is associated with dose‑dependent cardiotoxicity, known as DOX‑induced cardiotoxicity (DIC), which limits its clinical utility. DOX triggers cardiomyocyte pyroptosis via the NLRP3/caspase‑1/gasdermin D pathway, a potential underlying mechanism of DIC. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of lipid metabolism and inflammation, has been implicated in NLRP3 inflammasome activation and the progression of cardiovascular diseases; however, its role in DIC remains unclear. The present study demonstrated that DOX downregulates PCSK9 expression in cardiomyocytes in a dose‑dependent manner. Through proteomic analysis and PCSK9 knockout cell and mouse models, it was found that the deletion of PCSK9 exacerbated DOX‑induced pyroptosis and cardiac dysfunction. These results revealed the protective effect of PCSK9 in DOX‑mediated cardiotoxicity and indicated that PCSK9 regulation may provide a new cardioprotective strategy for patients receiving anthracycline chemotherapy.

Cardiac calcification is an age-associated pathological process that contributes to cardiac dysfunction, arrhythmia, and sudden cardiac death, yet its underlying mechanisms remain unclear. Cardiac fibroblasts (CFs) have emerged as key mediators of ectopic calcification through osteogenic differentiation. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of cholesterol metabolism, has been implicated in cardiovascular pathology beyond its canonical role, but its involvement in cardiac calcification is unknown. In this study, aged mice exhibited cardiac dysfunction, interstitial fibrosis, and myocardial calcium deposition, accompanied by upregulation of osteogenic markers, including Runx2, OCN, and Osx. PCSK9 expression was increased in aged hearts and enriched in DDR2-positive cells. In vitro, senescent CFs displayed enhanced osteogenic differentiation, characterized by increased calcium deposition, alkaline phosphatase activity, and elevated expression of osteogenic markers. Recombinant PCSK9 promoted osteogenic differentiation in young CFs, whereas genetic deletion of PCSK9 attenuated these effects in senescent CFs. Pharmacological experiments suggest that PCSK9-mediated osteogenic differentiation is associated with activation of the ATF4 pathway and upregulation of Runx2 expression. These findings support a role for the PCSK9-ATF4-Runx2 signaling axis in osteogenic differentiation of CFs, providing new insights into age‑related cardiac calcification and identifying this pathway as a hypothesis‑generating candidate for future investigation.

Per- and polyfluoroalkyl substances (PFAS) accumulate in the hippocampus, yet their effects on adult hippocampal neurogenesis (AHN) remain unclear. In this study, adult male mice were orally exposed to PFOA or GenX (2 or 10 mg/kg/day) for 28 days. Behavioral performance, AHN, synaptic remodeling, microglial morphology, and redox status were evaluated using behavioral assays, Nissl and Golgi staining, BrdU immunolabeling, microglial morphometric analyses, and Western blotting. PFOA exposure and high-dose GenX exposure reduced time spent and distance traveled in the center area of the open field and impaired spatial learning and memory performance in the Morris water maze, as indicated by increased escape latency and fewer platform crossings. In contrast, PFOA and low-dose GenX exposure reduced exploration of the open arms in the elevated plus maze. PFOA and GenX reduced dendritic spine density with fewer mushroom/thin spines and more stubby spines. PFOA preferentially decreased PSD95 (postsynaptic marker), whereas GenX reduced synaptophysin (presynaptic marker). In the subgranular zone (SGZ), survival and neuronal differentiation of neural stem cells were diminished, and asymmetric divisions of radial glia-like cells increased, suggesting stem-cell pool depletion. Microglia exhibited a hyper-ramified/bushy reactive phenotype. Hippocampal ROS/MDA rose, NOX2 components (GP91phox/P22phox) were upregulated, and ferroptosis defenses (SLC7A11/GLS2/GPX4) were downregulated. Collectively, PFOA and GenX disrupt hippocampal synaptic remodeling and AHN and are associated with increased oxidative stress and ferroptosis-related alterations. Differential pre- versus postsynaptic vulnerabilities may contribute to the distinct behavioral alterations observed following PFOA and GenX exposure. This work provides new insights into the neurotoxic effects of PFOA and GenX and identifies potential pathways involved in PFAS-induced hippocampal dysfunction.

