《Research》前沿速递：肝纤维化、癌症风险与脑损伤修复新发现！

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刊物介绍

ISSN：2096-5168 

eISSN： 2639-5274

国内刊号：CN 10-1541/N

刊物官网：

https://spj.sciencemag.org/research/

《Research》是中国科协与美国科学促进会于2018年共同创办的定位为国际化、高影响力、世界一流水平、综合性、大型OA科技期刊，是美国《Science》自1880年创刊以来第一本合作期刊。主要发表先进能源、先进制造、先进材料、人工智能、环境科学、柔性电子、健康科学、信息科学、微纳科技、量子信息、空间科学，11个热点交叉领域突破性原创研究成果。主编(中国)为中国科协副主席，中国科学院院士包为民，主编(国际)为美国明尼苏达大学麦克凯特杰出教授崔天宏。第二届编委会由许宁生、高松、黄如、李兰娟、饶子和、俞书宏、崔铁军等国内外60余位院士在内的170位编委组成。已被CAS、CNKI、CSCD、DOAJ、EI、SCIE、INSPEC、PMC、Scopus、SAO/NASA Astrophysics Data System数据库收录。

Contents

1.Scoparone-Induced Phase Separation of ZDHHC12 Drives Ferroptosis via ATG12 S-palmitoylation and Ferritinophagy in Liver Fibrosis/Scoparone诱导的ZDHHC12相分离通过ATG12 S-棕榈酰化和铁蛋白吞噬在肝纤维化中驱动铁死亡

双语摘要：

Activated hepatic stellate cells (HSCs) are central effectors of liver fibrogenesis, and their selective elimination is critical for fibrosis regression. Although ferroptotic clearance of HSCs has emerged as a promising antifibrotic strategy, the upstream mechanisms coupling metabolic remodeling to ferroptosis susceptibility remain unclear. This study investigated whether scoparone (SCO) suppresses liver fibrosis through zinc finger DHHC-type palmitoyltransferase 12 (ZDHHC12) condensate formation, leading to enhanced autophagy-related protein 12 (ATG12) S-palmitoylation, induction of autophagy, and increased ferroptosis susceptibility in HSCs. We found that SCO restrained cell proliferation, migration, and fibrogenic activation while inducing iron overload, lipid peroxidation, glutathione depletion, and ferroptosis-like mitochondrial remodeling. Metabolomic and S-palmitoylation analyses linked these effects to increased palmitic acid levels and enhanced global protein S-palmitoylation. ZDHHC12 emerged as a SCO-responsive palmitoyltransferase associated with autophagy activation, ferritin turnover, ferroptosis induction, and repression of fibrogenic markers. Mechanistically, SCO promoted the formation of liquid-like ZDHHC12 condensates, which enhanced its interaction with ATG12 and facilitated ATG12 S-palmitoylation at the conserved Cys134 residue. This modification was associated with increased ATG12 stability through reduced ubiquitin-dependent proteasomal degradation, thereby promoting autophagy activation and increasing ferroptosis susceptibility in HSCs. Mutation of ATG12 at Cys134 attenuated these effects and diminished HSC ferroptosis. In cholestatic and toxic models of liver fibrosis, SCO alleviated liver injury and collagen deposition, whereas HSC-targeted silencing of ZDHHC12 or ATG12 attenuated these protective effects, supporting biological consistency in vivo. Integrated bioinformatic and clinical cohort analyses suggested that ZDHHC12 expression positively correlated with ATG12 expression and was associated with fibrosis progression in patients with liver fibrosis. Collectively, these findings support a ZDHHC12-dependent ATG12 S-palmitoylation pathway linking lipid metabolic remodeling to autophagy-mediated ferroptosis in HSCs and suggest phase-regulated S-palmitoylation as a potential antifibrotic target.

