Peripheral artery disease (PAD) confers elevated risk for major adverse cardiovascular events (MACE), yet accurate risk stratification remains a challenge, particularly among patients with advanced disease necessitating endovascular revascularization. This study aimed to improve the prediction of MACE in a clearly defined high-risk PAD population (hospitalized patients undergoing endovascular intervention) by identifying novel protein biomarkers and developing a robust risk model. We prospectively analyzed blood samples from 164 hospitalized PAD patients scheduled for endovascular revascularization, employing untargeted plasma proteomics and metabolomics. Differential protein and metabolite profiles were compared between patients with and without subsequent MACE. Several proteins, including MMP3, MMP19, and PRB2, were markedly elevated in patients who developed MACE. A proteomics-based risk model incorporating these biomarkers achieved high discriminative accuracy (area under the curve > 0.80) for identifying individuals at increased risk. Metabolomic profiling revealed additional pathway alterations, notably involving tryptophan and glycogen metabolism, which provided mechanistic insights into cardiovascular complications but were not directly incorporated into the prediction model. This study demonstrates that integrating protein biomarkers markedly improves risk stratification in advanced PAD patients undergoing surgical intervention. The findings offer promising tools for early detection and enable more personalized management for this high-risk subgroup, while also deepening understanding of disease pathophysiology. However, further validation in larger and more diverse prospective cohorts is warranted before these findings can be broadly applied in clinical practice.

Chimeric antigen receptor T (CAR-T) cell therapy, a groundbreaking technology in tumor immunotherapy, has demonstrated unprecedented potential in the field of autoimmune diseases in recent years. This article provides a systematic review of the developmental trajectory and core concepts of CAR-T-cell therapy in autoimmune diseases, emphasizing its conceptual evolution from traditional “killing” strategies to “precision immune remodeling”. Leveraging multitarget approaches (e.g., CD19 and B-cell maturation antigen) and chimeric autoantigen receptor technology, it achieves efficient elimination of pathogenic B cells, plasma cells, and autoreactive T cells, along with profound remodeling of the immune microenvironment, thereby inducing long-term disease remission and restoring immune tolerance. Nevertheless, unresolved challenges still exist in monotherapy strategies, such as antigen escape, nontumor toxicity of emerging targets, limited in vivo persistence, high production costs, and immune reconstitution imbalance. Future research ought to concentrate on the development of multitarget/logic-gated chimeric antigen receptor constructs, the optimization of chimeric antigen receptor architecture and nonviral delivery systems, the validation of the long-term safety of universal CAR-T cells, the customization of personalized treatment regimens, and the exploration of mechanisms for modulating the immune microenvironment. This review emphasizes that CAR-T-cell therapy shows potential for initiating a new era of personalized, mechanism-driven treatment for autoimmune diseases, offering crucial insights for clinical translation.

Knee osteoarthritis (KOA) is clinically characterized by recurrent and progressively worsening episodes; however, its underlying pathological mechanisms remain incompletely understood. Phenotypic changes and the specific migration of circulating monocytes may be key factors contributing to the recurrence and progressive exacerbation of synovial inflammation in KOA. In this study, we report a specific subtype of circulating monocytes in KOA that highly express interleukin 1A (IL1A), IL1R1, tumor necrosis factor, CXCL12, CXCL3, CXCL2, CCL20, and G0S2. These monocytes exhibit a trained immune phenotype, and their CXCR4-dependent migration to the synovium exacerbates synovial inflammation. HMGB1 (high mobility group protein B1) primes the trained immunity of this subtype, resulting in increased chromatin accessibility, and the transcriptional storage of multiple proinflammatory factors enables them to exhibit a more positive inflammatory response when restimulated by HMGB1. In addition, we find that MyD88, downstream of HMGB1, recruits cytoplasmic interferon regulatory factor 1 to the nucleus and then stabilizes interferon regulatory factor 1 in chromatin through SUMOylation of tripartite motif containing 28 to exert transcriptional activity and epigenetic enhancement of proinflammatory factor expression. Finally, we found that KOA inflammation was effectively attenuated by blocking HMGB1. Taken together, this study reveals the mechanism by which trained immunity of circulating monocytes promotes the progression of synovial inflammation, supporting a future therapeutic approach in the management of KOA.

The persistent hyperglycemic microenvironment in diabetic wounds causes dysfunction of repair cells, resulting in impaired angiogenesis and disorganized extracellular matrix (ECM) deposition. Small extracellular vesicles (sEVs) derived from hypoxia-challenged chorionic plate mesenchymal stem cells (CP-MSC-sEVs^Hypo) have been explored as novel acellular therapeutics. However, the effects of oxygen tension during culturing parent cells on the pro-regenerative efficacy and mechanisms of CP-MSC-sEVs have not been systematically investigated. In addition, their rapid clearance and limited interaction with target cells at wound sites constrained therapeutic efficacy. In this study, oxygen tension was first optimized systematically during the precondition of CP-MSCs to improve the pro-regenerative properties of the derived sEVs^Hypo. Then, sEVs^Hypo-engineered nanofiber scaffolds were fabricated to achieve the sustained release of sEVs^Hypo at wound sites by polydopamine (PDA)-mediated interfacial adhesion. In vitro experiments revealed that sEVs obtained under 5% oxygen tension (sEVs^Hypo-5%) exhibited the most pronounced angiogenic and collagen-regenerative performance. Furthermore, small RNA sequencing and bioinformatic analyses revealed that miR-21-5p was the most abundant miRNA in sEVs^Hypo-5%, and functional rescue assays validated that miR-21-5p was the key mediator of endothelial activation and ECM remodeling. To improve the bioavailability of sEVs^Hypo-5%, PDA was leveraged to immobilize sEVs^Hypo-5% onto a biocompatible, ECM-mimicking poly(ε-caprolactone) nanofiber scaffold to achieve high loading efficacy and sustained release. In a full-thickness diabetic wound model, the sEVs^Hypo-5%-loaded nanoscaffold accelerated wound closure and achieved superior pro-healing effects on D14 via enhancing neovascularization and ECM deposition, as confirmed by histological and immunofluorescence analyses. Collectively, this sEVs^Hypo-5%-loaded nanoscaffold achieved efficient immobilization and sustained delivery of sEVs^Hypo-5% to promote angiogenesis and matrix repair by endogenously delivering miR-21-5p at diabetic wound sites, with strong potential for clinical translation.

4-Chromanone is a biologically important heterocyclic scaffold found in natural products and pharmaceuticals. Traditional syntheses of 2-substituted 4-chromanones often rely on high-temperature peroxide initiation, transition-metal catalysis, or complex photocatalytic systems, limiting functional-group tolerance and sustainability. Herein, we report a Giese-type strategy for direct C–H functionalization of chromone derivatives, where chromones act as both substrates and hydrogen atom transfer (HAT) reagents to active inert C(sp³)–H bonds and P–H bonds under mild, metal-free conditions. Upon light irradiation, chromones form triplet states that mediate HAT for diverse substrates, including ethers, esters, alcohols, alkanes, sulfides, and arylphosphines. The resulting radicals are captured by ground-state chromones, efficiently affording 2-substituted 4-chromanones. Mechanistic studies and density functional theory calculations support the radical-mediated pathway, and the method avoids the use of metal catalysts, external redox mediators, or photocatalysts, highlighting its scalability and sustainable potential.

