Background:Suboptimal adherence to preventive medications and inadequate management of risk factors are major barriers to effective post-discharge care for individuals at high risk of stroke, particularly in resource-constrained settings. Digital health interventions delivered via widely accessible platforms offer a promising scalable approach. We conducted this trial to evaluate the efficacy of Social Network based patient care in improving medication adherence in high-risk populations for stroke. Methods:COMPLIANCE-MT is a multicenter, prospective, randomized, open-label, parallel-group trial with blinded outcome assessment (PROBE design) assessing the superiority of Social Network-based care versus conventional care in medication adherence for high-risk populations for stroke. A total of 720 participants will be recruited across 33 hospitals in China and randomized in a 1:1 ratio to either a 12-month Social Network (WeChat) based coordinated care program or routine follow-up. The primary outcome is the proportion of patients achieving more than 80% adherence to all indicated vascular prevention medications (antihypertensives, hypoglycemics, lipid-lowering agents, anticoagulants, and antiplatelets) at 12 months. Analysis will be performed on an intention-to-treat approach. Discussion:The COMPLIANCE trial evaluates a social network-based intervention in improving adherence to five evidence-based vascular prevention medications in both primary prevention and secondary prevention. If proven effective, this model could inform national strategies for preventing strokes in resource-limited settings. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT05963828 ### Funding Statement This study did not receive any funding ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Shanghai Changhai Hospital Ethics Committee gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors

Triptolide has demonstrated potent immunosuppressive properties in multiple autoimmune disorders, but its severe toxicity has greatly hampered clinical application. Here, we synthesized a triptolide derivative STP1, which exhibits remarkably reduced toxicity compared with triptolide. Immune dysfunction plays a critical role in systemic lupus erythematosus (SLE), an archetypical and refractory autoimmune disorder with limited therapeutic options and suboptimal outcomes. To elucidate the drugability and effect, we investigated the therapeutic potential, safety, regulatory mechanism and target of STP1 on SLE. Our data indicated that STP1 significantly ameliorates imiquimod-induced murine SLE by reducing anti-IgG, anti-dsDNA IgG, proteinuria, and renal pathological injury. Mechanistically, STP1 exerts markedly immunosuppressive roles by modulating the differentiation of B cell into plasma cells and T cell into Tfh cells. Further investigation showed that STP1 regulates B-cell receptor and T-cell receptor signaling by directly targeting Fyn kinase responsible for its immunosuppressive activity. For safety of STP1, our findings indicated that the STP1 did not show any toxicity in biochemical parameters and organ pathological analysis in subacute toxicity experiment. The findings suggested that STP1 is an attractive novel candidate for SLE and other autoimmune diseases for thorough evaluation. STP1, a structurally modified derivative of triptolide with improved safety, alleviates murine systemic lupus erythematosus by targeting and inhibiting Fyn, a Src kinase family member that regulates B- and T- cell responses.

BackgroundEmerging evidence implicates the gut microbiota (GM) in the pathogenesis of ischemic stroke (IS). However, systematic evaluations synthesizing evidence on microbial shifts, functional alterations, and clinical correlations are lacking. This study aimed to comprehensively analyze GM characteristics in IS patients versus healthy controls (HC).MethodsA systematic search of PubMed, Web of Science, and Embase was conducted from inception to April 2025. Observational studies comparing GM in IS patients and HC were included. Data on alpha/beta diversity, relative microbial abundance (phylum to species), predicted functional pathways, and microbiota–clinical indicator correlations were extracted. A narrative synthesis summarized the direction and consistency of reported findings.ResultsTwenty-four studies involving 1,957 participants (1,159 IS, 798 HC) were included. The qualitative synthesis revealed no consistent differences in alpha diversity indices between IS and HC, while significant beta diversity separation was frequently reported (18/22 studies). At the phylum level, an increased relative abundance of Proteobacteria and a decreased abundance of Firmicutes were the most consistent findings in IS patients. Key genera frequently enriched in IS included Lactobacillus, Streptococcus, and Parabacteroides, while Faecalibacterium, Agathobacter, and Blautia were commonly depleted. LEfSe analysis confirmed these discriminative taxa. Predicted functional analysis suggested enrichment of pro-inflammatory pathways (e.g., lipopolysaccharide biosynthesis) and depletion of metabolic and neuroprotective pathways in IS. Clinically, Faecalibacterium abundance correlated negatively with NIHSS and mRS scores, while Lactobacillus and Streptococcus showed positive correlations with stroke severity and inflammatory markers.ConclusionIschemic stroke is associated with distinct gut microbial dysbiosis characterized by a pro-inflammatory, opportunistic pathogen-enriched, and butyrate-producer-depleted profile. These alterations correlate with disease severity and are linked to predicted disruptions in microbial metabolic functions. However, whether this dysbiosis is a cause, consequence, or exacerbating factor of IS remains to be determined. The gut microbiota may serve as a potential biomarker and therapeutic target in ischemic stroke.Systematic Review Registrationhttps://www.crd.york.ac.uk/PROSPERO/view/CRD420251117510, identifier CRD420251117510.