活化肝星状细胞（HSCs）是肝纤维化的主要效应细胞，其选择性消除对于纤维化逆转至关重要。尽管铁死亡清除HSCs已成为一种有希望的抗纤维化策略，但将代谢重塑与铁死亡易感性耦合的上游机制尚不清楚。本研究调查了 scoparone（SCO）是否通过锌指DHHC型棕榈酰转移酶12（ZDHHC12）凝聚体形成抑制肝纤维化，导致增强自噬相关蛋白12（ATG12）S-棕榈酰化，诱导自噬，并增加HSCs的铁死亡易感性。我们发现SCO抑制细胞增殖、迁移和纤维化激活，同时诱导铁负荷、脂质过氧化、谷胱甘肽耗竭和铁死亡样线粒体重塑。代谢组和S-棕榈酰化分析将这些效应与棕榈酸水平升高和全局蛋白S-棕榈酰化增强联系起来。ZDHHC12作为一种SCO响应的棕榈酰转移酶，与自噬激活、铁蛋白周转、铁死亡诱导和纤维化标记物抑制相关。机制上，SCO促进类似液体的ZDHHC12凝聚体形成，增强了其与ATG12的相互作用，并促进了ATG12在保守的Cys134残基处的S-棕榈酰化。这种修饰与ATG12稳定性的增加有关，通过减少泛素依赖性蛋白酶体降解，从而促进自噬激活并增加HSCs的铁死亡易感性。ATG12在Cys134处的突变减弱了这些效应并减少了HSC铁死亡。在胆汁淤积和毒性肝纤维化模型中，SCO减轻了肝损伤和胶原沉积，而ZDHHC12或ATG12的HSC靶向沉默减弱了这些保护作用，支持体内生物一致性。整合生物信息学和临床队列分析表明，ZDHHC12表达与ATG12表达呈正相关，并与肝纤维化患者的纤维化进展相关。总之，这些发现支持ZDHHC12依赖的ATG12 S-棕榈酰化途径，将脂质代谢重塑与HSCs中自噬介导的铁死亡联系起来，并建议阶段调节的S-棕榈酰化作为潜在的抗纤维化靶点。

2.Geometry–Mechanics Compatibility Enables Interpretable Inverse Design of Non-Rigid Origami/几何-力学兼容性实现非刚性折纸的可解释逆向设计

双语摘要：

Non-rigid origami offers a geometric route to programmable mechanical and kinematic functions in metamaterials, deployable structures, and robotic mechanisms. Yet, its inverse design remains constrained by a fundamental modeling dilemma: High-fidelity nonlinear simulations become prohibitively expensive when repeatedly applied across large design spaces, whereas reduced models are efficient but often rely on pattern-specific assumptions whose validity is difficult to assess across crease patterns. Here, we introduce a compatibility-guided inverse-design framework that uses a geometry–mechanics test to determine when a parameterized design family can be reliably represented by a single-degree-of-freedom (1-DOF) kinematic model. Once qualified, the reduced model enables rapid and interpretable exploration of the admissible design space, while incompatible cases remain evaluated using high-fidelity analysis. We demonstrate the framework by designing origami metamaterials with programmable multistability and multi-plateau mechanical responses, enabled by the identification and removal of key geometric constraints. Its broader applicability is further illustrated through target-shape morphing and task-specific robotic motion programming. By turning model reduction from an assumed approximation into an explicit design decision, this framework provides a geometry-driven route from target functions to manufacturable non-rigid origami while reducing reliance on simulation-intensive search.

非刚性折纸为超材料、可展开结构和机器人机构中的可编程机械和运动学功能提供了一种几何途径。然而，其逆向设计仍然受到一个基本建模困境的限制：当在大设计空间中反复应用时，高保真非线性模拟变得过于昂贵，而简化模型虽然高效，但通常依赖于特定图案的假设，这些假设在折痕图案中的有效性难以评估。在这里，我们介绍了一种兼容性引导的逆向设计框架，该框架使用几何-力学测试来确定何时一个参数化设计族可以可靠地由一个单自由度（1-DOF）运动学模型表示。一旦合格，简化模型能够快速且可解释地探索允许的设计空间，而不兼容的情况则继续使用高保真分析进行评估。我们通过设计具有可编程多稳定性和多平台机械响应的折纸超材料来演示该框架，这些响应是通过识别和去除关键几何约束实现的。其更广泛的应用通过目标形状变形和特定任务机器人运动编程进一步说明。通过将模型简化从假设近似转变为显式设计决策，该框架提供了一种从目标函数到可制造的非刚性折纸的几何驱动途径，同时减少了依赖于密集模拟搜索的依赖。

3.Waste-to-Treasure: Nanozyme-Integrated Photocatalytic Microneedles Reconfigure Diabetic Burn Wounds via Endogenous Glucose-to-H2 Conversion and Adaptive Hydrogel Scaffolding/废物变宝：纳米酶集成光催化微针通过内源性葡萄糖到H2的转化和自适应水凝胶支架重新配置糖尿病烧伤伤口

双语摘要：

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 (HO), leading to secondary oxidative injury. In this study, we developed a metabolism-driven microneedle platform (MN-PCN) by integrating photocatalytic Pt@Pd-PCN222-NH (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 (H) evolution, effectively suppressing the AGEs/receptor for AGEs signaling axis. Critically, the MN-PCN system actively scavenges catalytic HO 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.

