The recalcitrance of diabetic burn wounds is rooted in a hostile microenvironment characterized by a pathological surplus of glucose, advanced glycation end products (AGEs), and reactive oxygen species. Standard enzymatic and photocatalytic interventions are often limited by instability or the toxic accumulation of hydrogen peroxide (H₂O₂), leading to secondary oxidative injury. In this study, we developed a metabolism-driven microneedle platform (MN-PCN) by integrating photocatalytic Pt@Pd-PCN222-NH₂ (PCN) into a self-adjusting, antimicrobial, and antioxidant hydrogel matrix featuring highly moisture-resilient adhesion. Adopting a waste-to-treasure logic, the system exploits endogenous glucose as a primary reductant to facilitate continuous hydrogen (H₂) evolution, effectively suppressing the AGEs/receptor for AGEs signaling axis. Critically, the MN-PCN system actively scavenges catalytic H₂O₂ byproducts and environmental reactive oxygen species through the synergistic catalase-mimetic activity of the PCN sites and the antioxidant hydrogel matrix, thereby circumventing oxidative damage. Simultaneously, the microneedle architecture undergoes an in situ transition into a protective hydrogel upon contact with wound exudate, establishing a physical barrier that minimizes infection and fosters cellular infiltration. By neutralizing inflammatory circuit and accelerating vascularization, MN-PCN restores both physiological and structural equilibrium. This integrated strategy provides a sophisticated framework for complex wound management through systemic, metabolism-driven microenvironmental reconfiguration.

Current space transportation employs a multistage rocket system to deliver the payload to its destination in a single launch, and this integrated model significantly constrains payload capacity for medium-high earth orbits and deep-space missions. However, the medium-high earth orbits and deep-space domains are anticipated to become the next exploration and utilization frontier, which needs large payload capacity and low-cost transportation as support. This study proposes a decoupled design for space access and in-space transfer in a medium-high earth orbit or a deep-space mission. This design introduces a novel in-space transfer transportation system enabled by cryogenic propellant refueling in orbit. In the proposed model, Earth-to-orbit vehicles are responsible for space access, while in-space transfer vehicles handle orbital transfer. This separation allows for independent optimization of vehicle designs according to their specific flight environments. Additionally, on-orbit refueling enables long-term, reusable operations for in-space transfer vehicles. The advantages of the new model are analyzed, demonstrating significant improvements in payload capacity for medium and high earth orbits, as well as substantial reducing transportation costs, holding great practical significance. Relevant design challenges associated are also given, providing a reference for subsequent in-depth researches.

Vulnerable atherosclerotic plaques represent a critical pathological basis of acute cardiocerebrovascular events. Previous studies indicate that atherosclerotic plaques are more vulnerable under chronic kidney disease (CKD) milieus. Emerging evidence highlights that vascular smooth muscle cells (VSMCs) play a pivotal role in maintaining plaque stability, but the underlying mechanisms remain incompletely elucidated. Here, single-cell sequencing and functional enrichment analysis of arterial tissues from patients with CKD are performed, identifying lipid metabolism disorders in VSMCs. Further utilizing spatial and targeted lipidomics, apolipoprotein-E-deficient (ApoE^−/−) mouse with CKD (CKD/ApoE^−/− mouse) and bioinformatics analysis, we investigate the lipidomic profile of VSMCs and find that VSMCs in CKD-associated vulnerable plaques exhibit significant accumulation of polyunsaturated fatty acids (PUFAs), which induces VSMC ferroptosis and exacerbates plaque vulnerability. Mechanistically, the deficiency of ECH1 leads to the accumulation of PUFA in VSMCs, thereby inducing ferroptosis in fibrous cap VSMCs and fibrous cap thinning. Meanwhile, low expression of mRNA binding protein human antigen R (HuR) resulting from CKD milieus mediates the lack of ECH1 in VSMCs. In contrast, VSMC-specific overexpression of ECH1, inhibition of PUFA release using giripladib or suppression of PUFA lipid peroxidation with PRGL493 significantly alleviate VSMC ferroptosis and CKD-associated plaque vulnerability. These findings reveal that ECH1-deficiency-driven PUFA accumulation is responsible for VSMC ferroptosis and atherosclerotic plaque vulnerability. Targeted regulation of ECH1-mediated PUFA metabolism may be a promising preventive and therapeutic strategy for CKD-associated plaque vulnerability.

The pervasive inhalable particulate matter (PM) in the environment poses a marked threat to pulmonary health. However, the underlying pathogenic mechanisms remain poorly understood, largely due to the limitations of existing in vitro models in accurately mimicking the complex biological processes. This review critically examines the spectrum of in vitro models employed in PM research, spanning from traditional 2-dimensional models to advanced 3-dimensional (3D) constructs, including 3D bioprinted models and organoids, as well as the burgeoning field of lung-on-chips (LOCs). Each model type is meticulously assessed for its unique strengths and the challenges. A particular emphasis is placed on the innovative use of LOCs technology to replicate the dynamic nature of respiratory motion. The review delves into how integrating breath-mimicking stimuli can modulate the intricate interactions between PM and cellular/tissue interfaces. Ultimately, it unveils an innovative, highly integrated, and intelligent LOCs platform, offering a forward-looking insight into its evolution.