Abstract Background and aims Smoking is a primary risk factor for Large Artery Stroke (LAS), yet the molecular mediators remains elusive. This study sought to identify causal plasma proteins linking smoking to stroke through an integrative approach. Methods We performed a systematic screen of the UK Biobank proteome to identify smoking-associated proteins. A two-step Mendelian randomization (MR) analysis, integrated with pQTL and GIGAstroke data, was used to determine causal mediation, followed by validation in the DECODE database. Experimental validation was conducted using smoking-exposed Sprague-Dawley rats and vascular cell models (HASMCs and HUVECs) under oxidative stress. Results Screening identified 647 smoking-associated proteins, with Retinol-Binding Protein 5 (RBP5) identified as a critical causal mediator of LAS. In vivo, smoking induced systemic and vascular RBP5 upregulation. In HASMCs, RBP5 promoted a phenotypic switch from contractile to synthetic states, accelerating proliferation via cell cycle and ribosomal biogenesis pathways. Conversely, in HUVECs, RBP5 exacerbated endothelial dysfunction, amplified inflammatory signaling (NF-κB/TNF), and impaired DNA repair mechanisms, leading to barrier disruption. Conclusions Our findings identify RBP5 as a novel functional link between smoking and LAS. Unlike RBP4, which primarily promotes macrophage foam cell formation, RBP5 exerts divergent, cell-specific effects that drive vascular remodeling and endothelial collapse. RBP5 represents a promising therapeutic target for mitigating the cerebrovascular consequences of smoking Conflict of interest Qiuyu Lu, Minyu Bai, Xinjie He, Jianmin Liu, Pengfei Yang,Yu Zhou: nothing to disclose

Liquid chromatography-tandem mass spectrometry (LC-MS/MS) has become the preferred method for vitamin K quantification, yet conventional workflows are labor-intensive and scale poorly. We developed and validated a simple, high-throughput automated magnetic bead-assisted LC-MS/MS method for simultaneous quantification of vitamin K1 (VK1), menaquinone-4 (MK-4), and menaquinone-7 (MK-7) in human serum according to Clinical and Laboratory Standards Institute (CLSI) C62 (2nd ed.) guidelines. This method used MSi050/PLS magnetic beads (5 mg/mL) for extraction via methanol loading and acetonitrile elution, requiring only 100 μL of serum to complete sample pretreatment within 17 min. All three calibration curves were linear from 0.20 to 10.00 ng/mL (r > 0.99), with a lower limit of quantification of 0.10 ng/mL. Total coefficients of variation for VK1, MK-4, and MK-7 ranged from 1.98% to 3.54%, 2.53% to 3.73%, and 2.77% to 4.59%, respectively. The recoveries of VK1, MK-4, and MK-7 were 94.8% to 112%, 98.0% to 113%, and 90.3% to 106%, respectively. Both matrix effects and carryover met CLSI acceptance criteria. Because vitamin K2 is photosensitive, all samples were processed under light-protected conditions. Unextracted samples were stable for 14 days at -20 °C, and extracted samples were stable for 48 h at 4 °C. Additionally, our method was applied to 245 healthy volunteers to characterize serum VK distribution profiles. By integrating automated magnetic bead extraction with rapid LC-MS/MS detection, this robust strategy markedly improves analytical throughput and reproducibility while maintaining high accuracy, offering a practical solution for large-scale clinical vitamin K assessment.