糖尿病烧伤创面的顽抗性根植于一种敌对的微环境，其特征为葡萄糖、晚期糖基化终产物（AGEs）和活性氧种类的病理性过剩。标准的酶促和光催化干预通常受到不稳定或过氧化氢（HO）毒性积累的限制，导致继发性氧化损伤。在本研究中，我们通过将光催化Pt@Pd-PCN222-NH（PCN）整合到一种自我调节、抗菌和抗氧化、具有高度抗水性粘附性的水凝胶基质中，开发了一种代谢驱动的微针平台（MN-PCN）。采用废物变宝的逻辑，该系统利用内源性葡萄糖作为主要还原剂，以促进持续的氢（H）析出，有效抑制AGEs/AGEs受体信号轴。关键的是，MN-PCN系统通过PCN位点协同的过氧化氢酶模拟活性和抗氧化水凝胶基质，积极清除催化HO副产物和环境活性氧种类，从而避免氧化损伤。同时，微针结构在与创面渗出物接触时发生原位转变为保护性水凝胶，建立了一个最小化感染并促进细胞浸润的物理屏障。通过中和炎症回路和加速血管化，MN-PCN恢复了生理和结构平衡。这种综合策略通过系统、代谢驱动的微环境重新配置，为复杂伤口管理提供了一个复杂的框架。

4.Benign Uroandrological Ecosystem: A Thorough Overview from Single-Cell and Spatial Transcriptomics/良性泌尿生殖生态系统：单细胞和空间转录组学的全面概述

双语摘要：

Benign urological and andrological diseases (BUADs) represent common yet complex clinical challenges, where the diversity and dynamic nature of their microenvironments substantially influence disease onset and progression. In recent years, the emergence of single-cell RNA sequencing (scRNA-seq) and spatially resolved transcriptomic (SRT) technologies has provided unprecedented insights into the cellular heterogeneity and spatiotemporal architecture of these disease microenvironments. This review outlines current applications of scRNA-seq and SRT in BUADs, with a focus on their utility in mapping cell–cell interactions, uncovering pathological mechanisms, and prioritizing therapeutic targets. Across the upper urinary tract, prostate, bladder, urethra, and male reproductive organs, single-cell analyses reveal that parenchymal cell dysfunction and microenvironmental remodeling are the core pathological processes of disease progression. This review also discusses the limitations of scRNA-seq/SRT and the existing challenges of current research methods and paradigms in BUADs and outlines future research directions and integrative strategies to facilitate clinical translation and precision medicine. Collectively, these up-to-date findings not only deepen the understanding of the microenvironment in BUADs but also provide a scientific foundation for the development of novel therapeutic strategies.

良性泌尿和男性生殖系统疾病（BUADs）代表了常见但复杂的临床挑战，其中其微环境的多样性和动态性质在很大程度上影响了疾病的发病和进展。近年来，单细胞RNA测序（scRNA-seq）和空间分辨转录组学（SRT）技术的出现为这些疾病微环境的细胞异质性和时空结构提供了前所未有的见解。本综述概述了scRNA-seq和SRT在BUADs中的当前应用，重点关注它们在绘制细胞间相互作用、揭示病理机制和优先考虑治疗靶点方面的效用。在整个上尿路、前列腺、膀胱、尿道和男性生殖器官中，单细胞分析揭示了实质细胞功能障碍和微环境重塑是疾病进展的核心病理过程。本综述还讨论了scRNA-seq/SRT的局限性以及当前研究方法和范式在BUADs中存在的挑战，并概述了未来研究方向和整合策略，以促进临床转化和精准医学。总的来说，这些最新的发现不仅加深了对BUADs微环境的理解，还为开发新的治疗策略提供了科学基础。

