Inter-organ communication is governed by a complex "secretome," yet mapping the journey of these factors from their origin to precise cellular destinations remains a fundamental challenge. Proximity labeling emerges as a powerful tool to dissect the secretome, yet conventional workflows typically rely on single-compartment biotinylation at the endoplasmic reticulum (ER), failing to capture proteins that utilize unconventional secretion. Here, we present DuO-SCOUT (Dual-Organelle Secretome Conjugation and Organ-Uptake Tracking), a high-performance platform that simultaneously targets BioID2 to the ER and the trans-Golgi network (TGN). This integrated strategy captures the full secretory maturation relay, increasing protein identification by over 120% compared to traditional ER-anchored methods. We translated this in vivo using an Adipoq-Cre mouse model to map the adipose secretome. To bridge the gap between systemic transport and tissue-specific uptake, DuO-SCOUT integrates BSPA (Biotin-Specific Proximity Amplification), a visualization toolkit detecting biotinylated proteins with sub-nanomolar sensitivity. In obese mice, we identified the piriform cortex (PIR) as a previously unrecognized extra-hypothalamic sink for adipose-derived leptin. This is associated with a localized neuroinflammatory signature, including significant induction of Il6. DuO-SCOUT establishes a broadly applicable framework for dissecting the complex molecular logic of systemic organ-organ communication.

Coronary atherosclerosis underlies life-threatening conditions such as myocardial infarction and stroke, yet its cellular dynamics remain incompletely understood. Here, through single-cell RNA sequencing of 27,941 cells from 56 human coronary segments, we constructed a disease-stage-resolved cellular atlas, revealing pathological remodelling of endothelial cells (ECs) into a progenitor-like state (EC5SLCO4A1+) with low expression of canonical EC dysfunction signatures. EC5SLCO4A1+ abundance increased with atherosclerotic stage, and its emergence is driven by PRDM15 through direct transcriptional activation. Analysis of the EC5SLCO4A1+ interaction network revealed extensive crosstalk with immune cell types, the interaction between which contributed to atherosclerotic progression. Endothelial overexpression of Prdm15 in vivo exacerbated atherosclerosis, while its suppression ameliorated the disease phenotype, with diminished EC5SLCO4A1+-like cells and immune infiltration. Our findings underscore the central role of EC subtype remodelling in the progression of human coronary atherosclerosis and reveal tractable targets for therapeutic intervention.

