Foxp3⁺ regulatory T (T_reg) cells, as one of the subtypes of CD4⁺ T cells, are the crucial gatekeeper in the pathogenesis of self-antigen reactive diseases. In this context, we demonstrated that the selective ablation of early growth response gene 1 (Egr-1) in CD4⁺ T cells exacerbated experimental autoimmune encephalomyelitis (EAE) in murine models. The absence of Egr-1 in CD4⁺ T cells, obtained from EAE mice and naïve CD4⁺ T cells, impeded the differentiation and influence of T_reg. Importantly, in CD4⁺ T cells of multiple sclerosis patients, both Egr-1 and Foxp3 were found to decrease. Further studies showed that distinct from the classical Smad3 route, TGF-β could activate Egr-1 through the Raf–Erk signaling route to promote Foxp3 genetic modulation, thereby promoting T_reg cell differentiation and reducing EAE inflammation. A novel natural Egr-1 agonist, calycosin, was found to attenuate EAE progression by regulating the differentiation of T_reg. Together, the above results indicate the value of Egr-1, as a novel Foxp3 transactivator, for the differentiation of T_reg cells in the development of self-antigen reactive diseases.

Sepsis, a life-threatening inflammatory disorder characterized by multiorgan failure, arises from a dysregulated immune response to infection. Modulating macrophage polarization has emerged as a promising strategy to control sepsis-associated inflammation. The endogenous metabolite itaconate has shown anti-inflammatory potential by suppressing the stimulator of interferon genes (STING) pathway, but its efficacy is inhibited by hyperactive glycolysis, which sustains macrophage overactivation. Here, we revealed a critical crosstalk between the itaconate–STING axis and glycolysis in macrophage-mediated inflammation. Building on this interplay, we developed a novel nanoparticle LDO (lonidamine disulfide 4-octyl-itaconate), a self-assembled metabolic regulator integrating an itaconate derivative with the glycolysis inhibitor Lonidamine. By concurrently targeting glycolysis and STING pathways, LDO reprograms macrophages to restore balanced polarization. In sepsis models, LDO effectively attenuates CCL2-driven cytokine storms, alleviates acute lung injury, and significantly enhances survival via metabolic reprogramming. This study offers a cytokine-regulatory strategy rooted in immunometabolism, providing a foundation for the translational development of immune metabolite-based sepsis therapies.

Bariatric surgery has emerged as a promising intervention for obese women with polycystic ovary syndrome (PCOS), a condition strongly associated with obesity and anovulatory infertility. While weight management is a key therapeutic strategy, the optimal approach remains uncertain. A recent randomized controlled trial evaluated the impact of bariatric surgery on ovulation rates in obese women with PCOS. However, methodological limitations, including baseline body mass index discrepancies and minimal weight loss in the medical management group, necessitate cautious interpretation of the findings. To further investigate this issue, we conducted a prospective cohort study involving 192 women with PCOS who had undergone bariatric surgery. We assessed 30 reproductive and metabolic parameters at baseline and at 3, 6, and 12 months postoperatively. Most metabolic parameters improved significantly by 3 months postsurgery but plateaued thereafter, with only triglycerides and high-density lipoprotein cholesterol showing continued improvement. Reproductive outcomes demonstrated sustained improvements in ovulatory dysfunction, coinciding with a reduction in luteinizing hormone levels. However, testosterone levels and polycystic ovarian morphology showed limited improvement, while anti-Müllerian hormone levels remained unchanged. Despite the total weight loss exceeding 30%, further weight reduction did not proportionally enhance outcomes. These findings suggest that while bariatric surgery effectively improves metabolic health and ovulation in PCOS, its long-term hormonal and ovarian effects remain unclear and require further investigation. Head-to-head comparisons with emerging therapies are also urgently needed to refine weight management strategies for this high-risk population.