Abstract Background and aims Suboptimal adherence to preventive medications and inadequate management of risk factors are major barriers to effective post-discharge care for individuals at high risk of stroke, particularly in resource-constrained settings. Digital health interventions delivered via widely accessible platforms offer a promising scalable approach. We conducted this trial to evaluate the efficacy of Social Network based patient care in improving medication adherence in high-risk populations for stroke. Methods COMPLIANCE-MT is a multicenter, prospective, randomized, open-label, parallel-group trial with blinded outcome assessment (PROBE design) assessing the superiority of Social Network based patient care versus conventional care in medication adherence for high-risk populations for stroke. A total of 720 participants will be recruited across 33 hospitals in China and randomized in a 1:1 ratio to either a 12-month Social Network(WeChat) based coordinated care program or routine follow-up. The primary outcome is the proportion of patients achieving 80% adherence to all indicated secondary prevention medications (antihypertensives, hypoglycemics, lipid-lowering agents, anticoagulants, and antiplatelets) at 12 months. Analysis will be performed on an intention-to-treat approach. Results Data have been locked, with analysis currently in progress. The findings will be presented at the conference. Conclusions The COMPLIANCE trial evaluates a social network-based intervention in improving adherence to five evidence-based vascular prevention medications in both primary prevention and secondary prevention. If proven effective, this model could inform national strategies for preventing strokes in resource-limited settings. Conflict of interest

Prostate cancer remains one of the most common and aggressive cancers worldwide, but the molecular mechanisms underlying its progression are not yet fully understood. The ACSM1 gene is intimately associated with the development of prostate cancer. Here we demonstrated that down-regulation of ACSM1 expression in LNCaP prostate cancer cells significantly inhibits cell proliferation and migration, while overexpression enhances these processes in normal cells. Interestingly, the subcellular localization shift of ACSM1 to cytoplasm coincides with its interaction with 15-PGDH. Overexpression of ACSM1 also decreases 15-PGDH levels, increasing PGE2 production and altering ECM-related factors. Overexpression of 15-PGDH reverses these effects, suppressing the proliferation and migration of LNCaP cells. With specific PGE2 receptor inhibitors, AH6809 significantly affects the proliferation and migration of LNCaP cells with high ACSM1 expression. Based on our results, it appears that ACSM1 regulates prostate cancer cell behavior via the 15-PGDH-mediated PGE2 signaling pathway and Extracellular Matrix (ECM) remodeling.

The histopathological neurons in the brain tissue of drug-resistant epilepsy exhibit aberrant cytoarchitecture and imbalanced synaptic circuit function. However, the gene expression changes of these neurons remain unknown, making it difficult to determine the diagnosis or to dissect the mechanism of drug-resistant epilepsy. By integrating whole-cell patch clamp recording and single-cell RNA-seq approaches, we identified a transcriptionally distinct subset of cortical pyramidal neurons. These neurons highly expressed genes CDKN1A (P21), CCL2, and NFKBIA, which associate with mTOR pathway, inflammatory response, and cellular senescence. We confirmed the expression of senescent marker genes in a subpopulation of cortical pyramidal neurons with enlarged soma size in the brain tissue of drug-resistant epilepsy. We further revealed the expression of senescent cell markers P21, P53, COX2, γ-H2AX, and β-Gal, and reduction of nuclear integrity marker Lamin B1 in histopathological neurons in the brain tissue of patients with drug-resistant epilepsy with different pathologies, but not in control brain tissue with no history of epilepsy. Additionally, chronic, but not acute, epileptic seizures induced senescent marker expression in cortical neurons in mouse models of drug-resistant epilepsy. These results provide important molecular markers for histopathological neurons and what we believe to be new insights into the pathophysiological mechanisms of drug-resistant epilepsy.

Recently, the acute ischemic stroke (AIS) therapy including nanoprodrug mainly focuses on dredging thrombus. However, these therapeutic strategies can't prevent the permanent damage resulted from the rapid accumulation of reactive oxygen species (ROS) during blood flow reperfusion. In order to effectively address this urgent issue, we have fabricated a ROS-triggered charge-reversal preferential targeted neurons carrier-free nanoprodrug by self-assembly of curcumin (Cur)-thioketal-Cur (abbreviated as CTC) dimer and metformin (Met). Our new findings reveal that the skillful compatibility of Met and CTC endow nanodrug with the suitable diameter (ca. 100 nm), structural stability, and the positive charge (30 mV), therefore enhancing its brain-targeted effect, blood-brain barrier (BBB) permeability, and neuronal internalization. Once internalized into the ischemic neurons through positive charge-dominated transcytosis, nanoprodrug can enhance the lysosomal escape of neurons through Met and inhibit the neuronal death. Afterward, under trigger of the AIS-endogenous ROS, nanoprodrug can achieve the simultaneous spatiotemporal on-demand burst release of Cur and Met to scavenge ROS and remodeling the redox balance in the brain while reducing the toxic effect of Cur through Met introduction, thus reaching the ultimate purpose of reducing undesirable side effect and enhancing the therapeutic effect in AIS. Taken together, both nanoprodrug development and some molecular mechanism findings of Cur or Met from nanoprodrug provide new perspectives for the therapy and research of the clinical AIS.