Abstract BACKGROUND Atherosclerotic cardiovascular disease remains the leading cause of death worldwide. Most current pharmacotherapies target conventional risk factors that promote atherosclerosis (e.g., hyperlipidemia) rather than intrinsic resilience factors that protect against atherosclerosis in the face of risk factors. Here, we investigated the role of desert hedgehog ( DHH ), a canonical ligand of the hedgehog signaling pathway, as a novel resilience factor that restrains endothelial mesenchymal transition (EndoMT) and protects against atherosclerosis. METHODS Single-cell RNA sequencing (scRNA-seq) was performed on atheroprone and atheroprotective regions of the ApoE knockout mouse aorta to identify mechanoresponsive genes associated with atherosclerosis. Endothelial cell-specific Dhh knockout mice were subjected to partial carotid ligation and hypercholesterolemic conditions to investigate the role of endothelial Dhh in atherosclerosis progression. scRNA-seq, bulk RNA sequencing, endothelial lineage tracing, immunoprecipitation-coupled mass spectrometry, and surface plasmon resonance were used to in-vestigate the role and mechanism of DHH in EndoMT. Pharmacological interventions and recombinant DHH administration were performed in vivo to evaluate therapeutic potential of DHH targeting. DHH expression was also examined in human atherosclerotic arteries and serum samples from patients with coronary artery disease. RESULTS DHH protein expression was enriched in arterial endothelium from mice, porcine, and humans. However, DHH expression was significantly reduced in atherosclerotic arteries and serum from patients with coronary artery disease. scRNA-seq of atheroprone and atheroresistant region of mouse aorta identified Dhh as a novel mechanoresponsive gene enriched in aortic regions exposed to unidirectional laminar flow. Endothelial cell-specific Dhh knockout ( Dhh ecKO ) mice exhibited increased atherosclerotic lesion area, large necrotic cores, and reduced collagen content following partial carotid ligation. Similarly, under hypercholesterolemic conditions, both male and female Dhh ecKO mice showed aggravated atherosclerosis progression. scRNA-seq of Dhh ecKO mouse aortas revealed an increased proportion of endothelial cells undergoing mesenchymal transition, indicating enhanced EndoMT. These findings were corroborated by bulk RNA-sequencing of DHH depleted HUVECs and endothelial lineage tracing in inducible Dhh ecKO mice. Mechanistically, DHH directly interacted with plasminogen activator inhibitor type 1 (PAI-1) and suppressed PAI-1-induced EndoMT. PAI-1 promoted EndoMT in ECs through activation of canonical TGF-β signaling (SMAD2/3) and noncanonical AKT/ERK1/2 signaling via interaction with low-density lipoprotein receptor-related protein (LRP1). Neutralization of PAI-1 or inhibition of LRP1, AKT/ERK1/2, or SMAD3 signaling abolished DHH deficiency-induced EndoMT. DHH competitively inhibited PAI-1 binding to LRP1, thereby attenuating downstream pro-EndoMT signaling. Intriguingly, treatment with PAI-1 inhibitor TM5275 mitigated endothelial Dhh deficiency induced EndoMT in vivo . Of translational relevance, recombinant mouse DHH protein administration reduced atherosclerosis progression, stabilized plaque, and decreased the expression of EndoMT markers in ApoE knockout mice. CONCLUSIONS Desert hedgehog (DHH) is an intrinsic endothelial cell-enriched resilience factor that protects against EndoMT and atherosclerosis by preventing PAI-1 signaling. The present study implicates endothelial DHH as a potential therapeutic target for atherosclerotic cardiovascular disease. Graphical abstract Desert hedgehog (DHH) is an intrinsic endothelial cell-enriched resilience factor that protects against EndoMT and atherosclerosis by preventing PAI-1 binding to LRP1 and downstream AKT/ERK, as well as SMAD2/3 signaling. Clinical Perspective What Is New? DHH was identified as a flow-responsive resilience gene that is downregulated by disturbed flow in endothelial cells. Endothelial-specific deletion of Dhh promoted endothelial-to-mesenchymal transition (En-doMT) and atherosclerosis. DHH directly interacts with PAI-1 and preclude PAI-1 mediated pro-EndoMT signaling. What Are the Clinical Implications? DHH maintains endothelial homeostasis during atherosclerosis. Targeting endothelial DHH-PAI-1 axis may represent a potential therapeutic strategy to reduce EndoMT and limit plaque progression. Lower circulating DHH level may serve as a potential biomarker of endothelial dysfunction and plaque vulnerability in atherosclerotic disease.

Chronic nonhealing diabetic wounds present a critical global healthcare challenge owing to their highly complex and dysregulated pathological microenvironment. Although conventional standards of care and advanced adjunctive therapies offer recognized clinical efficacy, they remain predominantly passive interventions that fail to adapt to the highly dynamic, real‐time fluctuations within the wound bed. In recent years, stimuli‐responsive biomaterials have emerged to recognize endogenous pathological cues or external triggers, enabling preprogrammed, spatiotemporally matched therapeutic deployment. However, their intrinsic irreversibility and open‐loop nature inherently restrict continuous adaptation to the evolving wound status. To overcome these limitations, closed‐loop intelligent theranostic systems integrating flexible electronics, multimodal sensing, wireless communication, artificial intelligence, and feedback‐controlled actuation have emerged. These systems enable real‐time monitoring of wound biomarkers or digital markers along with adaptive drug delivery and on‐demand physical intervention, representing a transformative paradigm toward autonomous, personalized precision medicine. This review comprehensively delineates the evolutionary landscape of diabetic wound management from fundamental pathophysiology and conventional therapies through stimuli‐responsive materials to intelligent closed‐loop systems. Furthermore, we discuss the practical challenges facing clinical translation and offer future perspectives on next‐generation intelligent wound theranostic platforms.