5.Association of Circadian Syndrome with Incident Risk of 23 Site-Specific Cancers: A Large-Scale Prospective Study in the UK Biobank/昼夜节律综合征与23种特定部位癌症事件风险的相关性：英国生物库的一项大规模前瞻性研究

双语摘要：

Circadian disruption and metabolic dysfunction are linked to chronic disease, but whether circadian syndrome, which combines metabolic, sleep, and mood traits, relates to overall and site-specific cancer risk remains unclear. We prospectively studied 367,832 cancer-free participants in the UK Biobank, of whom 82,547 (22.4%) had circadian syndrome, defined by at least 4 of 7 features: abdominal obesity, high triglycerides, low levels of high-density lipoprotein cholesterol, high blood pressure, impaired glucose regulation, short sleep, and depression. Associations with overall cancer and 23 site-specific cancers were evaluated using Cox proportional-hazards and competing-risk models, with additional dose–response, biomarker, and population-burden analyses. During follow-up, 47,695 participants developed cancer. Circadian syndrome was associated with a higher incidence of overall cancer (hazard ratio [HR], 1.12; 95% confidence interval [CI], 1.10 to 1.14). The strongest positive associations were observed for endometrial cancer (HR, 1.88; 95% CI, 1.71 to 2.08), liver cancer (HR, 1.67; 95% CI, 1.47 to 1.89), and kidney cancer (HR, 1.55; 95% CI, 1.41 to 1.70). Findings remained similar after accounting for death from other causes and across sensitivity analyses, whereas inverse associations for prostate and brain cancers were exploratory. Sex-hormone-binding globulin statistically accounted for 51.0% of the endometrial cancer association, and C-reactive protein accounted for 26.4% of the overall cancer association. The highest population-attributable fractions were estimated for endometrial (13.5%) and liver cancers (13.4%). Circadian syndrome may help identify populations at increased cancer risk and inform prevention strategies integrating circadian and metabolic health.

昼夜节律紊乱和代谢功能障碍与慢性疾病有关，但昼夜节律综合征，即结合代谢、睡眠和情绪特征的综合征，是否与总体和特定部位的癌症风险相关尚不清楚。我们前瞻性地研究了英国生物样本库中的367,832名无癌症参与者，其中82,547人（22.4%）患有昼夜节律综合征，定义为至少有7个特征中的4个：腹部肥胖、高甘油三酯、低高密度脂蛋白胆固醇水平、高血压、葡萄糖调节受损、睡眠时间短和抑郁。使用Cox比例风险模型和竞争风险模型评估了与总体癌症和23个特定部位癌症的相关性，并进行了额外的剂量-反应、生物标志物和人群负担分析。在随访期间，47,695名参与者患上了癌症。昼夜节律综合征与总体癌症发病率较高相关（风险比[HR]，1.12；95%置信区间[CI]，1.10至1.14）。最强的正相关出现在子宫内膜癌（HR，1.88；95% CI，1.71至2.08）、肝癌（HR，1.67；95% CI，1.47至1.89）和肾癌（HR，1.55；95% CI，1.41至1.70）。在考虑其他原因导致的死亡和敏感性分析后，结果保持相似，而前列腺癌和脑癌的负相关性是探索性的。性激素结合球蛋白在子宫内膜癌关联中统计上解释了51.0%，C反应蛋白在总体癌症关联中解释了26.4%。子宫内膜癌和肝癌的归因人群比例最高，分别为13.5%和13.4%。昼夜节律综合征可能有助于识别癌症风险增加的人群，并为整合昼夜和代谢健康的预防策略提供信息。

6.Polymer Separators and Solid Polymer Electrolytes for Lithium-Metal Batteries/聚合物隔膜和固态聚合物电解质用于锂金属电池