The utility of silk protein spans from East Asian traditions to promising applications in modern biomaterials science. While its bioactive effect is widely accepted, its molecular mechanisms and the supporting data have remained elusive. This study reveals the anti-photoaging mechanism of silk protein enzymatic hydrolysate (SEH), identifying key peptides SO1 from silk seroin and SC1 from silk sericin. Mechanistically, SO1 targets PDGFRβ to inhibit the NF-κB/ERK/SASP cellular senescence axis, while SC1 targets TRPV4 to suppress MITF-driven melanin synthesis. Additionally, the SO1 and SC1 combination suppresses key hallmarks of photoaging. It reduced senescence, confirmed by diminished β-galactosidase activity and SASP, while concurrently mitigating oxidative stress and hyperpigmentation, and promoting cell migration. Further network pharmacology analysis reveals a multi-component interaction network connecting bioactive silk peptides, target receptors, and downstream signaling pathways involved in mitigating photoaging. This integrative mechanism was defined as the “Silk Peptides Mesh”, with SO1 and SC1 identified as representative core peptides within this system. Finally, a 28-d skin clinical trial involving 30 participants confirms these findings, showing that a cream containing SO1 and SC1 improves photoaging-related skin indicators. Importantly, this work establishes a paradigm shift from conventional single-molecule approaches to a multi-component network understanding of bioactive peptide functionality.

Renal metabolic behavior constitutes a critical evaluation parameter during drug development, toxicity assessment, and biodistribution. However, the inherent biological architecture of existing animal and cell-based models fails to recapitulate the authentic metabolic processes and spatial distribution patterns of drugs in the human kidney at a macroscopic level. Therefore, developing a standardized human-derived kidney model was necessary. In this work, the ex vivo tumor-bearing kidney (ETK) model was established using kidneys from 50 clinically diagnosed patients after the radical surgery. The standardized ETK model included the following: (a) selected according to the proportion of preserved normal tissue, vascular status suitable for ETK perfusion, and overall structural integrity of the kidneys; (b) surgical preparation exposed the renal pelvis and enabled catheterization of the renal artery and ureter; (c) perfused with hypothermic (4 to 10 °C) saline at a flow rate of 70 ml/min within perfusion system; and (d) ETK detection efficiency and drug biodistribution were assessed using biological sample indicators. Results showed that ETK maintained intact glomerular and tubular microstructures throughout perfusion and produced stable urine output with preserved filtration capacity. When treated with different kinds of nephrotoxic agents (cisplatin, gentamicin, and cephalosporins), the ETK model reproduced drug-specific injury patterns and exhibited biochemical changes and histological features that were consistent with real clinical observations. In drug-distribution analysis, indocyanine green (ICG) showed a negative fluorescence tumor contrast and enriched fluorescence in the normal kidney in the ETK model, which were consistent with real clinical observations, whereas mouse orthotopic renal cancer models showed positive ICG tumor accumulation, indicating species-dependent differences in renal drug distribution. Overall, the ETK model provided a structurally preserved and functionally responsive human-derived renal system for investigating renal drug metabolism, nephrotoxicity, tumor imaging, and drug-delivery strategies.

High-glucose microenvironment in diabetic wound exacerbates the risk of bacterial infections and perpetuates chronic inflammation, thereby complicating wound healing. To meet these challenges, we develop antibacterial agents by integrating probiotics with nanozymes targeting high glucose levels and multidrug-resistant bacterial infections in diabetic wound healing. We engineer probiotic Lactobacillus plantarum (LP) with Fe-based nanozymes containing glucose oxidase (GOx) as antibacterial agents (LP@FeG) for diabetic wound therapy. The bioactivity of LP ferments glucose in the wounds, thereby reducing local pH through lactic acid production. Besides, GOx catalyzes the conversion of glucose into gluconic acid and hydrogen peroxide, further lowering local pH. In addition, GOx stimulates the peroxidase-like activity of Fe-based nanozymes, thereby generating reactive oxygen species that attack the cellular membrane, facilitating the entry of Fe²⁺/Fe³⁺ into bacteria and inducing bacterial death through ferroptosis and lipid peroxidation. In vivo studies demonstrate that LP@FeG exhibits prolonged sterilization of methicillin-resistant Staphylococcus aureus with an almost 100% antibacterial rate, marked anti-inflammatory, and proangiogenic effects in diabetic wounds. This strategy resolves both the high glucose level and bacterial infections in wound healing, being promising for the treatment of diabetic wounds.

SUN1/2, core components of the linker of nucleoskeleton and cytoskeleton complex, transmit extracellular mechanical forces to nuclear lamina and chromatin. However, their role in regulating peripheral chromatin in mechanosensing and mechanoadaptation remains unclear. Using CRISPR/Cas9-mediated knockout of Sun1 or Sun2 in myoblasts, we identified a SUN1/2-dependent mechano-feedback loop. SUN1/2 depletion down-regulates genes for cell adhesion (e.g., integrin alpha-4) and for mechanotransduction (e.g., cell division cycle 42 and Ras homolog family member A). The primary mechanism involves redistribution of heterochromatin from nuclear periphery to the nucleoplasm and remodeling of lamina-associated domains (LADs), as an adaptive response to the loss of SUN proteins. Furthermore, lamin A/C acts as a key downstream effector, consistently modulating adhesion-related gene expression through the remodeling of LADs. Functionally, knockout of either Sun1/2 or Lmna aggravates differentiation defects in C2C12 myoblasts and abolishes adaptive responses to mechanical cues. This study provides proof of concept that nuclear mechanotransduction proteins can modulate cellular mechanoadaptation via a mechano-feedback loop, which coordinates LAD reorganization with the expression of upstream mechanotransduction genes.

Pomelo (Citrus maxima cv. Wentan) peel represents a major agricultural byproduct rich in pectin with potential applications in functional foods and biomedical materials. This study aimed to elucidate the structure–activity relationship of pomelo peel pectin extracted at different temperatures (100 to 140 °C) and to evaluate its neuro–gut protective effects using a zebrafish model. Pectins obtained under varying thermal conditions were structurally characterized, and their bioactivities were systematically compared. Among them, pectin extracted at 130 °C (P-130) exhibited higher galacturonic acid content, molecular weight, and hydroxyl group abundance. Functionally, P-130 effectively mitigated bisphenol AF-induced toxicity in zebrafish. It significantly improved developmental outcomes, reduced oxidative stress, and preserved neuronal integrity by promoting axonal growth and up-regulating neurodevelopment-related genes. Notably, P-130 regulated the gut–brain axis by restoring neurotransmitter balance (5-hydroxytryptamine and dopamine), attenuating intestinal inflammation, and modulating gut microbiota composition, particularly by enriching beneficial taxa such as Bacteroidetes. These effects were associated with reduced anxiety-like behavior. Histopathological analyses further confirmed its protective roles in cerebellar and intestinal tissues. This study highlights the critical influence of extraction temperature on pectin structure and identifies P-130 as a promising natural agent against environmental toxicants. The findings provide novel insights into the synergistic mechanisms linking antioxidant activity, neuroprotection, and microbiota regulation, offering a scientific basis for the valorization of pomelo peel in developing plant-derived protective strategies.