BACKGROUND:Atherosclerotic vascular diseases remain the leading cause of death despite the use of lipid-lowering drugs. The development of more efficacious therapies targeting endothelial inflammation and endothelial-to-mesenchymal transition (EndMT) is an essential endeavor, aiming for better treatment outcomes. The increased mutation frequency of the TBK1 (TANK-binding kinase 1) gene has been observed in patients with coronary heart disease. However, the precise function of TBK1 in endothelial dysfunction, inflammation, and atherogenesis is yet to be elucidated. METHODS:The results of liquid chromatography-mass spectrometry, immunostaining, RNA sequencing, and Western blot in mouse and human arteries with atherosclerotic plaques identified TBK1 as one of the key mediators of EndMT and atherogenesis. Its role was then investigated in endothelium-specific TBK1 knockdown ApoE-/- mice. To gain mechanistic insights, TurboID-based liquid chromatography-mass spectrometry and co-immunoprecipitation techniques were used. The potential therapeutic efficacy of a putative TBK1 inhibitor, GSK8612 (TANK-binding kinase 1 [TBK1] inhibitor), was evaluated in ApoE-/- mice and human endothelial cells. RESULTS:An increased expression of TBK1 was observed by liquid chromatography-mass spectrometry analysis in the aortas of ApoE-/- mice on a Western diet in comparison with those of normal diet-fed mice. Increased endothelial TBK1 phosphorylation at Ser172 (serine 172; reflecting the elevated TBK1 activation) was detected in human and mouse atherosclerotic arteries. Furthermore, atherogenic factors, TNF-α (tumor necrosis factor-alpha) and IL-1β (interlukin-1β), induced a rapid and sustained phosphorylation of TBK1 at S172 in human endothelial cells. RNA sequencing analysis revealed that TBK1 activation promoted EndMT, a pivotal event during the development of atherosclerosis. TBK1 activation increased the expression of EndMT markers in endothelial cells. Of greater significance, endothelium-specific TBK1 knockdown inhibited the development of atherosclerosis in both male and female ApoE-/- mice. Moreover, TBK1 knockdown reduced EndMT both in vivo and in vitro. Mechanistically, TBK1 activation led to phosphorylation of RAC1 (Ras-related C3 botulinum toxin substrate 1)-PAK1 (p21-activated protein kinase) and subsequent phosphorylation of ERK1/2 (extracellular signal-regulated protein kinases 1 and 2), thereby initiating EndMT. This is achieved by the TBK1 interaction with a PAK1IP1 (PAK1 interacting protein 1), resulting in a reduced binding of PAK1IP1 to PAK1. Furthermore, chronic administration of a TBK1 inhibitor, GSK8612, suppressed EndMT and the formation of atherosclerotic plaques in ApoE-/- mice without affecting serum lipid levels. CONCLUSIONS:The interaction between activated TBK1 and PAK1IP1 inhibits the binding of PAK1IP1 to PAK1, which, in turn, increases the phosphorylation of PAK1 and ERK1/2 in endothelial cells. This process drives EndMT. Endothelium-specific TBK1 knockdown or GSK8612 treatment inhibits EndMT and plaque formation. Safe TBK1 inhibitors could be developed into effective agents for the treatment of atherosclerotic vascular disease.