双语摘要：

Rhythm perception enables humans to navigate dynamic environments. The auditory system is particularly adept at processing rhythmic temporal structure, and auditory training exerts a greater influence than visual training on visual rhythm perception, leading to the hypothesis that auditory coding may support visual rhythm representation. This raises a fundamental question: whether and to what extent the deprivation of auditory coding capabilities influences visual rhythm processing. To investigate this issue, we assessed cortical tracking of hierarchical visual rhythms in hearing and early deaf participants using electroencephalography (EEG). Participants viewed 2 types of rhythmic sequences: geometric shapes and point-light walkers. Each stimulus type consists of a lower-order basic rhythm defined by stimulus recurrence and a higher-order chunk rhythm built on perceptual or cognitive organization. Results showed that hearing participants exhibited robust cortical tracking of both basic and chunk rhythms across stimuli. In contrast, deaf participants exhibited preserved tracking of basic rhythms but reduced tracking of chunk rhythms. Moreover, compared with the hearing group, the deaf group showed reduced visual–auditory and visual–frontal functional connectivity, and individual differences in connectivity strength were positively correlated with chunk-rhythm tracking. These findings support a hierarchical auditory scaffolding framework, in which auditory experience is selectively associated with higher-order visual rhythm perception through temporal chunking mechanisms.

节奏感知使人类能够导航动态环境。听觉系统特别擅长处理节奏性时间结构，听觉训练对视觉节奏感知的影响大于视觉训练，这导致了一个假设：听觉编码可能支持视觉节奏表征。这引发了一个基本问题：听觉编码能力的剥夺在多大程度上以及是否会影响视觉节奏处理。为了研究这个问题，我们使用脑电图（EEG）评估了听力和早期聋参与者对层次视觉节奏的皮层追踪。参与者观看了两种类型的节奏序列：几何形状和点光行人。每种刺激类型由一个低阶基本节奏组成，该节奏由刺激的重复性定义，以及一个基于感知或认知组织的更高阶块节奏。结果显示，听力参与者对刺激中的基本和块节奏都表现出强大的皮层追踪。相比之下，聋参与者对基本节奏的追踪保持不变，但对块节奏的追踪减少。此外，与听力组相比，聋组在视觉-听觉和视觉-额叶功能连接方面表现出减少，并且连接强度的个体差异与块节奏追踪呈正相关。这些发现支持了一个层次听觉支撑框架，其中听觉经验通过时间块机制选择性地与更高阶视觉节奏感知相关联。

The gene mutations are marked risk factors for autism spectrum disorder, one of the neurodevelopmental disorders (NDDs) that often extends into adulthood and has a complex etiology involving genetic and environmental factors. encodes 2 major isoforms, AnkB-220 (220-kDa isoform of ankyrin-B) and giant AnkB-440. We previously generated a targeted knockout (KO) of giant AnkB-440 in 2 cynomolgus and 2 rhesus monkeys. While no autism-spectrum-disorder-like phenotypes were observed during infancy, we found marked brain volume loss. In this study, we conducted a longitudinal multimodal study in these giant KO monkeys during adolescent and young adulthood. Behavioral results from these giant KO monkeys revealed increased locomotor activity, deficient cognition (including working memory, cognitive flexibility, and operant lever-press learning), and impaired emotional regulation and social interaction. Furthermore, the giant KO monkeys exhibited persistent structural and functional brain abnormalities, up-regulation of brain triglyceride and glycerophospholipids, and peripheral blood transcriptome signatures of immune dysregulation, which may be related to their behavioral alternations. These observations suggest that giant depletion in non-human primates phenocopies aspects of behavioral, neural, and molecular features characteristic of NDDs. This study provides an in-depth exploratory longitudinal characterization of giant functions in primate brains, which may contribute to translational research on NDDs.

基因突变是自闭症谱系障碍的标志风险因素，自闭症谱系障碍是一种神经发育障碍（NDDs），通常延续至成年，其病因复杂，涉及遗传和环境因素。编码2种主要异构体，AnkB-220（ankyrin-B的220-kDa异构体）和巨型AnkB-440。我们之前在2只猕猴和2只狨猴中生成了一种针对巨型AnkB-440的靶向敲除（KO）。尽管在婴儿期没有观察到自闭症谱系障碍样表型，但我们发现了显著的脑体积减少。在本研究中，我们在这些巨型KO猴子青春期和年轻成年期进行了一项纵向多模式研究。这些巨型KO猴子的行为结果显示，运动活动增加，认知能力缺陷（包括工作记忆、认知灵活性和操作性杠杆按压学习），以及情绪调节和社会互动受损。此外，巨型KO猴子表现出持续的结构和功能脑部异常，脑甘油三酯和甘油磷脂上调，以及免疫失调的外周血转录组特征，这些可能与它们的行为改变有关。这些观察结果表明，非人灵长类动物中巨型的缺失模拟了NDDs的特征行为、神经和分子特征。本研究对灵长类大脑中巨型功能进行了深入的探索性纵向描述，可能有助于NDDs的转化研究。

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.