While current dural repair patches achieve mechanical sealing to prevent cerebrospinal fluid leakage, they fail to address the critical pathological cascades of traumatic brain injury, including structural disruption of meningeal lymphatic vessels and dysregulation of neuroimmune responses. Here, we break this therapeutic stalemate through lymphatic-immune microenvironment engineering using rapamycin-eluting poly(l-lactide-co-ε-caprolactone) nanofibers. This bioactive patch exerts its therapeutic effects through 3 mechanisms: (a) restoring immune homeostasis by modulating the T helper 17/regulatory T cell balance; (b) morphologically normalizing the meningeal lymphatic network; and (c) preventing cerebral tissue adhesion by suppressing fibroblasts proliferation. In rat traumatic brain injury models, 4% rapamycin-loaded poly(l-lactide-co-ε-caprolactone) nanofibers achieved much higher functional recovery and markedly reduced cerebral tissue loss compared to controls. Crucially, it reconstructed the immune microenvironment and normalized the morphology of the meningeal lymphatic system. This study represents a paradigm shift from passive dural closure to active neuroimmunomodulation, offering a neuroprotective therapeutic strategy for traumatic brain injury.

Down-regulated O-linked β-N-acetylglucosamine modification (O-GlcNAcylation) has been implicated in Parkinson’s disease (PD), and restoring O-GlcNAcylation levels in the central nervous system via O-GlcNAcase (OGA) suppression represents a potential therapeutic strategy for PD intervention. Nevertheless, naturally derived OGA inhibitors remain insufficiently explored, and the molecular mechanisms underlying OGA-inhibition-mediated restoration of O-GlcNAcylation to alleviate PD remain poorly defined. Here, a fluorescence-based high-throughput inhibitor screening platform was established and subsequently used to identify sennoside A (SA) as a potent OGA inhibitor from an in-house phytochemical library. As a competitive OGA inhibitor, SA exhibited potent anti-OGA activity both in vitro and in vivo, along with favorable blood–brain barrier permeability and a well-tolerated safety profile. Moreover, SA markedly elevated protein O-GlcNAcylation levels, which in turn attenuated neuroinflammatory response and ameliorated key PD-associated pathological and behavioral deficits. Mechanistically, SA directly inhibits OGA activity in neurons and microglia, predominantly enhancing the O-GlcNAcylation of EphrinB2 at the Ser40/Thr183 sites and stabilizing EphrinB2. This site-specific modification activates the EphrinB2–EphB4 signaling cascade and subsequently blunts mitogen-activated protein kinase-mediated neuroinflammation. Disruption of EphrinB2 O-GlcNAcylation by Ser40A/Thr183A mutation eliminates its neuroprotective function and abolishes the anti-PD effects of SA. Collectively, this work establishes the pharmacological inhibition of OGA as a promising therapeutic strategy for PD and identifies SA as a naturally occurring anti-PD agent that alleviates PD-associated pathological phenotypes by inhibiting OGA-mediated de-O-GlcNAcylation of EphrinB2.

Accurately tracking the spatiotemporal evolution of road distress is essential for formulating informed repair and maintenance strategies. However, existing road performance prediction approaches typically rely on weighted composite indices such as the Pavement Condition Index (PCI) rather than fine-grained, distress-level observations. This coarse representation limits the ability to detect early-stage deterioration and constrains the development of precise, predictive maintenance models. To address these limitations, this study proposes a physics-embedded diffusion (PED) model that provides a physically consistent spatiotemporal framework for jointly modeling distress evolution, maintenance interventions, and environment-induced disturbances. Validation using real-world datasets from China demonstrates strong agreement between PED predictions and observations, achieving a mean PCI mean absolute percentage error (MAPE) of 9.262% and a mean weighted percentage error of area (area MWPE) of 4.484%. Furthermore, evaluation on the US Long-Term Pavement Performance dataset confirms the model’s strong cross-regional generalization capability, achieving a mean PCI MAPE of 28.054% and an area MWPE of 8.957%, underscoring the robustness and transferability of the proposed framework. Experimental results further indicate that the optimal historical environmental window for short-term distress prediction is approximately 50 d. As the volume of training data increases, the model continues to maintain stable convergence performance, demonstrating the scalability and robustness of the proposed physics-guided deterioration modeling approach. This scalable tool is invaluable for simulating realistic road deterioration processes, providing a reference for evaluating subsequent maintenance decision-making strategies.