ABSTRACT Endothelial cells (ECs) form the dynamic interface between blood and tissue, serving as key regulators of vascular homeostasis, inflammation, and repair. Among the molecular systems governing endothelial behavior, the C‐X‐C motif chemokine receptor (CXCR) family—originally characterized in immunology for its roles in leukocyte trafficking and immune signaling—has recently emerged as a pivotal regulator of vascular biology. Accumulating evidence indicates that CXCRs orchestrate endothelial development, angiogenesis, and injury responses through context‐dependent signaling mechanisms. This review integrates recent advances in endothelial CXCR research, highlighting their molecular functions and translational relevance. We first describe the developmental and homeostatic subgroup in which CXCR4 and its atypical partner CXCR7/ACKR3 coordinate vascular morphogenesis and regeneration. In parallel, we contrast the proangiogenic ELR + receptors (CXCR1 and CXCR2) with the angiostatic ELR − receptor CXCR3 and discuss the emerging roles of CXCR5 and CXCR6 in linking chronic inflammation and adaptive immunity to vascular dysfunction. Collectively, these findings position the CXCR family as an integrated network that fine‐tunes endothelial phenotype and vascular fate, revealing new opportunities for precision therapeutic intervention.

The progression of cardiovascular disease shows significant sexual dimorphism: although females generally develop the disease later in life, they exhibit a higher age-related incidence than males. While current studies have separately reported sex differences in atherosclerotic development in Apoe−/− and Ldlr−/−, a comparative assessment of these sex-specific characteristics across both models is lacking. This study therefore aimed to assess the influence of sex on atherosclerosis using both Apoe−/− and Ldlr−/− mice. Eight-week-old mice were fed an atherogenic ALMN diet for 20 weeks to promote plaque development. We performed comprehensive analyses of: (1) systemic metabolic parameters (lipid profile, glucose metabolism); (2) atherosclerotic burden (whole aorta and aortic sinus plaque area); and (3) plaque composition (necrotic core size, collagen content, macrophage infiltration) in mice of both sexes. As a result, male mice showed higher lipid levels, worse glucose tolerance, and reduced insulin sensitivity compared to females in both models. Apoe−/− mice showed minimal sex differences in atherosclerosis with a trend toward increased plaque size in females. Plaque composition did not differ significantly between sexes in Apoe−/− mice. In contrast, Ldlr−/− males exhibited greater whole aortic plaque burden than females, yet plaque stability also remained similar across sexes. This comparative analysis of two widely used murine atherosclerosis models reveals genotype-dependent sexual dimorphism. This study underscores the importance of considering the distinct sex-specific characteristics of Apoe−/− and Ldlr−/− mice when selecting animal models for exploring atherosclerosis pathomechanisms as well as effective pharmacotherapies, and further supports the necessity of developing sex-specific therapies.

The incidence and mortality rate of atherosclerotic cardiovascular disease (ASCVD) is increasing yearly worldwide. Recently, a growing body of evidence has unveiled the anti-atherosclerotic properties of fisetin, a natural polyphenol compound. In this article, we reviewed the pharmacologic actions of fisetin on experimental atherosclerosis and its protective effects on disease-relevant cell types such as endothelial cells, macrophages, vascular smooth muscle cells, and platelets. Based on its profound cardiovascular actions, fisetin holds potential for clinical translation and could be developed as a potential therapeutic option for atherosclerosis and its related complications. Large-scale randomized clinical trials are warranted to ascertain the safety and efficacy of fisetin in patients with or high risk for ASCVD.