Immune regulation is essential in both the pathogenesis and treatment of various diseases. Plant-derived extracellular-vesicle-like particles (PDEVLPs), especially herbal medicine, are emerging as promising cross-species nanotherapeutic carriers for immune regulation due to their intrinsic bioactive components. Compared with traditional small-molecule drugs, these natural nanocarriers offer superior pharmacokinetic properties in mammalian systems, including enhanced targeting capacity and penetration efficiency as well as prolonged circulation time. Due to the biogenic structures and low immunogenicity, most PDEVLPs exhibit generally favorable biocompatibility and substantial advantages in specific contexts. However, their immunological profile in humans, particularly the risk of immunogenicity from heterologous plant proteins, requires further investigation compared to established platforms such as liposomes. While diverse active ingredients endow PDEVLPs with effective regulation of various immune cells, they support body homeostasis and offer marked potential for treating multifactorial inflammatory and immune-related diseases. This review examines disease-specific immune microenvironments to provide a theoretical foundation for selecting PDEVLP-based therapies. It also evaluates engineering strategies to enhance the targeted delivery and therapeutic efficacy of these interkingdom mediators. By summarizing recent advancements, this review aims to guide the development of next-generation immune regulatory carriers tailored to specific microenvironments.

The cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING)-mediated type I interferon response plays a crucial role in antitumor immunity, yet the regulatory factors involved in this innate immune response remain incompletely understood. Here, we identified methyltransferase-like 3 (METTL3), an RNA N⁶-methyladenosine methyltransferase, as a key suppressor of the cGAS/STING pathway in lung adenocarcinoma (LUAD) cells. METTL3 was overexpressed in LUAD tissues, and elevated METTL3 expression was associated with decreased CD8⁺ T-cell infiltration and poor clinical outcomes. Mechanistically, METTL3 deficiency promoted nuclear DNA leakage into the cytoplasm, thereby activating the cGAS pathway and enhancing antitumor immunity. Specifically, METTL3 knockdown decreased the efficiency of homologous recombination repair by down-regulating MutS homolog 5, leading to cytosolic DNA accumulation. On the other hand, N⁶-methyladenosine methylation of cGAS messenger RNA destabilized the transcript and suppressed its protein expression. Functionally, METTL3 knockdown sensitized LUAD cells to poly(ADP-ribose) polymerase inhibitors. In vivo and clinical data confirmed the beneficial effects of METTL3-inhibition-induced activation of the cGAS/STING axis on tumor growth and LUAD progression. Collectively, our findings reveal that METTL3 inhibition activates cGAS/STING-mediated antitumor immunity by inducing cytosolic DNA accumulation and cGAS up-regulation, thereby modulating poly(ADP-ribose) polymerase inhibitor response and cancer progression in LUAD.

This study sought to investigate the link between sleep disorders and cardiac microvascular injury in myocardial ischemia–reperfusion injury (MI/RI) mice. Mice were subjected to a sleep deprivation protocol within a designated chamber. During the light phase (ZT0 to ZT12), a sweep bar moved across the cage floor at 2-min intervals, whereas it remained static throughout the dark phase (ZT12 to ZT24), with this routine maintained for 16 weeks. Subsequently, an MI/RI model was established to assess the extent of cardiac microvascular injury, and the underlying mechanisms were explored via proteomic analyses. It was demonstrated that 16 weeks of sleep fragmentation (SF) intensified cardiac microvascular damage in MI/RI mice. From a mechanistic perspective, SF was found to induce sympathetic hyperactivity, elevate plasma epinephrine levels, and consequently facilitate neutrophil chemotaxis and the generation of neutrophil extracellular traps (NETs). Moreover, the findings revealed that NETs suppressed Atox1 expression, impaired ATP7A-mediated copper transport, and contributed to copper accumulation within cardiac microvascular endothelial cells (CMECs) and oxidative stress. This copper overload further augmented cuproptosis, while these pathological alterations were shown to be reversible through sympathetic denervation, vagal electrical stimulation (ES), targeted delivery of copper chelators, or the inhibition of NETs. Overall, our data established that SF exacerbated MI/RI by promoting copper overload in CMECs. This study elucidated a molecular pathway through which sleep disturbances aggravated cardiac microvascular damage and suggested prospective targets for treatment strategies.

Diffuse large B cell lymphoma (DLBCL) presents a critical clinical challenge due to declining chemosensitivity and difficult-to-manage dose-limiting toxicities. Although gut microbiota modulation shows potential for “toxicity reduction and efficacy enhancement”, its mechanism in DLBCL remains unclear. Comparative analysis revealed a marked reduction of beneficial bacteria in patients with DLBCL versus healthy volunteers, with a marked decrease in the abundance of core probiotics, particularly Limosilactobacillus reuteri. Fecal microbiota transplantation from healthy donors into DLBCL mouse models reduced tumor burden, improved chemosensitivity, and alleviated intestinal toxicity. A core probiotic strain, L. reuteri HG001, was isolated and shown to replicate these effects alone, with the tryptophan metabolite indole-3-carbaldehyde (ICAld) identified as the key component responsible for its adjunctive antitumor activity. Mechanistic studies demonstrated that ICAld exerts significant adjunctive antitumor effects both in vitro and in vivo in a dose-dependent manner in mouse models; it acts by activating the aryl hydrocarbon receptor (AHR)/cytochrome P450 family 1 subfamily A member 1 (CYP1A1)/reactive oxygen species (ROS) axis, inhibiting the phosphatidylinositol 3-kinase (PI3K)/AKT/mechanistic target of rapamycin (mTOR) signaling pathway, promoting apoptosis, and synergizing with cyclophosphamide. An aryl hydrocarbon receptor antagonist reversed both the chemosensitizing and intestinal protective effects of L. reuteri HG001 and ICAld. This study elucidates a microbiota-mediated mechanism in DLBCL and supports L. reuteri HG001 as a probiotic adjuvant to enhance therapy while reducing toxicity.