The transforming growth factor-β1 (TGF-β1)/Smad3 pathway drives DNA damage, necrosis, and ventricular remodeling following acute myocardial infarction (AMI); however, effective therapies targeting this cascade remain limited. Here, we investigated the role of the deubiquitinating enzyme BRCA1/BRCA2-containing complex subunit 3 (BRCC3) in postinfarction cardiac remodeling and dysfunction using a mouse AMI model established via left coronary artery ligation. The cardiac structure and function were evaluated by echocardiography, Western blotting, and histomorphometry. We found that cardiac BRCC3 expression was markedly down-regulated after AMI. Cardiac-specific BRCC3 overexpression inhibited TGF-β1/Smad3 activation, reduced the infarct size, attenuated adverse remodeling and DNA double-strand breaks, improved cardiac function, and enhanced survival, whereas cardiac-specific Brcc3 gene knockout exacerbated these phenotypes. In vitro, BRCC3 suppressed TGF-β1-induced hypertrophic gene expression and DNA damage in cardiomyocytes, as well as profibrotic responses in cardiac fibroblasts. Mechanistically, BRCC3 bound to the MH2 domain of Smad3 and removed K63-linked polyubiquitination at lysine 333 (K333), thereby inhibiting Smad3 phosphorylation at Ser423/425. Collectively, these findings demonstrate that BRCC3 protects against ischemic injury and pathological remodeling by deubiquitinating Smad3 at K333 to antagonize TGF-β1/Smad3 signaling, identifying BRCC3 as a potential therapeutic target for preventing post-AMI heart failure.

Intestinal epithelial injury is increasingly linked to ferroptosis, yet how dietary bioactives engage the gut microbiota to restrain this process remains largely unresolved. Here, astaxanthin (ASTA) was identified as a microbiota-engaged regulator of intestinal ferroptosis and lipid peroxidation. ASTA markedly ameliorated dexamethasone-induced intestinal injury, and this protection was closely associated with the attenuation of epithelial ferroptosis. Depletion of the gut microbiota largely abolished the protective effect of ASTA, establishing the gut microbiota as an essential mediator of its intestinal bioactivity. Microbiome and metabolome profiling further revealed that ASTA reshaped the microbial metabolic landscape, with retinol metabolism emerging as a dominant pathway linked to ferroptosis resistance. Among the altered metabolites, retinoic acid was identified as a pivotal ASTA-associated metabolite that connected microbial remodeling with the restoration of epithelial anti-ferroptosis capacity. Metagenomics combined with in vitro bacterial metabolic assays identified Lepagella muris as a candidate ASTA-responsive bacterium capable of contributing to retinoic acid production. Mechanistically, retinoic acid protected intestinal epithelial cells from ferroptosis and barrier disruption through activation of SLC7A11, thereby reinforcing the anti-ferroptosis defense system. This study moves beyond the conventional view of ASTA as a direct antioxidant and reveals a microbiota-enabled redox metabolic mechanism that may be therapeutically exploited for ferroptosis-associated diseases.

Imbalances between osteoblastogenesis and osteoclastogenesis represent the fundamental pathological feature of primary osteoporosis; however, safe and cost-effective therapies that simultaneously promote bone formation and suppress bone resorption are lacking. Given the central roles of runt-related transcription factor 2 and the nuclear factor κB pathway in bone remodeling, we performed a phenotypic screen of a Food and Drug Administration-approved drug library to identify dual-acting regulators of bone homeostasis and identified the orally approved anticoagulant dabigatran (DAB) as a novel candidate. In vivo, DAB administration markedly attenuated bone loss and preserved bone microarchitecture in both ovariectomized and aged mouse models of osteoporosis. In vitro, DAB not only inhibited receptor activator of nuclear factor κB ligand-induced osteoclastogenesis from bone-marrow-derived macrophages but also directly enhanced the osteogenic differentiation of bone marrow mesenchymal stem cells. Mechanistically, using limited proteolysis-coupled mass spectrometry, we identified protein kinase adenosine-monophosphate-activated noncatalytic subunit β1 and v-Rel reticuloendotheliosis viral oncogene homolog A as direct targets of DAB. In bone marrow mesenchymal stem cells, DAB binds to protein kinase adenosine-monophosphate-activated noncatalytic subunit β1 via the alanine-77 residue, leading to adenosine-monophosphate-activated protein kinase activation, subsequent mechanistic target of rapamycin complex 1 inhibition, enhanced autophagic flux, and ultimately promoted osteogenesis; in osteoclast precursors, DAB interacts with v-Rel reticuloendotheliosis viral oncogene homolog A at arginine-50, resulting in suppression of the nuclear factor κB pathway and attenuated osteoclast differentiation. Collectively, our findings reposition DAB as a promising therapeutic candidate for restoring osteoblast–osteoclast balance and maintaining skeletal homeostasis while establishing a novel single-molecule, dual-target pharmacological strategy and providing novel mechanistic insights for bone metabolic disease treatment.