Rationale: Atherosclerotic cardiovascular disease (ASCVD) represents the predominant cause of mortality and morbidity globally. Given the established role of hypercholesterolemia as a significant risk factor for ASCVD, the discovery of new lipid-lowering medications is of paramount importance. ATP citrate lyase (ACLY) is a crucial enzyme in cellular metabolism, providing acetyl-CoA as the building block for the biosynthesis of fatty acids and cholesterol. Consequently, it has emerged as a promising drug target for innovative treatments of lipid metabolic disorders. Methods: Virtual screening of a natural product library was performed to identify small-molecule ACLY inhibitors, leading to the discovery of isoginkgetin (ISOGK). The lipid-lowering and anti-atherosclerotic effects of ISOGK were validated in hypercholesterolemic diet-induced animal models (mice and hamsters). The inhibitory effects of ISOGK on ACLY enzymatic activity were measured using commercial assay kits. The direct interaction between ISOGK and ACLY was confirmed by surface plasmon resonance (SPR) and cellular thermal shift assays (CETSA). Liver-specific ACLY knockdown mice were generated using GalNAc-conjugated siRNA (GalNAc-siAcly). Results: ISOGK directly bind to ACLY and inhibit its enzymatic activity in vitro and in vivo. By inhibiting ACLY, ISOGK treatment thus alleviates hypercholesterolemia and atherosclerosis in mice and hamsters. However, ISOGK fails to attenuate lipid accumulation and the expression of lipid-metabolism related genes in Acly knockout or depleted hepatocytes. In vivo, the lipid-lowering and anti-atherosclerotic effects of ISOGK were reversed by hepatic knockdown of Acly via treatment with GalNAc-siAcly in mice. Conclusions: Taken together, the present study identifies ISOGK as an effective and naturally-occurring small-molecule inhibitor of ACLY that limits hypercholesterolemia and atherosclerosis. ISOGK thus serves as a promising drug lead in cardiovascular therapeutics.

BACKGROUND:Atherosclerosis is characterized by the accumulation of fatty and fibrotic plaques, which preferentially develop at curvatures and branches along the arterial trees that are exposed to disturbed flow. However, the mechanisms by which endothelial cells sense disturbed flow are still unclear. METHODS:The partial carotid ligation mouse model was used to investigate disturbed flow-induced atherogenesis. In vitro experiments were performed using the ibidi system to generate oscillatory shear stress and laminar shear stress. ApoE-/- mice with endothelium-specific knockout or overexpression of 5-HT1B (serotonin receptor 1B) were used to investigate the role of endothelial 5-HT1B in atherosclerosis. RNA sequencing analysis, immunofluorescence analysis, and molecular biological techniques were used to explore the role of 5-HT1B in mechanotransduction and endothelial activation. RESULTS:The data showed that human endothelial cells express a high level of 5-HT1B, which is a serotonin receptor subtype. Endothelial 5-HT1B is upregulated in atherosclerotic areas of both humans and rodents and is increased by disturbed flow both in vivo and in vitro. Endothelium-specific overexpression of 5-HT1B exacerbates, whereas knockout or knockdown of 5-HT1B in endothelium inhibits disturbed flow-induced endothelial inflammation and atherogenesis in both male and female ApoE-/- mice. We reveal a previously unknown role of 5-HT1B as a mechanosensor in endothelial cells in response to mechanical stimuli. Upon activation by oscillatory shear stress, 5-HT1B recruits β-arrestin, orchestrates RhoA (ras homolog family member A), and then activates mechanosensitive YAP (yes-associated protein), thereby enhancing endothelial inflammation and monocyte infiltration. Pharmacological blockade of 5-HT1B suppresses endothelial activation and atherogenesis via inhibition of YAP. CONCLUSIONS:Taken together, these results uncover that endothelial 5-HT1B acts as a mechanosensor for disturbed flow and contributes to atherogenesis. Inhibition of 5-HT1B could be a promising therapeutic strategy for atherosclerosis.

Hemodynamic shear stress, the frictional force exerted by blood flow on the endothelium, mediates vascular homeostasis. This review examines the biophysical nature and biochemical effects of shear stress on endothelial cells, with a particular focus on its impact on cardiovascular pathophysiology. Atherosclerosis develops preferentially at arterial branches and curvatures, where disturbed flow patterns are most prevalent. The review also highlights the range of shear stress across diverse human arteries and its temporal variations, including aging-related alterations. This review presents a summary of the critical mechanosensors and flow-sensitive effectors that respond to shear stress, along with the downstream cellular events that they regulate. The review evaluates experimental models for studying shear stress in vitro and in vivo, as well as their potential limitations. The review discusses strategies targeting shear stress, including pharmacological approaches, physiological means, surgical interventions, and gene therapies. Furthermore, the review addresses emerging perspectives in hemodynamic research, including single-cell sequencing, spatial omics, metabolomics, and multiomics technologies. By integrating the biophysical and biochemical aspects of shear stress, this review offers insights into the complex interplay between hemodynamics and endothelial homeostasis at the preclinical and clinical levels.