Micro- and nanoplastics (MNPs), due to their widespread distribution and chemical stability, have emerged as novel environmental contaminants threatening cardiovascular health. Evidence links MNPs to conditions such as atherosclerosis, cardiac fibrosis, myocardial infarction, and other cardiovascular diseases (CVDs). Recently, MNPs have been found within atherosclerotic plaques and in the myocardial tissues of surgery patients, highlighting their close association with cardiovascular pathology. Investigations have demonstrated that MNPs can enter the human body through oral ingestion, inhalation, dermal contact, and medical procedures, and subsequently accumulate in the blood, blood vessels, and cardiac tissues. Once deposited, these particles induce oxidative and endoplasmic reticulum stress, disrupt mitochondrial function, and activate inflammatory signaling pathways, ultimately triggering cell death. These processes contribute to endothelial dysfunction, cardiac damage and fibrosis, vascular smooth muscle cell phenotypic switching, and macrophage foam cell formation, thereby likely contributing to the onset and progression of CVDs. Despite these findings, the potential cardiovascular risks of MNPs and the underlying mechanisms remain largely unexplored. This review summarizes the basic properties of MNPs, their biodistribution within the cardiovascular system, toxic effects, and underlying molecular mechanisms, providing a foundation for future risk assessment and the development of preventive strategies.

Background Alzheimer's disease (AD) is a neurodegenerative disorder characterized by memory impairment. Neuroinflammatory processes, mediated by glial and immune cells, contribute to neuronal damage. Emerging evidence implicates innate immune mechanisms, including trained immunity and cell trans-differentiation, in AD pathogenesis, though their roles remain unclear. Objective To investigate transcriptomic changes in the 3xTg-AD mouse model, focusing on trained immunity and cell trans-differentiation in disease mechanisms. Methods RNA-sequencing was performed on brain tissue (cortex plus hippocampus) from 11-month-old female 3xTg-AD and wild-type mice (n = 3/group). Differentially expressed genes (fold change > 1.5, p < 0.05) were identified and followed by bioinformatics and knowledge-based transcriptomic profiling. Public AD datasets were also analyzed. Results 3xTg-AD mice exhibited 316 upregulated and 412 downregulated genes. Downregulated genes included those for blood-brain barrier protein, while upregulated genes related to cerebrospinal fluid. Increased expression of proinflammatory markers, as well as genes related to cell differentiation, proliferation, activation, and adhesion. Upregulation of genes associated with cell migration and trans-differentiation suggests a potential role for inflammation and cellular plasticity. Additionally, genes involved in inflammasome pathways, immunometabolism, and trained immunity were upregulated. Mechanistically, these genes were modulated by knockdown of trained immunity promoter SET-7, overexpression of trained immunity inhibitor IL-37, and knockout of inflammasome genes IL-1 receptor, caspase-1, and pattern recognition receptor CD36. Conclusions The finding underscore the potential role of trained immunity and cell trans-differentiation in AD, revealing a mechanistic framework in which danger-associated molecular patterns drive innate immune responses, inflammasome activation, and cell plasticity contribute to AD, offering therapeutic targets for neuroinflammation and cellular reprograming.

Hexafluoropropylene oxide dimer acid (HFPO-DA), commonly known as GenX, is a replacement for perfluorooctanoic acid (PFOA) which readily accumulates in the brain and exhibits neurotoxic effects. However, the adverse impacts of GenX on neurons and its underlying mechanisms remain poorly understood. In this study, primary cortical neurons isolated from neonatal mice were exposed to varying concentrations of GenX to assess cell viability, intracellular reactive oxygen species (ROS) levels, and morphological alterations. Additionally, the expression of apoptosis-related proteins Bcl-2, Bax, Caspase-3, NF-κB, and Tomm20 was examined. The results showed that increasing concentrations of GenX significantly elevated intracellular ROS levels and markedly reduced cell viability and the number of cells. Neuronal morphology was severely disrupted, characterized by decreased neurite branching, shortened neurite length, and reduced soma size. At 200 μM and 400 μM GenX, apoptosis rates were dramatically increased (p < 0.0001), accompanied by a pronounced increase in NF-κB fluorescence intensity and nuclear translocation. Western blot analysis further revealed a progressive downregulation of Bcl-2 and Tomm20, while levels of Bax, Cleaved Caspase-3/Caspase-3 increased in a dose-dependent manner. Notably, pretreatment with N-Acetylcysteine (NAC) effectively reversed GenX-induced ROS accumulation (p = 0.0001), NF-κB activation, and neuronal apoptosis. Collectively, these findings demonstrate that GenX exposure induces ROS accumulation in primary cortical neurons, leading to apoptosis through mitochondrial dysfunction mediated by Tomm20 downregulation and the activation of Caspase-3 and NF-κB. This study provides novel mechanistic insights into the neurotoxicity of the emerging environmental contaminant GenX and offers a theoretical basis for developing neuroprotective targets against such exposures.