BACKGROUND:Exercise is acknowledged for its beneficial effects on brain health; however, the intricate underlying molecular mechanisms remain poorly understood. AIMS:This study aimed to explore aerobic exercise-induced metabolic alterations in the brain. METHODS:We conducted an eight-week treadmill running exercise program in two-month-old male C57/BL6J mice. Body weight, serum lipid, glucose levels, and spatial cognition were measured. Spatial metabolomic analysis was performed to compare the metabolomic profiles across different brain regions. Immunohistochemical methods were used to compare the expression of carnitine palmitoyltransferase 1c (CPT1c). RESULTS:Exercise induced significant changes in the analysed metabolomic profiles. There were 904 differentially expressed metabolites (DEMs) detected in the whole brain section. Notable alterations in lipid profiles were observed, and among the 292 lipids detected, there were 74 (25.34 %), 85 (29.11 %), and 78 (26.71 %) lipids differentially expressed in the hippocampus, thalamus, and hypothalamus of the Exe group, respectively. Lipid metabolism related pathways and enzymes were also altered, with L-carnitine and CPT1c upregulated in the three regions (p<0.05), and epinephrine levels decreased in the hippocampus (p<0.05). Furthermore, the vitamin B6 metabolism pathway was altered in the hypothalamus. CONCLUSIONS:This study highlighted the significant changes in lipid metabolism induced by involuntary exercise in the brains of young male mice. Exercise also altered epinephrine levels and the vitamin B12 metabolic pathway in specific brain regions, which indicated the multifaceted effects of exercise on the brain.

Following an injury at the implantation position, blood-material interactions form a fibrin architecture, which serves as the initial activator of foreign body response (FBR). However, there is limited knowledge regarding how the topography of fibrin architectures regulates macrophage behavior in mitigating FBR. Mechanical cues of the microenvironment have been reported to shape immune cell functions. Here, we investigated macrophage mechanobiology at the organelle level by constructing heterogeneous fibrin networks. Based on findings in vivo, we demonstrated that adhesion-mediated differentiation of mitochondrial function modulated macrophage polarization. The finite activation of integrin signaling upregulated transglutaminase 2 (Tgm2) in a trans-manner, augments PGC1α-mediated mitochondrial biogenesis. Our study highlighted the previously overlooked spatial structures of host proteins adsorbed on material surfaces, advocating for a paradigm shift in material design strategies, from focusing solely on physical properties to considering the modification of host proteins.

BackgroundDiabetic kidney disease (DKD) is the leading risk factor for end-stage renal disease (ESRD). Hydroxyurea (HU), a sickle cell disease (SCD) drug approved by FDA, shows protective effect in nephropathy. This study aims to understand whether the application of HU could be effective to treat DKD.MethodsThe streptozotocin (STZ)-induced diabetic mice, and high glucose (HG)-treated human renal mesangial cells (HRMCs) were used to investigate the effect of HU on DKD. Serum creatinine and blood urea nitrogen levels reflecting renal function were evaluated. Histology was used to evaluate pathological changes. Indicators of inflammation and apoptosis were detected. Lastly, the mTOR-S6K pathway was explored by detecting the protein expression of S6K and phosphorylated S6K.ResultsIn STZ-induced diabetic mice, administration of HU (20 mg/kg) in drinking water for 16 weeks resulted in significant reductions in creatinine and urea nitrogen levels, alongside mitigating histopathological damage. Additionally, HU effectively suppressed the inflammatory response and apoptosis within the kidneys. HRMC cells were cultivated in HG conditions, and HU effectively attenuated the HG-induced inflammation and apoptosis. Moreover, HU treatment significantly inhibited the mTOR signaling pathway in both in both in vivo and in vitro experiments.ConclusionThis study unveils a new role of HU in alleviating diabetic kidney disease by modulating inflammation and apoptosis through the mTOR-S6K pathway. However, since HU did not significantly affect blood glucose levels, its therapeutic potential may be best realized when used in combination with standard antidiabetic therapies. Such a combination approach could simultaneously address hyperglycemia and renal dysfunction, offering a more comprehensive management strategy for DKD.