骨生成与破骨细胞生成之间的不平衡是原发性骨质疏松的基本病理特征；然而，同时促进骨形成和抑制骨吸收的安全且经济的疗法却缺乏。鉴于run-related转录因子2和核因子κB通路在骨重塑中的核心作用，我们对食品药品监督管理局批准的药物库进行了表型筛选，以识别骨稳态的双效调节剂，并确定了口服抗凝剂达比加群（DAB）作为一种新型候选药物。在体内，DAB给药显著减轻了去卵巢和老龄骨质疏松小鼠模型的骨丢失并保留了骨微结构。在体外，DAB不仅抑制了核因子κB配体激活剂诱导的骨髓来源巨噬细胞的破骨细胞生成，而且还直接增强了骨髓间充质干细胞的成骨分化。机制上，利用限性蛋白水解-耦合质谱分析，我们确定了蛋白激酶腺苷酸单磷酸激活的非催化亚基β1和v-Rel网状内皮细胞病毒癌基因同源物A为DAB的直接靶点。在骨髓间充质干细胞中，DAB通过丙氨酸-77残基与蛋白激酶腺苷酸单磷酸激活的非催化亚基β1结合，导致腺苷酸单磷酸激活蛋白激酶激活，随后抑制mTOR复合物1，增强自噬通量，最终促进成骨；在破骨细胞前体中，DAB与v-Rel网状内皮细胞病毒癌基因同源物A在精氨酸-50处相互作用，导致核因子κB通路抑制和破骨细胞分化减弱。总之，我们的研究结果将DAB重新定位为恢复成骨细胞-破骨细胞平衡和维持骨骼稳态的潜在治疗候选药物，同时建立了一种新的单分子、双靶点药理学策略，并为骨代谢疾病治疗提供了新的机制见解。

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 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.

转化生长因子-β1（TGF-β1）/Smad3通路驱动急性心肌梗死（AMI）后的DNA损伤、坏死和心室重塑；然而，针对这一级联反应的有效疗法仍然有限。在这里，我们使用通过左冠状动脉结扎建立的鼠AMI模型，研究了去泛素化酶BRCA1/BRCA2含有复合物亚基3（BRCC3）在梗死后心脏重塑和功能障碍中的作用。通过超声心动图、Western印迹和形态计量学评估了心脏结构和功能。我们发现AMI后心脏BRCC3表达显著下调。心脏特异性BRCC3过表达抑制了TGF-β1/Smad3激活，减少了梗死面积，减轻了不良重塑和DNA双链断裂，改善了心脏功能，并提高了生存率，而心脏特异性基因敲除则加剧了这些表型。在体外，BRCC3抑制了TGF-β1诱导的心肌细胞肥大基因表达和DNA损伤，以及心脏成纤维细胞的促纤维化反应。机制上，BRCC3与Smad3的MH2结构域结合，并去除赖氨酸333（K333）上的K63连接的多泛素化，从而抑制Smad3在丝氨酸423/425位点的磷酸化。总之，这些发现表明BRCC3通过去泛素化K333处的Smad3来拮抗TGF-β1/Smad3信号，从而保护缺血性损伤和病理性重塑，将BRCC3确定为预防AMI后心力衰竭的潜在治疗靶点。

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.

当前的空间运输采用多级火箭系统，在一次发射中将有效载荷运送到目的地，这种集成模型显著限制了中高地球轨道和深空任务的有效载荷容量。然而，预计中高地球轨道和深空领域将成为下一个探索和利用的前沿，这需要大容量有效载荷和低成本运输作为支持。本研究提出了一种中高地球轨道或深空任务中空间进入和空间转移的解耦设计。该设计引入了一种由轨道上低温推进剂加注驱动的创新空间转移运输系统。在所提出的模型中，地球至轨道车辆负责空间进入，而空间转移车辆处理轨道转移。这种分离允许根据其特定的飞行环境独立优化车辆设计。此外，轨道加注使得空间转移车辆能够进行长期、可重复使用的操作。分析了新模型的优势，证明了在中高地球轨道中有效载荷容量的显著提高，以及运输成本的实质性降低，具有重大的实际意义。还给出了相关的设计挑战，为后续深入研究提供了参考。

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 () mouse with CKD (CKD/ 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 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 in VSMCs. In contrast, VSMC-specific overexpression of , 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 -deficiency-driven PUFA accumulation is responsible for VSMC ferroptosis and atherosclerotic plaque vulnerability. Targeted regulation of -mediated PUFA metabolism may be a promising preventive and therapeutic strategy for CKD-associated plaque vulnerability.