BACKGROUND AND AIM:Gastrodin, an active compound derived from the traditional Chinese herbal medicine Gastrodia, demonstrates a variety of pharmacological effects, particularly in the enhancement of neural functions. Thus, the aim of this study is to explore the therapeutic effects of gastrodin on Alzheimer's disease (AD) and its underlying molecular mechanisms. EXPERIMENTAL PROCEDURE:Cognitive function was assessed via Morris water maze and Y-maze tests. Tau pathology, neuroinflammation, and BBB dysfunction were analyzed using various techniques, including Western blot, immunohistochemistry, and ELISA. ADRA1 overexpression was induced by lentiviral infection, and gastrodin's impact on NF-κB p65, NLRP3, IL-1β, and IL-18 levels was evaluated. KEY RESULTS:In the in vivo experiment, gastrodin enhanced learning and spatial memory in 3xTg-AD mice, as well as reducing p-Tau protein expression in the hippocampus and cortex. Gastrodin inhibited the ADRA1/NF-κB/NLRP3 pathway, which decreased glial cell activation and inflammatory cytokines IL-1β and IL-18, improving neuron and BBB function. In the in vitro experiment, gastrodin inhibited the activation of the NF-κB/NLRP3 pathway due to ADRA1 overexpression and prevented the Aβ42-induced increase in ADRA1/NF-κB/NLRP3 protein expression in SH-SY5Y cells. It also reduced IL-1β and IL-18 cytokine release, restoring tight junction protein expression in bEnd.3 cells. CONCLUSIONS AND IMPLICATIONS:gastrodin ameliorates learning and memory abilities by alleviating neuroinflammation and tau pathology, restoring the structure and function of neurons and BBB, suggesting that gastrodin may serve as an effective drug for the treatment of AD.

Type 2 diabetes mellitus (T2DM) is one of the most prevalent chronic metabolic disorder characterized by insulin resistance and relative insulin deficiency. PPARδ activation has been reported to have several beneficial effects in alleviating dyslipidemia and insulin resistance. GW501516, a synthetic PPARδ agonist, was developed to target hyperlipidemia and reported to alleviating insulin resistance in T2DM. Studies indicate that PPARδ activation by GW501516 can reduce adiposity, enhance β-oxidation of fatty acids, and improve insulin sensitivity in T2DM animal models. Despite its therapeutic promise, potential carcinogenic effects also have been reported. Therefore, a comprehensive non-targeted and targeted lipidomics study was carried out to evaluate the regulatory effect of GW501516 in the plasma of db/db mice. The results revealed that GW501516 is effective in reducing the accumulation of lipids in the fatty acid metabolism pathway and lipid classes including triglycerides and phosphatidylglycerols. Furthermore, activation of PPARδ by GW501516 demonstrated a beneficial effect on improving circulating cholesterol homeostasis. However, while the levels of hexosylceramides and sphingomyelin were partially reversed, ceramide levels, which are negatively associated with insulin sensitivity, were significantly elevated by GW501516. Despite these mixed outcomes, the study highlights both the promising therapeutic potential of PPARδ activation in metabolic disorders and the safety concerns regarding long-term clinical use. The findings provide valuable insights into the impact of GW501516-induced PPARδ activation on lipid metabolism in T2DM, contributing to a better understanding of its therapeutic potential and risks.