Terahertz (THz) waves occupy a unique spectral region where they can resonantly interact with collective vibrational modes of biomolecules, thereby modulating protein conformation and subsequently affecting neural signaling. However, whether noninvasive THz wave stimulation can be extended to Alzheimer’s disease and related dementias (ADRD) remains unknown. Here, we demonstrate that 14 d of noninvasive THz wave binocular stimulation (33 THz) effectively restores cognitive performance and neural homeostasis in Aβ_1–42-induced dementia mice, a widely used experimental model of ADRD with the features including neuroinflammation and cognitive decline. Behavioral assessments revealed a marked restoration of spatial learning and memory ability, with a 53.1% ± 22.0% improvement compared with untreated dementia mice. Furthermore, THz wave stimulation reduced sleep fragmentation and restored physiological sleep–wake dynamics, indicating improved neural homeostasis. In the hippocampus, binocular stimulation attenuated microglial activation and normalized the levels of pro-inflammatory cytokines including interleukin-1β and tumor necrosis factor-α. Concurrently, THz wave stimulation activated hippocampal cyclic adenosine monophosphate (cAMP)–cAMP-response element binding protein (CREB)–brain-derived neurotrophic factor (BDNF) signaling, promoting neurotrophic support and re-establishing cholinergic functional integrity. Our findings demonstrate that THz wave binocular stimulation is a noninvasive approach capable of improving cognitive function in a dementia mouse model, offering a potential strategy to restore brain function in neurodegenerative diseases.

Hydroxyl radicals (•OH) generated under redox fluctuations in paddy soils are crucial for biogeochemical processes. Artificial humic acid (A-HA), as an emerging soil amendment, has been widely applied to improve soil quality. However, the impacts of A-HA on •OH generation and biogeochemical consequences remain under-explored. This study investigated the effects of A-HA on •OH generation, revealing that A-HA enhanced •OH accumulation from 43.93 to 142.30 μM upon oxygenation. The 0.5 M HCl-extracted Fe(II) was the dominant driver for •OH production via H₂O₂ as an intermediate. Multi-omics analyses demonstrated that A-HA reshaped the microbial community from a sulfate-reducing state to a copiotrophic state dominated by iron-reducing and fermentative bacteria. By acting as an electron shuttle and accelerating intermediate metabolism, A-HA overcame Fe(III) reduction kinetic barriers, providing a thermodynamic advantage that competitively suppressed sulfate-reducing bacteria. Additionally, •OH-induced mineralization and adsorption/fractionation by Fe(III)(oxyhydr)oxides decreased the content of dissolved organic matter (DOM). Fourier transform ion cyclotron resonance mass spectrometry confirmed that “saturated and oxidized” compounds were enriched during anaerobic incubation and subsequently preferentially degraded by •OH through dealkylation, decarboxylation, and oxygen addition, revealing a complementary pattern between anaerobic enrichment and oxidative degradation. Machine learning identified N/C, S/C, m/z, and O/C as key predictors of DOM transformation susceptibility, aligning with the metabolic enrichment of nitrogenous pathways. Furthermore, the enhanced •OH degraded propanil with a removal rate of up to 56.54%, suggesting that contaminants adsorbed on mineral surfaces were more susceptible to degradation. This study revealed a coupled mechanism in which microbial metabolic regulation during reduction enhances iron reduction for subsequent abiotic oxidation, providing new insights into microbial iron reduction, organic matter, and contaminant transformation in paddy ecosystems. Overall, these results further emphasized that A-HA substantially impacts paddy environments far beyond improving soil fertility.

Sensory neurons act as crucial hubs for host defense, tumor immunity, and tissue homeostasis by detecting environmental cues and fine-tuning immune responses. Across a diversity of tissues, these neurons establish specialized neuroimmune units with resident immune cells, translating local stimuli into coordinated physiological adaptations. Central to this crosstalk is calcitonin gene-related peptide (CGRP). Released by activated sensory neurons, CGRP dynamically governs immune cell function, neurogenic inflammation, and tissue repair. This review synthesizes current evidence establishing CGRP as a master regulator of neuroimmune communication. We dissect its highly context-dependent roles in microbial infections, the tumor microenvironment, and barrier tissues, emphasizing how microbial identity, spatial niches, and concurrent signaling cues dictate its functional outcomes. Mechanistically, we explore the molecular cascades through which diverse cell types decode CGRP signals, focusing on receptor subtype selectivity and cell-specific adaptor switching. Furthermore, we evaluate emerging therapeutic strategies targeting the CGRP axis—ranging from small-molecule modulators to monoclonal antibodies—and their transformative potential for treating immune-mediated conditions, from chronic inflammation to malignancies. Ultimately, we identify critical knowledge gaps, such as the “CGRP receptor code” and neuromicrobial feedback loops, which must be resolved to fully harness the therapeutic promise of this neuroimmune axis.

Breast cancer remains the most common malignancy in women worldwide, and its marked heterogeneity continues to impede effective treatment. Immunotherapy has reshaped the therapeutic landscape, yet only a subset of patients achieves durable benefit, in large part because of immune and metabolic diversity within the tumor microenvironment. Posttranslational modifications are key regulators that couple cellular signaling to metabolic and immune homeostasis. Here, we generated a multiomics immune-metabolic atlas of breast cancer by integrating genomics, transcriptomics, proteomics, lactylomics, and phosphoproteomics from 115 tumor and 99 matched adjacent tissue samples. Using immune infiltration profiling, we defined 3 immune-related breast cancer subtypes with distinct metabolic states, posttranslational modifications cross-talk, and mutational landscapes. Integrated analyses revealed that the interplay between protein lactylation and phosphorylation orchestrates glycolytic reprogramming and immune modulation. Furthermore, we identified subtype-specific histone lactylation patterns and signaling rewiring associated with therapeutic response. This atlas provides a comprehensive framework for dissecting immune-metabolic regulation in breast cancer and yields molecular insights to guide subtype-specific precision immunotherapeutic strategies.

Brown adipose tissue (BAT) plays a crucial role in maintaining energy balance and regulating glucose and lipid metabolism. Preserving BAT activity has been considered a potential strategy to mitigate metabolic dysfunctions such as diet-induced obesity (DIO). Here, we identified a pronounced copper overload in the BAT of DIO mice. Normalization of copper levels through copper chelation or cold exposure effectively restored the expression of the thermogenic effector protein UCP1, prevented BAT whitening, and improved systemic metabolic parameters. Proteomic profiling revealed ATP-citrate lyase (ACLY)—a key enzyme in acetyl-CoA synthesis and de novo lipogenesis—as a critical mediator in BAT copper homeostasis. ACLY expression was down-regulated in BAT of DIO mice but increased in cold-challenged or copper-chelated BAT. Loss of ACLY promoted NRF2 acetylation and nuclear translocation, leading to the transcriptional repression of the copper chaperone ATOX1, which exacerbated copper accumulation in BAT, resulting in BAT whitening and dysfunction. Connectivity Map screening identified succinylsulfathiazole (SST) as an upstream activator of ACLY expression. Both in vitro and in vivo administration of SST restored ACLY expression, corrected copper dysregulation, and re-established BAT activity. Collectively, these findings uncover a mechanism linking ACLY to copper homeostasis in BAT and highlight SST as a promising repurposed candidate for correcting obesity and BAT dysfunction-associated metabolic disorders.