Endothelial cell (EC) injury is highly significant in both health toxicology and cardiovascular disease. In the context of environmental and occupational health, ECs are frequently the frontline responders to pathogens and toxicants. Upon exposure to such agents, endothelial dysfunction ensues, triggering a cascade of cellular fates including pyroptosis, apoptosis, and necroptosis, which together constitute PANoptosis. The NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammasome is a sentinel of cellular stress and is activated in response to environmental pollutants and chemical toxins. Notably, strategies aimed at suppressing NLRP3 activation, such as the potential deployment of specific antidotes or detoxifying agents, have shown promise in impeding endothelial injury and halting the progression of cardiovascular diseases (CVDs). In this review, we summarize the role of NLRP3 in endothelial injury, highlight its PANoptosis ramifications, and partially discuss its relationship with vascular toxicity, which may aid in the prevention and treatment of vascular disorders and toxicology.

Cancer remains the foremost cause of mortality on a global scale. Immunotherapy has yielded remarkable outcomes in the fight against cancer and is regarded as one of the most crucial and promising therapeutic modalities. PCSK9, a critical target for plasma lipids control, has been extensively and deeply studied in multiple diseases. Currently, the functions of PCSK9 in cancer, particularly its immunomodulatory role, have been progressively revealed. PCSK9 is capable of modulating a variety of immune response throughout tumor progression by orchestrating lipid metabolism. Moreover, PCSK9 governs the cell fate of diverse immune cells, such as inflammatory factor signals, MHC signals, and TCR signals. This review comprehensively summarizes the current state of knowledge regarding the role and underlying mechanisms of PCSK9 in tumorigenesis, progression, immune escape, and drug resistance.

Myocarditis is a life-threatening inflammatory disorder that affects the cardiac muscle tissue. Current treatments merely regulate heart function but fail to tackle the root cause of inflammation. In myocarditis, the initial wave of inflammation is characterized by the presence of neutrophils. Subsequently, neutrophils secrete chemokines and cytokines at the site of heart tissue damage to recruit additional immune cells and regulate defense responses, thereby exacerbating myocarditis. Recent discoveries showing neutrophil extracellular traps (NETs) and their components not only reinforce the proinflammatory functions of neutrophils, inducing enhanced interleukin (IL)-8 secretion, but also induce monocyte/macrophage activation, differentiation, and phagocytic function through the inflammasome pathway. The inflammasome cascade triggers a positive feedback loop through the secretion of proinflammatory cytokines, which leads to further neutrophil activation and degranulation, NET release, monocyte and macrophage infiltration, tissue degradation, and myocardial damage, indicating that neutrophils promote myocarditis-induced cardiac necrosis and an anti-cardiac immune response. In addition, neutrophils can induce oxidative stress and damage cellular structures by releasing excess reactive oxygen species (ROS), thus exacerbating tissue damage in myocarditis. Meanwhile, the recruitment of cells, which is facilitated by neutrophil-secreted chemokines, and the consumption of cells through neutrophil phagocytosis can form a closed loop that continuously maintains a proinflammatory state. This review summarizes the role of neutrophil secretion, phagocytosis and their relationship in myocarditis, and discusses the function of certain agents, such as chemokine antagonists, midkine blockers and neutrophil peptidyl arginine deiminase 4 (PAD4) inhibitors in inhibiting neutrophil secretion and phagocytosis, to provide perspective for myocarditis treatments through the inhibition of neutrophil secretion and phagocytosis.

Bone tissue damage and associated disorders significantly compromise the quality of life of affected patients, and existing therapeutic options remain limited. Bone marrow mesenchymal stem cells (BMSCs) play a crucial role in bone regenerative medicine, owing to their ability to differentiate into osteoblasts. Utilizing cutting-edge technologies, nanomaterials, and bioactive compounds can emulate the natural bone tissue microenvironment, offer a three-dimensional scaffold that facilitates the osteogenic differentiation of BMSCs, and modulate signals at the molecular level, thereby showing promise for applications in bone regeneration and repair. This review seeks to discuss the latest research advancements, elucidate the underlying mechanisms, and highlight the potential benefits of these technologies in augmenting the osteogenic capacity of BMSCs. Furthermore, the challenges and future directions for integrating these technologies in practical settings are discussed to pioneer new vistas in bone regenerative medicine.