BACKGROUND:Breast cancer survivors often require concurrent treatment with antidepressants and anticancer drugs, raising concerns about potential drug-drug interactions and complex safety issues. METHODS:This retrospective pharmacovigilance study analyzed adverse event (AE) reports from the FDA Adverse Event Reporting System database spanning from 2014 to 2024. The analysis focused on breast cancer survivors who were receiving five or more concomitant medications and had reported two or more AEs. An artificial intelligence-driven clustering methodology was employed to identify distinct patterns of AE co-reporting. RESULT:Among 12 076 eligible patients, representing 255 020 medication records and 89 369 AE records, three distinct patient subgroups (2.1% of the total) with unique AE co-reporting profiles were identified. The patients in Cluster 1, predominantly middle-aged males, mainly treated with mirtazapine, antipsychotics, chemotherapy, and anti-HER2 monoclonal antibodies, showed high co-reporting rates for gastrointestinal symptoms, extrapyramidal disorders, peripheral neuropathy, and seizures. The patients in Cluster 2, comprising young females, mainly used citalopram combined with chemotherapy and anti-HER2 drugs, co-reported severe gastrointestinal AEs. The patients in Cluster 3, consisting of middle-aged to elderly females, mainly received citalopram, chemotherapy, anti-HER2 monoclonal antibodies, and steroid hormone drugs exhibited extremely high co-reporting rates of respiratory AEs. CONCLUSION:Certain polypharmacy regimens with antidepressants in specific breast cancer survivor subgroups may lead to complex safety signals. Personalized risk evaluation and vigilant medication safety strategies are crucial for these distinct, non-representative patients.

The selection of initial systemic treatment for advanced non-small cell lung cancer (NSCLC) depends on histological subtypes, oncogenic driver identification through genomic profiling, and programmed death-ligand 1 (PD-L1) expression quantification. The choice of first-line treatment is crucial as patients with advanced NSCLC may not have the opportunity to receive second- or later-line therapies due to the rapid progression of the disease. Current guidelines recommend pretreatment PD-L1 expression quantification evaluation prior to initiating systemic therapy in advanced NSCLC. Except for histology, PD-L1 expression, and absence of actionable driver mutations, single-agent immune checkpoint inhibitors (ICIs) are foundational first-line interventions. ICIs combined with chemotherapy or other ICIs have shown improved survival outcomes compared to ICI monotherapy. However, choosing the best option can be challenging due to limited head-to-head comparisons. Treatment decisions are often influenced by drug availability, reimbursement coverage, and patient's economic conditions. Despite the development of new ICI therapies, overall survival data seem to have plateaued, highlighting the need for sustained investigations and extensive clinical validation studies to develop novel therapies, optimize ICI combinations, and monitor adverse effects. Collaboration among data scientists, clinicians, biologists, and policymakers is essential to establish biomarkers that enhance patient selection and overall survival in NSCLC.

The interaction between infiltrating immune cells and brain-resident cells is critical for inducing an inflammatory response to ischemic stroke. However, the direct effects of CD11b+CD45int microglia in the brain on infiltrating CD11b+CD45highLy6G- monocytes/macrophages (Mos/MΦs) and the precise molecular mechanisms underlying these effects after acute ischemic stroke (AIS) remain unknown. Here, ischemia-induced microglial peroxisome proliferator-activated receptor-alpha (PPARα) downregulation was found to be critical for enhancing the inflammatory response and exacerbating ischemic brain injury by priming peripheral pro-inflammatory Mo/MΦ infiltration. The targeted microglial PPARα signal exerted neuroprotective effects on ischemic stroke by protecting blood-brain barrier (BBB) integrity and inhibiting the infiltration of innate immune cells. Furthermore, overexpression of microglia-specific PPARα exerted neuroprotective effects by enhancing the interleukin (IL)-4 signal-mediated crosstalk of microglia-MΦs. Therefore, our study reveals that ischemia-induced microglial PPARα deficiency expands the inflammatory response and exacerbates ischemic brain injury by enhancing the interaction with infiltrating peripheral Mos/MΦs and suggests that targeting microglial PPARα is a potential therapeutic strategy for improving acute cerebral ischemic injury.