Fibroblast activation plays a critical role in renal fibrosis, the final common pathway of chronic kidney disease (CKD). Previously, we and others reported that yes-associated protein (YAP) is activated in the renal tubular cells of fibrotic kidneys in human patients. However, the mechanisms by which YAP activation in tubular cells contributes to the activities of renal fibroblasts remain unclear. Here, we demonstrate that activation of YAP specifically in renal tubular cells induces E2F transcription factor 2 (E2F2) binding and promotes fibroblast activation through the secretion of fibroblast growth factor 2 (FGF2). FGF2 stimulated the activation of renal interstitial fibroblasts, which exhibited two key characteristics: enhanced synthesis of collagens and fibronectins, which are hallmarks of the fibrotic process, and increased secretion of chemoattractant cytokines that promoted the migration and activation of macrophages. The recruitment and activation of macrophages further exacerbated renal inflammation, thereby accelerating the progression of fibrogenesis. As confirmed by the clinical data, the serum levels of FGF2 were significantly higher in patients with diabetic kidney disease (DKD) and inversely correlated with the estimated glomerular filtration rate. In addition, inhibition of either YAP, E2F2, or FGF2 significantly ameliorated renal fibrosis and improved kidney function in mouse models of chronic kidney disease and renal fibrosis. Our results revealed that YAP complexed with E2F2 and promoted FGF2 expression and secretion in renal tubular cells, which in turn activated fibroblasts, followed by increased macrophage infiltration and activation. The YAP-E2F2-FGF2 axis represents a potential therapeutic target for renal fibrosis.

Direct reprogramming of fibroblasts into induced cardiomyocytes (iCMs) offers a regenerative strategy for heart repair, but efficiency declines in adult and aged cells. Transcriptomic and epigenetic profiling identified cellular senescence as a major barrier limiting cardiac fibroblast (CF) plasticity and cardiogenic conversion. Postneonatal fibroblasts exhibited impaired activation of cardiac gene programs and persistent expression of fibrotic and inflammatory signatures. A loss-of-function screen identified Nr4a3 as a central repressor. Nr4a3 overexpression promoted senescence and suppressed iCM induction, whereas knockdown enhanced reprogramming in murine and human senescent CFs. Mechanistically, Nr4a3 depletion remodeled the chromatin landscape from a fibrotic and inflammatory state to a regenerative cardiac program. Blocking downstream Cxcl14 restored reprogramming in refractory fibroblasts. In vivo, Nr4a3 knockdown improved heart function following myocardial infarction. These findings established cellular senescence as a major barrier to cardiac reprogramming and identified Nr4a3 and its effectors as potential targets to enhance heart regeneration.

BackgroundKunxian (KX) has been reported to be effective in treating Immunoglobulin A nephropathy (IgAN) and autoimmune disorders, such as lupus nephritis, but there is a lack of controlled trial on its effectiveness and safety for treating IgAN.MethodsThis multicenter, prospective cohort study was conducted with individuals aged 18–60 years with biopsy-confirmed primary IgAN, proteinuria greater than 0.75 g/d, and estimated glomerular filtration rate (eGFR) greater than 60 mL/min/1.73 m2. Patients were treated with KX or Mycophenolate mofetil (MMF) after receiving a stable dose of an angiotensin-converting-enzyme inhibitor or angiotensin-receptor blocker for at least 4 weeks.Results67 patients were assigned to the KX group and 72 to the MMF group. The mean (standard deviation) eGFR was 87.75 (15.94) mL/min/1.73 m2, and the mean (standard deviation) proteinuria was 1.70 (0.74) g/d. Patients in the KX group had a greater reduction in proteinuria than those in the MMF group did. Complete remission occurred in 43 patients (64.2%) in the KX group and 37 patients (51.4%) in the MMF group (hazard ratio [HR] 0.612, 95% CI 0.385–0.972, P = 0.038). Overall response occurred in 59 participants (88.1%) in the KX group and 59 participants (81.9%) in MMF group (HR 0.658, 95% CI 0.447–0.970, P = 0.034). Adverse events were observed in 6 patients (8.9%) in the KX group and 5 patients (6.9%) in the MMF group with no significant difference.ConclusionCompared with MMF, KX was safe and significantly decreased proteinuria in IgAN.