Background: Colorectal cancer (CRC) is a major cause of cancer morbidity and mortality worldwide, and its progression is closely associated with redox imbalance. The biological role and upstream regulation of the antioxidant enzyme glutathione peroxidase 3 (GPx3) remain poorly understood in CRC. Methods: This study integrated analyses from clinical CRC tissues, in vitro functional experiments, molecular biology assays, and public The Cancer Genome Atlas datasets. Techniques included gene expression profiling, N⁶-methyladenosine methylation analysis, mitochondrial reactive oxygen species detection, lipophagy assays, lipid droplet staining, transcriptomic and proteomic analyses, ferroptosis sensitivity testing, and in vivo xenograft and metastasis models to investigate the role and underlying mechanisms of GPx3 in CRC. In addition, lung metastatic burden was assessed using in vivo bioluminescence imaging and high-resolution micro-computed-tomography scanning. Results: GPx3 was substantially down-regulated in CRC tissues and cells, primarily due to N⁶-methyladenosine modification catalyzed by methyltransferase-like protein 3 (METTL3) and METTL14. Down-regulation of GPx3 expression elevated mitochondrial reactive oxygen species, impaired lipophagy flux, and caused excessive lipid droplet accumulation. Multiomics analyses identified Dickkopf-1 (DKK1) as a downstream target negatively regulated by GPx3 through reactive-oxygen-species-dependent β-catenin signaling. The GPx3–DKK1–solute carrier family 7 member 11 (SLC7A11) axis modulated lipid peroxidation and influenced ferroptosis sensitivity. In vivo xenograft and metastatic models showed that GPx3 suppressed tumor growth and metastasis, and these effects were partially reversed by DKK1. Conclusion: This study demonstrates that METTL3/14-mediated N⁶-methyladenosine modification is a key upstream mechanism leading to GPx3 down-regulation in CRC. Down-regulation of GPx3 expression promotes malignant progression by increasing mitochondrial oxidative stress, disrupting lipophagy, and cooperating with the DKK1–SLC7A11 pathway to reduce ferroptosis sensitivity. Targeting this regulatory axis may provide promising molecular strategies for CRC diagnosis and therapy.

Due to the importance of vision in human lives, 3-dimensional (3D) display has become a key and hot topic in the field of information research. With the advancement of computer science technology, holographic 3D display, capable of fully recording and reconstructing the complete wavefront information of 3D scenes, is considered as one of the most ideal 3D display technologies and has long been pursued by researchers. In recent years, substantial breakthroughs have been achieved in holographic 3D display; however, some bottlenecks continue to constrain its applications, such as slow hologram generation speed and limited space–bandwidth product. Here, the technical bottlenecks restricting the further development of holographic display are comprehensively analyzed. The latest development and progress of the key technologies of holographic 3D display are summarized. First, different fast generation methods for computer-generated holograms are analyzed. Then, the latest progress of holographic 3D display with high space–bandwidth product and low speckle noise is summarized. Finally, various application fields of holographic 3D display technology and its future development trends are discussed. This is aimed to summarize and analyze the key issues and progress in holographic 3D display technology and gain a deeper understanding of the cutting-edge developments in this rapidly developing field, providing assistance for its future applications in holographic near-eye display, virtual reality, augmented reality, optical encryption, and other fields.

Locomotion in animals such as fish, snakes, inchworms, and octopuses exhibits a remarkable diversity, with each species utilizing distinct body morphologies and movement strategies. Currently, no existing kinematic model is capable of describing the full range of locomotion exhibited by these animals. Addressing this challenge holds important implications for both the study of biomechanics of animals and the development of bioinspired robots. In this work, we propose a general kinematic model that integrates the curvature equation with a nonlinear oscillator. Through parameter adjustments, its morphology can transition between the motions of various animals. It is the most versatile kinematic model to date for describing multimodal locomotion of animals so far as we know. By translating the general kinematic model into a motion control algorithm and combining it with virtual simulation, we create a motion optimization framework that substantially simplifies the complexity of multimodal control for bionic robots with diverse actuation mechanisms, thereby enhancing their maneuverability. Using fish locomotion as an example, we validate the methodology on an untethered multijoint robotic fish, successfully enabling the robotic fish to perform cruising and various fast turn motions, thereby demonstrating its effectiveness in guiding motion control. This work is believed to have laid the foundation for the study of bionic motion and bioinspired robots.

Lipopolysaccharides are important components of the gram-negative bacterial cell envelope that are involved in immune evasion and act as a protective barrier. Employing cryo-electron microscopy, we resolved the structure and dynamics of FepE, the copolymerase component of the Wzy-dependent pathway, responsible for the length modulation of very long O-antigen molecules. Comparison of the interior volumes of related copolymerases’ periplasmic domains with the volume of hydrated sugars suggests that the size of the periplasmic domain controls the length of the O-antigen, implying that polysaccharide chain polymerization occurs inside the copolymerase periplasmic domain. Moreover, we show the opening of the FepE complex as well as other large mechanistically relevant movements. The opening of the complex presents an attractive corridor for the release of completed polysaccharide chains.

Droplet manipulation technology plays a crucial role in academic research and engineering applications. However, current manipulation technology requires integrated circuits and electrode configurations, which introduce the risk of short circuits and droplet cross-contamination during operation. Herein, we developed an omnidirectional wireless electro-droplet manipulation system (WEDMS) without using electrode/circuit control that obviates droplet cross-contamination to precisely manipulate droplet movement in separated or isolated space. This system innovatively generates localized electric fields through the synergistic effects of dielectric polarization and air discharge, achieving a noncontact, electrode-free droplet charging and driving strategy. It achieves synchronous movement of the slider and droplets via hand movement, enhancing droplet operation flexibility and human–droplet interaction on triboelectric nanogenerators. Moreover, WEDMS is capable of manipulation droplets with high speed across a wide range of volumes (10 to 2,000 μl) and effective control of droplets in both gas and oil phases, achieving a series of manipulations such as droplet positioning, chemical reactions, flexible steering, and droplet climbing, showcasing an innovative, efficient, portable, and comprehensive droplet manipulation strategy. Based on the prominent advantages of WEDMS in structural simplicity and high-efficiency control, its adaptability in multidisciplinary microfluidic applications can be further enhanced, demonstrating tremendous potential in drug delivery, green chemical synthesis, and environmental monitoring.

Tumor-infiltrating neutrophils are increasingly recognized as key drivers of cancer progression, but the mechanisms that govern their protumoral reprogramming remain elusive. Here, we demonstrated that lung cancer-derived exosomes (LDEs) deliver free fatty acids into neutrophils, triggering lipid accumulation, fatty acid β-oxidation, and mitochondrial reactive oxygen species production. This metabolic reprogramming culminates in enhanced neutrophil extracellular traps (NETs) formation, which accelerates lung cancer growth. Mechanistically, Ras-related protein Rab-34 (Rab34), a small guanosine triphosphatase, regulates neutrophil uptake of LDEs. Knockdown of Rab34 in neutrophils dramatically attenuated LDEs-induced lipid accumulation, fatty acid β-oxidation activation, and NETs formation, thereby mitigating neutrophil-involved lung cancer progression in vivo. Deoxyribonuclease I-mediated NETs degradation further confirmed the dependency of lung cancer growth on NETs. These findings uncovered a Rab34-dependent way by which LDEs reprogram neutrophils via exosomal free fatty acids, offering Rab34 and NET-associated pathways as potential therapeutic targets in lung cancer.