The convergence of the Metaverse and the Internet of Things (IoT) paves the way for extensive data interaction between connected devices and digital twins; however, this simultaneously introduces considerable cybersecurity threats, including data breaches, ransomware, and device tampering. Existing intrusion detection algorithms struggle to effectively defend against emerging cyberattacks in the rapidly evolving Metaverse environment. Designing effective neural networks for intrusion detection algorithms relies heavily on expert experience, making the manual process time-consuming and often yielding suboptimal results. This paper addresses a critical gap in cybersecurity for Metaverse devices, which are often overlooked in traditional detection methods, and proposes an adaptive multiobjective evolutionary generative adversarial network (AME-GAN) as a novel, scalable solution for optimizing network intrusion detection. An inversely proportional hybrid attention-based long short-term memory GAN is proposed, combining GANs to generate minority class samples and alleviate the imbalance problem in training datasets, which has long hindered accurate intrusion detection. Additionally, an adaptive evolutionary neural architecture search algorithm for the supernet of the GAN is designed to guide the mutation direction of the supernet, enhancing the training stability. This paper further introduces a double mutation multiobjective evolutionary neural architecture search algorithm, integrating both the multiobjective evolutionary algorithm and the neural architecture search to optimize accuracy, real-time performance, and model diversity—a crucial aspect for Metaverse devices with diverse hardware constraints. Experiments conducted on 3 well-known datasets—NSL-KDD, UNSW-NB15, and CIC-IDS2017—demonstrate that AME-GAN outperforms state-of-the-art approaches, with improvements of 0.32% in accuracy, 0.31% in F1 score, 0.47% in precision, and 0.37% in recall. This paper offers a promising, adaptive framework to enhance cybersecurity in the Metaverse, improving detection performance and real-time applicability, and contributing to the future of network intrusion detection in next-generation digital environments.

Stimuli-responsive materials have shown promising applications in the areas of sensing, bioimaging, information encryption, and bioinspired camouflage. In particular, multi-stimuli-responsive materials represent a hot topic due to their modulated properties under multiple stimuli. Herein, we successfully developed multi-stimuli-responsive inks and a series of complex multi-stimuli-responsive 3-dimensional (3D) structures were fabricated via digital light processing 3D-printing technology. Notably, these complex 3D structures show shape memory, fast-response photochromic and thermochromic behavior, and excellent repeatability due to the combination of photochromic molecules (4-(2,2-bis(4-fluorophenyl)vinyl) benzyl methacrylate) and thermochromic pigments. Furthermore, a programmable encrypted box that changes colors and morphology by controlling temperature and ultraviolet irradiation was designed and printed, and this encrypted box exhibits strong security using OpenCV-based image recognition technology. This strategy provides a promising approach for the design of multi-stimuli-responsive materials and complex encryption systems in the future.

Facial masks are often used to treat skin problems, and the introduction of microcurrent ion penetration technology can improve drug penetration and help facial tissue repair. However, most microcurrent stimulation masks contain a direct current power supply and require external power sources, resulting in inconvenient portability and use. Herein, we provide a noninvasive self-powered iontophoresis mask with a water-driven power supply, which is continuously prepared by self-constructing equipment to continually construct a zinc–manganese fiber battery (Zn-Mn@FB) and then seamlessly integrated with a nonwoven cellulose-based superabsorbent fiber substrate. The mask can be activated by water and is simple and portable to use. Zn-Mn@FB demonstrated a capacitance retention of 65.22% (1,000 cycles) and a specific discharge capacity of 27.33 mAh/g (10 cm), which improved with an increase in battery length to up to 41 mAh/g (30 cm). The iontophoresis mask exhibited a stable current within the safe range of 0.09 to 0.59 mA (within 800 s) after water activation, and the drug penetration area increased by 102.64%. The platform is expected to become a practical device for enhanced transdermal drug delivery in the medical field, with the potential to integrate additional components for expanded functionality and productization in the future.