Cardiovascular diseases (CVD) are the leading cause of morbidity and mortality globally, with elevated low-density lipoprotein cholesterol (LDL-C) levels being a major risk factor. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a critical role in regulating LDL-C levels by promoting the degradation of hepatic low-density lipoprotein receptors (LDLR) responsible for clearing LDL-C from the circulation. PCSK9 inhibitors are novel lipid-modifying agents that have demonstrated remarkable efficacy in reducing plasma LDL-C levels and decreasing the incidence of CVD. However, the broader clinical impacts of PCSK9 functions beyond cholesterol metabolism, including both desired and undesired effects from therapeutic PCSK9 inhibition, underscore the urgent necessity to elucidate the underlying mechanisms. Recent studies have shown that local PCSK9 in the vascular system can interact with other receptors such as CD36, LRP-1, and ABCA1. This provides new evidence supporting the potential contribution of PCSK9 to CVD through LDLR-independent signaling pathways. Therefore, this review aimed to outline the diverse effects of PCSK9 on CVD and discuss the underlying mechanisms in non-cholesterol-related processes, which will provide a rational basis for its long-term pharmacological inhibition in the clinic.

Background:Osteogenic differentiation is a crucial process in which bone marrow mesenchymal stem cells (BMSCs) differentiate into osteoblasts, involving the regulation of multiple genes and signaling pathways. The TSC22D3 gene plays an important role in various biological processes (BPs), but its specific function in osteogenic differentiation remains unclear. This study aims to explore the regulatory role of the TSC22D3 gene in osteogenic differentiation and its molecular mechanisms. Methods:By analyzing microarray datasets (GSE12266, GSE18043, and GSE80614), the limma package was used to screen for differentially expressed genes (DEGs). Combined with Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, key genes and signaling pathways related to osteogenic differentiation were identified. Further, through protein-protein interaction (PPI) network analysis and the Finding Regulatory Elements by Differential Expression and Network-Based Statistical Analysis (FRIEND) method, TSC22D3 was screened out as a core hub gene. For experimental validation, the bioinformatics analysis results were intersected with the transcriptome sequencing data from our research group to further confirm the core molecules. Lentivirus-mediated interference technology was used to downregulate and overexpress TSC22D3 expression, and the impact of TSC22D3 on osteogenic differentiation was assessed through RT-qPCR, Western blotting, alkaline phosphatase (ALP) staining, phalloidin staining, and calcium deposition assays. Results:TSC22D3 is significantly upregulated during osteogenic differentiation; its downregulation can lead to reduced expression of osteogenic differentiation marker genes (such as runt-related transcription factor 2 [Runx2], osterix [OSX], osteocalcin [OCN], and osteopontin [OPN]), as well as a significant decrease in ALP activity and calcium deposition. GO and KEGG analyses indicate that TSC22D3 is closely associated with pathways including the cell cycle, cytoskeleton, and WNT signaling. Furthermore, Gene Set Enrichment Analysis (GSEA) analysis has further revealed the potential regulatory mechanism of TSC22D3 in osteogenic differentiation. Rescue experiments have confirmed that TSC22D3 can promote the osteogenic differentiation of BMSCs and induce the rearrangement of cytoskeletal structure. Conclusion:This study reveals that TSC22D3 is essential for osteogenic differentiation. Its upregulation promotes osteogenic marker expression, ALP activity, and calcium deposition, while its downregulation inhibits these processes. TSC22D3 affects cytoskeletal rearrangement during osteogenesis.

In this study, we observed worsening metabolic crosstalk in mouse models with concomitant metabolic disorders such as hyperhomocysteinemia (HHcy), hyperlipidemia, and hyperglycemia and in human coronary artery disease by analyzing metabolic profiles. We found that HHcy worsening is most sensitive to other metabolic disorders. To identify metabolic genes and metabolites responsible for the worsening metabolic crosstalk, we examined mRNA levels of 324 metabolic genes in Hcy, glucose-related and lipid metabolic systems. We examined Hcy-metabolites (Hcy, SAH and SAM) by LS-ESI-MS/MS in 6 organs (heart, liver, brain, lung, spleen, and kidney) from C57BL/6J mice. Through linear regression analysis of Hcy-metabolites and metabolic gene mRNA levels, we discovered that SAH-responsive genes were responsible for most metabolic changes and all metabolic crosstalk mediated by Serine, Taurine, and G3P. SAH-responsive genes worsen glucose metabolism and cause upper glycolysis activation and lower glycolysis suppression, indicative of the accumulation of glucose/glycogen and G3P, Serine synthesis inhibition, and ATP depletion. Insufficient Serine due to negative correlation of PHGDH with SAH concentration may inhibit the folate cycle and transsulfurarion pathway and consequential reduced antioxidant power, including glutathione, taurine, NADPH, and NAD+. Additionally, we identified SAH-activated pathological TG loop as the consequence of increased fatty acid (FA) uptake, FA β-oxidation and Ac-CoA production along with lysosomal damage. We concluded that HHcy is most responsive to other metabolic changes in concomitant metabolic disorders and mediates worsening metabolic crosstalk mainly via SAH-responsive genes, that organ-specific Hcy metabolism determines organ-specific worsening metabolic reprogramming, and that SAH, acetyl-CoA, Serine and Taurine are critical metabolites mediating worsening metabolic crosstalk, redox disturbance, hypomethylation and hyperacetylation linking worsening metabolic reprogramming in metabolic syndrome.