Organelle-targeted photodynamic therapy (PDT) shows substantial promise for precision tumor treatment. However, the clinical translation of oxygen-independent photosensitizers (PSs) designed for mitochondrial localization remains challenging. Herein, we propose a “dual-boosting” strategy to enhance the type-I PDT efficacy of mitochondria-targeted PSs. The first boost leverages multi-branched donor/π-bridge engineering to develop a series of mitochondria-targeted pyrido cyanines. Among them, McL3 displays broad visible-light absorption and a reduced singlet–triplet energy gap (ΔE_S1-T3 = 0.24 eV), which collectively lead to a 4.2-fold increase in superoxide anion radical (•O₂⁻) generation compared to McL1. The second boost is achieved through the self-assembly of McL3 with human serum albumin (HSA) into McL3@HSA nanoparticles (~40 nm). This confinement further narrows ΔE_S1-T2 to 0.08 eV, amplifying •O₂⁻ production by 20.3-fold. Mechanistic studies indicate that HSA confinement modulates molecular conformation and promotes ISC efficiency from 33% to 52%, enabling efficient •O₂⁻ generation. Upon white-light irradiation, McL3@HSA selectively accumulates in mitochondria, inducing apoptosis and effectively inhibiting tumor growth even under hypoxic conditions. This work establishes a “dual-boosting” paradigm for the rational design of mitochondria-targeted, hypoxia-tolerant PSs, offering a promising avenue for clinical phototheranostics.

ACE2 binding of spike proteins and concomitant viral uptake are the first and most decisive membrane-coupled events of SARS-CoV-2 infection, which rely on cholesterol-rich lipid raft microdomains of the host cell plasma membrane. Therefore, lowering membrane cholesterol levels may combat the infection, potentially complementing specific, resistance-prone antiviral approaches such as vaccines. High-throughput flow cytometry and quantitative 3-dimensional microscopy reveal that SH42, a novel, extremely potent, and highly selective 24-dehydrocholesterol reductase (DHCR24) blocker, markedly inhibits ACE2 binding of SARS-CoV-2 spike receptor-binding domains and entry of spike trimers of Wuhan-Hu-1 (WT), Delta, and Omicron BA.1 variants into living cells. These effects are related to SH42-induced reduction of plasma membrane cholesterol abundance and subsequent lipid raft disruption, which are accompanied by decreased cell surface ACE2 expression and its lowered raft partitioning. SH42 exhibits superior efficacy and potency in all aspects compared to the reference atorvastatin. Furthermore, inhibitory effects of SH42 are also corroborated by reduced SARS-CoV-2 RNA copy numbers of replication-competent complete virions of WT-resembling D614G, Delta, and Omicron-derived JN.1 strains. These results suggest that selective DHCR24 blockers such as SH42 may be promising novel candidates for inhibiting initial membrane-coupled events of SARS-CoV-2 infection and serve as potential alternative therapeutic option for COVID-19.

A₃BX₆ perovskites, a family of vacancy-ordered structures, exhibit diverse luminescence behaviors upon photon, electron, and high-energy excitation, primarily originating from intrinsic self-trapped excitons or dopant-induced electronic transitions. Upon B-site cation engineering, ns² cations tune intrinsic luminescence, whereas transition-metal and rare-earth dopants activate characteristic d–d, d–f, and f–f transitions, enriching A₃BX₆ optical diversity. The tunable crystal structure and electronic configuration endow A₃BX₆ perovskites with exceptional versatility for photoluminescence, electroluminescence, and scintillation applications. This review systematically elucidates how B-site chemistry modulates the structure–property–application relationships in this material family. P-block B-site A₃BX₆ perovskites exhibit high photoluminescence efficiency, broadband emission, and strong ultraviolet absorption, enabling applications in high-sensitivity photodetectors (1.23 × 10¹² Jones), information encryption, and white light-emitting diodes. In comparison, rare-earth-based A₃BX₆ perovskites enable high-efficiency electroluminescent devices, featuring deep-blue light-emitting diode with an external quantum efficiency of 7.9%. Moreover, they exhibit superior scintillation performance, including high x-ray light yield (88,800 ph/MeV), low x-ray detection limit (63 nGy/s), and notable γ-ray response under ¹³⁷Cs excitation (47,000 ph/MeV; 4.0% energy resolution). These insights highlight the pivotal role of B-site cation engineering in tailoring luminescence mechanisms and enabling multifunctional A₃BX₆ perovskites for photonic and radiation applications.

Multifunctional polyurethanes face a fundamental design trade-off: enhanced cross-linking and rigidity improve mechanical robustness but inevitably restrict chain mobility, thereby compromising essential features such as self-healing and recyclability. This inherent compromise severely constrains their multifunctional application. Here, we report a supramolecular polyurethane (COPUSL) comprising a “dynamic switch” constructed from dynamic disulfide bonds and hydrogen bonds, together with a “rigid–flexible balanced network” composed of castor oil long fatty chains and polyphenol-functionalized lignin. This design endows COPUSL with excellent mechanical properties while also enabling rapid self-healing (self-healing efficiency: 87%) and efficient recyclability. Furthermore, COPUSL with introduced aromatic structures and extended conjugate systems exhibits 100% ultraviolet-blocking efficiency and a high photothermal conversion capability (surface temperature: 153 °C) due to the electron transition and energy release of the lignin structure after absorbing light energy. By systematically investigating the relaxation kinetics, dynamic behavior, and macroscopic properties, we elucidate the distinct roles of the “dynamic switch” and “rigid–flexible balanced network” in regulating the polymer architecture and connecting dynamic behavior with mechanical and functional performance. These findings provide molecular-level insights for the design of high-performance, bio-based polyurethane with tailored multifunctional responsiveness.

The elemental composition of brains changes progressively with age, yet these metallome alterations remain largely unexplored as diagnostic biomarkers in neurological disease. Here, we present a comprehensive analysis of 24 inorganic elements in paired cerebrospinal fluid and serum samples from 1,608 individuals spanning healthy aging through 14 neurological conditions, representing the largest systematically standardized cohort for neurological metallomics. Uniquely, our unselected, consecutively admitted clinical cohort captures the full heterogeneity of neurological presentations, overcoming the limitations of traditional case–control designs focused on isolated disease entities. Machine learning analysis reveals that aging is associated with distinct cerebrospinal fluid elemental signatures independent of peripheral blood changes, primarily reflecting blood–brain barrier permeability alterations that correlate with established albumin quotient measurements. We identify 2 predominant patterns of neurological elemental dysregulation: one mainly consistent with passive barrier-mediated leakage in inflammatory conditions, and another mainly indicative of disease-intrinsic perturbations of metal homeostasis in neurodegenerative disorders. Age-stratified analysis reveals that elemental signatures evolve differently across the lifespan for distinct pathological processes. The integration of elemental signatures with routine clinical parameters through ensemble learning approaches enhances diagnostic accuracy across all tested neurological categories, establishing metallomics as a complementary biomarker class that captures orthogonal pathophysiological information. These findings establish brain metallomics as an emerging field where artificial intelligence reveals complex multi-element interactions present in neurological aging, opening new avenues for precision medicine in age-related neurological disorders.