Ventilator induced lung injury (VILI) is caused by improper use of mechanical ventilation, and its pathogenesis remains unclear. The aim of this study was to establish animal and cell models of VILI, and to explore the mechanism of miR-125b-5p in alleviating VILI by inhibiting ferroptosis through targeted regulation of Keap1/Nrf2/GPX4 axis. Firstly, ferrostain-1(Fer-1), a ferroptosis inhibitor, was used to confirm that ferroptosis was involved in the progression of VILI. Secondly, overexpression and knockdown of miR-125b-5p were performed to validate its function; Further, mechanistically, miR-125b-5p targets negatively regulated Keap1 to activate Nrf2 and then increased the expression of GPX4, thereby inhibiting the occurrence of ferroptosis. Finally, the rescue experiment shows, overexpression of Keap1 and use of the GPX4 inhibitor RSL3 reversed the miR-125b-5p effect, respectively. Through real-time quantitative polymerase chain reaction (qRT-PCR), western blotting (WB), immunofluorescence (IF), hematoxylin and eosin (H&E), and iron death related factor detection, it was confirmed that, overexpression of miR-125b-5p upregulates ferroptosis inhibitory protein and downregulates ferroptosis promoting protein, leading to alleviation of lung injury. However, overexpression of Keap1 and RSL3 reverses the effect of miR-125b-5p, respectively. Therefore, miR-125b-5p can inhibit ferroptosis and alleviate lung injury in VILI rats by targeting the Keap1/Nrf2/GPX4 axis, miR-125b-5p may be a potential intervention target for VILI.

Aberrant autophagy mediated by AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR)/unc-51 like kinase 1 (ULK1) pathway (a canonical autophagy pathway) plays important roles in diabetic cardiomyopathy (DCM). Asprosin (ASP) secreted by white adipose tissue involves in systemic metabolism disorders. However, its role in DCM remains poorly understood. Therefore, the purpose of this study was to investigate its roles and underlying mechanisms in the DCM from the perspective of autophagy and apoptosis. In the in vivo experiments, we observed the effects of ASP deficiency (ASP-/-) or ASP intervention on cardiac function, fibrosis, autophagy, and apoptosis in a diabetes mellitus (DM) mouse model induced by high-fat feeding and streptozotocin (STZ) injection; in the in vitro experiments, we evaluated the effects of ASP intervention with or without 3-methyladenine (3-MA) (autophagy inhibitor) or siAMPK in a H9c2 model injured by high glucose (HG). Our results show that ASP intervention attenuates the myocardial injury induced by DM (P < 0.05) and HG (P < 0.05). In addition, the autophagy level markedly increases (P < 0.05) in diabetic mice, and ASP deficiency worsens the increase induced by DM (P < 0.05). In contrast, ASP intervention alleviates overautophagy induced by DM (P < 0.05) or HG (P < 0.05). Mechanistically, the protective effect of ASP against myocardial injury is through inhibiting the overautophagy mediated by AMPK/mTOR/ULK1 pathway (P < 0.05). Taken together, the findings suggest that ASP would be a potential therapeutic target and the recombinant ASP might be a promising candidate to treat metabolism-associated CVD. Although the findings would present a promise for the treatment of DCM, it is worth noting that the mouse model used fails to fully mimic the human DCM pathophysiology.NEW & NOTEWORTHY We demonstrated for the first time that asprosin (ASP) has protective effects against diabetic cardiomyopathy. We found that ASP could stimulate the AMPK/mTOR/ULK1 pathway to reduce the level of autophagy and apoptosis of cardiomyocytes, thereby maintaining the normal physiological function of the heart.