Cardiovascular disease (CVD) is one of the leading causes of mortality in humans, and oxidative stress plays a pivotal role in disease progression. This phenomenon typically arises from weakening of the cellular antioxidant system or excessive accumulation of peroxides. This review focuses on a specialized form of oxidative stress—disulfide stress—which is triggered by an imbalance in the glutaredoxin and thioredoxin antioxidant systems within the cell, leading to the accumulation of disulfide bonds. The genesis of disulfide stress is usually induced by extrinsic pathological factors that disrupt the thiol-dependent antioxidant system, manifesting as sustained glutathionylation of proteins, formation of abnormal intermolecular disulfide bonds between cysteine-rich proteins, or irreversible oxidation of thiol groups to sulfenic and sulfonic acids. Disulfide stress not only precipitates the collapse of the antioxidant system and the accumulation of reactive oxygen species, exacerbating oxidative stress, but may also initiate cellular inflammation, autophagy, and apoptosis through a cascade of signaling pathways. Furthermore, this review explores the detrimental effects of disulfide stress on the progression of various CVDs including atherosclerosis, hypertension, myocardial ischemia-reperfusion injury, diabetic cardiomyopathy, cardiac hypertrophy, and heart failure. This review also proposes several potential therapeutic avenues to improve the future treatment of CVDs.

Commonly, articular osteochondral tissue exists significant differences in physiological architecture, mechanical function, and biological microenvironment. However, the development of biomimetic scaffolds incorporating upper cartilage, middle tidemark-like, and lower subchondral bone layers for precise articular osteochondral repair remains elusive. This study proposed here a novel strategy to construct the trilayered biomimetic hydrogel scaffolds with dual-differential microenvironment of both mechanical and biological factors. The cartilage-specific microenvironment was achieved through the grafting of kartogenin (KGN) into gelatin via p-hydroxyphenylpropionic acid (HPA)-based enzyme crosslinking reaction as the upper cartilage layer. The bone-specific microenvironment was achieved through the grafting of atorvastatin (AT) into gelatin via dual-crosslinked network of both HP-based enzyme crosslinking and glycidyl methacrylate (GMA)-based photo-crosslinking reactions as the lower subchondral bone layer. The introduction of tidemark-like middle layer is conducive to the formation of well-defined cartilage-bone integrated architecture. The in vitro experiments demonstrated the significant mechanical difference of three layers, successful grafting of drugs, good cytocompatibility and tissue-specific induced function. The results of in vivo experiments also confirmed the mechanical difference of the trilayered bionic scaffold and the ability of inducing osteogenesis and chondrogenesis. Furthermore, the articular osteochondral defects were successfully repaired using the trilayered biomimetic hydrogel scaffolds by the activation of endogenous recovery, which offers a promising alternative for future clinical treatment.

Somatic mutations related to clonal hematopoiesis of indeterminate potential (CHIP) are risk factors for stroke. The impact of DNMT3A, the most mutated gene in CHIP, on clinical functional outcomes of acute ischemic stroke (AIS) remains unclear. In a well-characterized cohort of 8524 ischemic stroke patients, we demonstrated that DNMT3A-driven CHIP was significantly associated with neurological disability in these patients. With a stroke mouse model of transient middle cerebral artery occlusion (tMCAO), we demonstrated that DNMT3A protein levels in the brain penumbra increased. The DNMT3A inhibitor RG108 administration amplified neutrophil proliferation in the blood, promoted neutrophil infiltration into the brain penumbra, and exaggerated proinflammatory activation in tMCAO male mice. DNMT3A inhibition also significantly increased infarct volume and worsened neurobehavioral function in tMCAO male mice. In conclusion, DNMT3A somatic mutations are associated with worsened neurological disability in some patients with AIS, potentially through increased neutrophil proliferation and infiltration in the ischemic brain region. These findings suggest a possible mechanism for proinflammatory activation and tissue damage in the affected brain tissue, highlighting the need for further research in this area.