Bioelectronic patches have emerged as promising tools for localized and precise intracellular delivery. However, their application is limited by poor conformability and suboptimal delivery efficiency on anatomically complex organs. A recent study published in Cell introduced POCKET, a kirigami-based electrotransfection bioelectronic patch for conformable intracellular delivery on complex organ surfaces. This study establishes a universal conformality framework for maximizing organ coverage. POCKET connects nanopores to target cells, enhancing electroporation and transmembrane transport for efficient drug delivery to organs. By integrating mechanical conformality with interfacial bioelectronics, this platform enhances spatial precision and therapeutic efficacy in complex organs, promising advances in gene therapy, organ protection, and regenerative medicine.

The function of ganglioside oligosaccharides critically depends on the number, linkage, and spatial arrangement of sialic acid residues, yet direct discrimination of highly sialylated ganglioside oligosaccharides, particularly at the isomeric level, remains challenging due to their high charge density and subtle structural differences. Here, we present a nanopore-based strategy for single-molecule identification of ganglioside oligosaccharides. By engineering the sensing region of an α-hemolysin nanopore with synergistic cationic and aromatic mutations, we markedly enhance the capture of multisialylated glycans and prolong their residence within the pore. This interaction-mediated slowdown converts otherwise transient blockade events into extended trajectories containing rich molecular dynamics information. Beyond conventional blockade amplitude and dwell time descriptors, we introduce time- and spectral-domain features to characterize intraevent current fluctuations, thereby overcoming the key limitations of traditional nanopore analyses. Using this approach, we reliably discriminate 4 linkage isomers of trisialylated ganglioside glycans and accurately identify ganglioside oligosaccharides containing 3 to 5 sialic acid residues in heterogeneous mixtures. When combined with a machine-learning framework, the extracted time- and spectral-domain features enable single-level isomer identification and mixture deconvolution and remain effective even in complex biological matrices such as neural cell line and brain tissue lysates. Together, these results demonstrate that controlling analyte–pore interactions to unlock higher-order dynamical signatures enables nanopore analysis of highly sialylated ganglioside oligosaccharides, providing a general strategy for single-molecule glycan sequence elucidation in biologically relevant environments.

Lipid accumulation drives the development of atherosclerotic cardiovascular disease, the leading cause of death worldwide. The liver is the primary target for lipid-lowering therapies due to its central role in lipid metabolism. Despite advances in small-molecule drugs, substantial residual cardiovascular risk remains. Recent clinical evidence in 2026 reaffirms the “lower is better” paradigm, showing that achieving very low low-density lipoprotein cholesterol (<55 mg/dl) improves outcomes versus standard goals (<70 mg/dl). RNA-targeted therapeutics, including antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs), offer a transformative approach by durably silencing genetically validated lipid targets. Conjugation to N-acetylgalactosamine (GalNAc) enables hepatocyte-specific delivery. Examples include inclisiran (targeting proprotein convertase subtilisin/kexin type 9 [PCSK9]) and agents against apolipoprotein C-III (APOC3), lipoprotein(a) [Lp(a)], and angiopoietin-like protein 3 (ANGPTL3). Beyond protein-coding messenger RNAs (mRNAs), RNA therapeutics can also target noncoding RNAs (microRNAs and long noncoding RNAs) that regulate cholesterol homeostasis. Additionally, mRNA lipid nanoparticle-based in vivo base editing (e.g., VERVE 101/102 targeting PCSK9) has entered clinical trials, offering potential for permanent genetic correction with a single infusion. In the future, RNA-targeted therapeutics may expand beyond hepatic lipid modulation to directly target vascular lipid metabolism and plaque biology. Advances in extrahepatic delivery and rational combination regimens could transform RNA therapy from transient lipid-lowering to long-term, disease-modifying interventions. The recent 2026 American College of Cardiology/American Heart Association dyslipidemia guideline emphasizes the clinical importance of targeting PCSK9, APOC3, Lp(a), and ANGPTL3. This review provides a state-of-the-art overview of RNA-targeted therapeutics in hyperlipidemia and discusses future research directions in this emerging field.

Cellulose, the most abundant natural polymer, is a promising platform for sustainable bioplastics. However, cellulose-based bioplastics derived from macrofibers or nanocellulose still fall short of petrochemical plastics in thermal stability, mechanical performance, and processability. In this work, we systematically examine molecular-scale design strategies to bridge the gap between material properties and processing behavior, including supramolecular network reconstruction, dynamic dissipative systems, and programmable architectures. These approaches enable cellulose bioplastics with improved formability, thermal resistance, mechanical strength, and programmable responsiveness, thereby expanding their potential in aerospace, intelligent construction, high-end protective equipment, and biomedicine. Finally, we outline future research directions to accelerate the development of cellulose-based materials toward high-performance, recyclable, intelligent, and environmentally friendly applications.

Fusion oncogenes are among the most potent and clinically actionable cancer drivers, contributing to approximately 15% to 20% of human malignancies. Traditionally viewed as stable consequences of chromosomal translocations, fusion oncogenesis has long been interpreted through a DNA-centric paradigm. However, this view is now challenged by the discovery of a vast and dynamic landscape of fusion RNAs. Recent integrative genomic studies suggest that extrachromosomal DNA (ecDNA) can serve as a platform for the formation, diversification, and amplification of oncogenic fusion transcripts in multiple cancer contexts. Here, we propose the “ecDNA fusion factory” as a unifying conceptual framework that integrates nonchromosomal genome architecture, structural instability, and RNA-level regulatory consequences to expand current understanding about the origin and adaptive evolution of some fusion drivers. In this model, fusion output can be dynamic and heterogeneous, shaped by ecDNA copy-number flux and context-dependent structural remodeling rather than exclusively by a single, fixed chromosomal breakpoint. This reframing suggests distinct therapeutic vulnerabilities, potentially motivating strategies that target both the fusion oncoprotein and the ecDNA platform that sustains it, and necessitates a revision of diagnostic paradigms to detect these structurally plastic and dynamically evolving oncogenic elements. Together, this perspective broadens current models of fusion-driven oncogenesis and highlights possible implications for precision oncology.