Previous genome-wide association studies (GWAS) have identified several risk genes for stroke; however, it remains unclear how they confer risk for the disease. We conducted an integrative analysis to identify candidate genes for stroke and stroke subtypes by integrating blood-derived multi-omics data with genetic data. We systematically integrated the latest stroke GWAS database with human plasma proteomes and performed proteome-wide association studies, Mendelian randomization (MR), Bayesian colocalization analysis and transcriptome-wide association study to prioritize genes that associate the risk of stroke and its subtypes with their expression and protein abundance in plasma. The target genes were verified by performing tissue and cell type specificity, and functional analysis using the Genotype-Tissue Expression database, single-cell RNA sequencing and Gene Ontology databases. A two-step MR analysis was followed to explore the potential mechanisms. We found that the protein abundance of seven genes (MMP12, F11, SH3BGRL3, ENGASE, SCARA5, SWAP70 and SPATA20) in the plasma was associated with stroke and its subtypes, and six genes (MMP12, F11, SH3BGRL3, SCARA5, SWAP70 and SPATA20) causally related with stroke and its subtypes. The effect of F11, SH3BGRL3, SPATA20 and SWAP70 on each subtype was mediated by Factor XI inhibitors, atrial fibrillation, type 2 diabetes and systolic blood pressure, respectively (P < 0.05). We also found that SCARA5 and SWAP70 were related to stroke and ischemic stroke at the transcriptome level. Our present proteomic findings may offer potential future therapeutic targets for stroke prevention.

Understanding the anatomical connection and behaviors of transcriptomic neuron subtypes is critical to delineating cell type-specific functions in the brain. Here we integrated single-nucleus transcriptomic sequencing, in vivo circuit mapping, optogenetic and chemogenetic approaches to dissect the molecular identity and function of heterogeneous GABAergic neuron populations in the zona incerta (ZI) in mice, a region involved in modulating various behaviors. By microdissecting ZI for transcriptomic and spatial gene expression analyses, our results revealed two non-overlapping Ecel1- and Pde11a-expressing GABAergic neurons with dominant expression in the rostral and medial zona incerta (ZIrEcel1 and ZImPde11a), respectively. The GABAergic projection from ZIrEcel1 to periaqueductal gray mediates self-grooming, while the GABAergic projection from ZImPde11a to the oral part of pontine reticular formation promotes transition from sleep to wakefulness. Together, our results revealed the molecular markers, spatial organization and specific neuronal circuits of two discrete GABAergic projection neuron populations in segregated subregions of the ZI that mediate distinct innate behaviors, advancing our understanding of the functional organization of the brain.

Acute kidney injury (AKI) remains a critical clinical challenge due to its complex pathophysiology and lack of targeted therapies. We hypothesize that the ubiquitin-proteasome system (UPS) and ubiquitin-like modifiers (UBLs) are not merely isolated players but constitute an intricate and coordinated regulatory network whose dysregulation is a central driving force in AKI progression. This review synthesizes the pivotal roles of the ubiquitin–proteasome system and ubiquitin-like modifiers in driving AKI progression, emphasizing their regulation of inflammatory responses, cell death pathways (apoptosis, pyroptosis, ferroptosis), mitochondrial dysfunction, and aberrant repair. We detail enzymatic cascades involving E1-E2-E3 ligases, deubiquitinating enzymes, and ubiquitin-like modifiers (SUMOylation, neddylation, ISGylation, UFMylation), highlighting their integration into a coordinated network modulating NF-κB/NLRP3 signaling, mitophagy, and growth factor pathways, thereby providing novel strategies for targeted therapy.

Human cortical neural progenitor cell transplantation holds significant potential in cortical stroke treatment by replacing lost cortical neurons and repairing damaged brain circuits. However, commonly utilized human cortical neural progenitors are limited in yield a substantial proportion of diverse cortical neurons and require an extended period to achieve functional maturation and synaptic integration, thereby potentially diminishing the optimal therapeutic benefits of cell transplantation for cortical stroke. Here, we generated forkhead box G1 (FOXG1)-positive forebrain progenitors from human inducible pluripotent stem cells, which can differentiate into diverse and balanced cortical neurons including upper- and deep-layer excitatory and inhibitory neurons, achieving early functional maturation simultaneously in vitro. Furthermore, these FOXG1 forebrain progenitor cells demonstrate robust cortical neuronal differentiation, rapid functional maturation and efficient synaptic integration after transplantation into the sensory cortex of stroke-injured adult rats. Notably, we have successfully utilized the non-invasive 18F-SynVesT-1 PET imaging technique to assess alterations in synapse count before and after transplantation therapy of FOXG1 progenitors in vivo. Moreover, the transplanted FOXG1 progenitors improve sensory and motor function recovery following stroke. These findings provide systematic and compelling evidence for the suitability of these FOXG1 progenitors for neuronal replacement in ischemic cortical stroke.