Hydrogel microparticles that can effectively deliver mesenchymal stem cells (MSCs) are expected to accelerate wound repair progress. Attempts in the area are focusing on improving the functions of the microparticles and MSCs to promote the therapeutic effect. Here, inspired by the topological morphology of ice branches, we propose novel freeze-derived anisotropic porous microparticles for hepatocyte growth factor (HGF)-overexpressing MSCs (MSCs^HGF) loading and wound healing. The microparticles were fabricated by introducing microfluidic methacrylated gelatin pre-gel droplets into low-temperature silicone oil, followed by photo-cross-linking and freeze-drying processes. Drawing an advantage from the biocompatible chemical composition and the structured pore arrangement of the microparticles, MSCs^HGF can be efficiently encapsulated and released, maintaining continuous HGF secretion to enhance cell migration and support vascular regeneration. Leveraging these characteristics, we have shown that MSCs^HGF-loaded porous microparticles could substantially promote angiogenesis, polarize macrophages toward the M2 phenotype, and reduce inflammation during the wound repair process, consequently enhancing skin wound repair efficiency. Thus, we believe that our MSCs^HGF-integrated freeze-derived anisotropic porous microparticles hold promising prospects for clinical wound-healing applications.

Pulmonary arterial hypertension (PAH) is a devastating disease characterized by perivascular inflammation, immune dysregulation, and vascular remodeling. Recent studies have unveiled a potential link between the gut microbiome and PAH pathogenesis, suggesting that microbial dysbiosis and increased intestinal permeability may contribute to the inflammatory pathology in PAH and ultimately disease progression. This perspective highlights the emerging evidence of the role of leaky gut in PAH, the interplay between microbiota-induced immune responses, and the activation of endogenous retroviruses like human endogenous retrovirus K. Understanding these complex interactions opens new interdisciplinary avenues for research and therapeutic interventions, potentially transforming PAH management through microbiome-targeted strategies.

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, and addressing its intrinsic heterogeneity has emerged as a valuable avenue for novel clinical treatment strategy. Here, we put forward an innovative strategy for TNBC treatment by simultaneously suppressing both p21-activated kinase 1 (PAK1) and histone deacetylase (HDAC) class IIb (HDAC6/10). A series of pyrido [2,3-d]pyrimidin-7(8H)-one moiety derivatives was successfully designed and synthesized to target PAK1/HDAC6/HDAC10 by utilizing structure-based screening and pharmacophore integration. ZMF-25 demonstrates marked inhibitory activity against PAK1, HDAC6, and HDAC10 with respective IC₅₀ values of 33, 64, and 41 nM, remarkable selectivity over HDACs and PAKs, as well as prominent antiproliferative efficiency in MDA-MB-231 cells. Additionally, ZMF-25 effectively suppresses TNBC proliferation and migration by inhibiting PAK1/HDAC6/HDAC10. Moreover, it was found to impair glycolysis and trigger reactive oxygen species generation, resulting in autophagy-related cell death by inhibiting the AKT/mTOR/ULK1 signaling. Furthermore, ZMF-25 exhibits remarkable therapeutic potential with no obvious toxicity in vivo and good pharmacokinetics. In summary, these observations indicate that ZMF-25 is a novel and potent triple-targeting PAK1/HDAC6/HDAC10 inhibitor, which is expected to provide a novel and effective strategy for TNBC treatment.

High-grade lung neuroendocrine carcinomas (Lu-NECs) are clinically refractory malignancies with poor prognosis and limited therapeutic advances. The biological and molecular features underlying the histological heterogeneity of Lu-NECs are not fully understood. In this study, we present a multi-omics integration of whole-exome sequencing and deep proteomic profiling in 93 Chinese Lu-NECs to establish the first comprehensive proteogenomic atlas of this disease spectrum. Our analyses revealed a high degree of mutational concordance among the subtypes at the genomic level; however, distinct proteomic profiles enabled a clear differentiation of histological subtypes, unveiling subtype-specific molecular and biological features related to tumor metabolism, immunity, and proliferation. Furthermore, RB1 mutations confer divergent prognostic effects through subtype-specific cis- and trans-proteomic regulation. In addition, we identified potential protein biomarkers for histological subtype classification and risk stratification, which were validated by immunohistochemistry in an independent cohort. This study provides a valuable proteogenomic resource and insight into Lu-NEC heterogeneity.