The detection and identification of low-frequency underwater sounds remain challenging due to inefficient acoustic–mechanical–electrical coupling, which limits the conversion of low-frequency weak pressure fluctuations into stable electrical signals in conventional hydrophones. Here, we develop a capacitive hydrogel acoustic sensor (CHAS) that enhances low-frequency transduction through a micro-pyramid iontronic structure governed by dynamic electric double layer (EDL) effects. By combining the EDL-based sensing mechanism with a phase-sensitive lock-in amplification circuit providing a 40 dB gain, the system preserves weak acoustic information within the 20 to 1,000 Hz range. The sensor achieves an average sensitivity of −158.86 dB and reliably detects diverse low-frequency underwater acoustic events, including human speech, water impacts, and vessel-radiated noise. A neural network trained on the ShipsEar database yields 96.3% accuracy and, especially, maintains 89.1% accuracy when directly applied to CHAS-acquired signals without retraining, demonstrating that the iontronic sensing mechanism preserves physically meaningful acoustic features and enables reliable cross-domain intelligent analysis. This work establishes an integrated sensing framework that links iontronic device physics, circuit-level signal conditioning, and data-driven acoustic interpretation, providing a practical pathway toward intelligent low-frequency underwater acoustic monitoring and target recognition.

Platelets are traditionally recognized for their roles in hemostasis, but their involvement as active immune modulators in cutaneous neuroimmune signaling remains poorly understood. In this study, we integrated multi-modal genetic and pharmacological strategies to investigate the functional contribution of platelets to skin inflammation and chronic itch. Optogenetic activation of platelets was sufficient to elicit localized skin inflammation, erythema, and robust pruritus, with transcriptomic profiling of lesions showing strong concordance with the clinical signatures of atopic dermatitis (AD). In experimental AD models, platelet depletion markedly reduced scratching behavior, inflammatory cell infiltration, and C-fiber excitability, whereas platelet activation exacerbated these phenotypes. Mechanistically, activated platelets release serotonin [5-hydroxytryptamine (5-HT)], which compromises vascular integrity and facilitates platelet extravasation into the dermis. This “neuroimmune hub” promotes macrophage recruitment and sensitizes TRPV1⁺ pruriceptors. Transcriptomic analysis revealed that platelet-derived 5-HT drives these processes via HTR2B and HTR7 signaling. Specifically, genetic ablation of HTR2B in TRPV1⁺ neurons selectively impaired itch transmission. Furthermore, re-analysis of clinical datasets confirmed the enrichment of HTR2B and HTR7 in skin macrophage populations during inflammation. Systemic administration of HTR antagonists or the anti-platelet agent clopidogrel markedly attenuated both inflammation and pruritus across multiple models. Our findings identify the platelet–immune–neuron axis as a key driver of cutaneous dysfunction and a promising therapeutic target for chronic inflammatory skin disorders.

Although predatory behaviors are evolutionarily conserved, they can be enhanced through experience-dependent plasticity. While vibrissal somatosensation is recognized as a key mediator of hunting behavior, the mechanism underlying vibrissal somatosensory-mediated predatory hunting learning remains not yet well understood. In this study, we report that vibrissal tactile input plays an essential role in hunting learning. Activation of the vGlut1⁺ S1BF–SC pathway is sufficient to evoke predatory hunting, while its inactivation abolished practice-induced behavioral improvements. SC-projecting vGlut1⁺ S1BF neurons exhibited robust responses to whisker mechanosensory stimulation. Furthermore, hunting training selectively enhanced α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptormediated excitatory transmission in the vGlut1⁺ S1BF–SC pathway. Together, these data reveal the corticotectal neural circuit from the primary somatosensory cortex to superior colliculus that was specifically engaged in vibrissal somatosensory-mediated hunting learning by strengthening synaptic connections.

Acute-phase neuroinflammation and early brain injury progressing rapidly is responsible for substantial severity and mortality in subarachnoid hemorrhage (SAH). While cohort studies have confirmed that aerobic exercise (AE) was associated with decreased short-term mortality, its precise mechanisms remain elusive. We employed a murine SAH model subjected to preconditioning AE to validate the above hypothesis, combining early neurological function assessment and histological staining. Whole-transcriptome profiling and single-cell RNA sequencing were performed to capture differentially expressed genes and to delineate subtype-specific differentiation. To recapitulate the neuroimmune crosstalk in vitro, we established a primary neutrophil–microglia coculture system. Targeted receptor–ligand interaction studies were employed to validate the specific environmental variables driving their synergistic activation. Our data indicated that AE significantly ameliorated neurological outcomes, cerebral edema, and neuronal apoptosis post-SAH. Sequencing data identified classical pro-inflammatory M1-like microglia, alongside a novel early-response microglial subset characterized by high expression of transforming growth factor beta 1; both populations were regulated by AE for modulating neuroinflammation and significantly correlated with infiltrating neutrophil counts. This crosstalk was mediated by mature neutrophil-derived leucine-rich alpha-2-glycoprotein 1 (Lrg1), which differentially activated the microglial transforming growth factor beta signaling pathway. Collectively, AE-mediated suppression of neutrophil infiltration rebalanced microglial differentiation, thereby attenuating neuroinflammation following SAH. We identified Lrg1 as a key immune mediator in this process, highlighting exercise-induced reprogramming at the receptor level as a potential therapeutic strategy for SAH.

Accurate prediction of pathological complete response (pCR) to neoadjuvant therapy in luminal breast cancer remains challenging, hindering precise treatment decisions. Here, we present the Lumi-Guide system, a novel multimodal framework that integrates deep-learning-based MRI analysis with clinical and genomic data to enable personalized treatment selection. In this multicenter study, we analyzed 1,097 patients with luminal breast cancer from 6 international datasets. We developed a Swin Transformer-based Lumi-I model using 3-plane dynamic contrast-enhanced MRI data and integrated it with clinical factors to construct the Lumi-CI model, which demonstrated robust performance across the validation and 2 external test sets, with areas under the receiver operating characteristic curves of 0.810, 0.819, and 0.864, respectively. Radiogenomic analysis revealed distinct biological characteristics: The Lumi-I high-score group exhibited immunologically active and proliferative microenvironments, while the low-score group showed estrogen-response-driven signaling. To further enhance predictive accuracy, a genomic model (Lumi-G) based on 22 established RNA biomarkers was further developed and integrated with the Lumi-CI model to create a multimodal Lumi-CIG model. We subsequently designed a Lumi-Guide 2-step triage system that prioritizes clinical-imaging information (Lumi-CI) while selectively incorporating genomic data (Lumi-CIG) when beneficial, thus optimizing resource allocation. Critically, by integrating Lumi-Guide system prestratification with response-predictive-subtype-recommended therapies, patients predicted to achieve pCR demonstrated substantially higher actual pCR rates than controls across 3 treatment patterns: 77.8% vs. 61.5% (optimal treatment), 57.6% vs. 24.7% (non-optimal treatment), and 35.3% vs. 4.7% (double-negative response-predictive subtype). This clinically practical and biologically interpretable framework transforms personalized neoadjuvant therapy in luminal breast cancer into a scalable reality.