易损的动脉粥样硬化斑块是急性心脑血管事件的关键病理基础。先前的研究表明，在慢性肾脏病（CKD）环境下，动脉粥样硬化斑块更容易受到损害。新出现的证据强调，血管平滑肌细胞（VSMCs）在维持斑块稳定性中起着关键作用，但其潜在机制尚未完全阐明。在此，我们对CKD患者的动脉组织进行了单细胞测序和功能富集分析，发现了VSMCs中的脂质代谢紊乱。进一步利用空间和靶向脂质组学、CKD/apolipoprotein-E缺乏（ApoE-/-）小鼠和生物信息学分析，我们研究了VSMCs的脂质组特征，发现CKD相关易损斑块中的VSMCs表现出显著的聚不饱和脂肪酸（PUFAs）积累，这导致VSMC铁死亡并加剧斑块易损性。机制上，ApoE缺乏导致VSMCs中PUFA积累，从而诱导纤维帽VSMC铁死亡和纤维帽变薄。同时，由于CKD环境导致mRNA结合蛋白人抗原R（HuR）的低表达，介导了VSMCs中ApoE的缺乏。相反，VSMC特异性过表达ApoE、使用giripladib抑制PUFA释放或使用PRGL493抑制PUFA脂质过氧化显著减轻VSMC铁死亡和CKD相关斑块易损性。这些发现揭示了ApoE缺乏驱动的PUFA积累是VSMC铁死亡和动脉粥样硬化斑块易损性的原因。针对ApoE介导的PUFA代谢的靶向调节可能是一种有希望的预防治疗策略，用于CKD相关斑块易损性。

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.

环境中普遍存在的可吸入颗粒物（PM）对肺健康构成了明显的威胁。然而，其潜在的致病机制仍了解甚少，这主要归因于现有体外模型在准确模拟复杂生物过程方面的局限性。本文批判性地审视了在PM研究中应用的体外模型范围，从传统的二维模型到先进的立体三维（3D）构建，包括3D生物打印模型和类器官，以及蓬勃发展的肺芯片（LOCs）领域。每种模型类型都对其独特的优势和挑战进行了细致评估。特别强调的是LOCs技术的创新应用，以复制呼吸运动的动态特性。本文深入探讨了如何通过整合模拟呼吸的刺激来调节PM与细胞/组织界面之间的复杂相互作用。最终，它揭示了一个创新、高度集成和智能的LOCs平台，为该平台的未来发展提供了前瞻性的见解。

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.

准确追踪道路病害的空间时间演变对于制定有针对性的维修和维护策略至关重要。然而，现有的道路性能预测方法通常依赖于加权综合指数，如路面状况指数（PCI），而不是细粒度、病害级别的观测。这种粗略的表示限制了检测早期恶化阶段的能力，并限制了精确预测维护模型的发展。为了解决这些限制，本研究提出了一种物理嵌入扩散（PED）模型，该模型提供了一个物理上一致的时空框架，用于联合建模病害演变、维护干预和环境引起的扰动。使用来自中国的真实世界数据集进行验证表明，PED预测与观测之间具有强一致性，实现了平均PCI平均绝对百分比误差（MAPE）为9.262%和平均加权百分比误差面积（面积MWPE）为4.484%。此外，对美国长期路面性能数据集的评估证实了该模型强大的跨区域泛化能力，实现了平均PCI MAPE为28.054%和面积MWPE为8.957%，强调了所提出框架的鲁棒性和可迁移性。实验结果进一步表明，短期病害预测的最佳历史环境窗口约为50天。随着训练数据量的增加，该模型继续保持稳定的收敛性能，证明了所提出的物理引导退化建模方法的可扩展性和鲁棒性。这种可扩展的工具对于模拟真实的道路退化过程至关重要，为评估后续维护决策策略提供了参考。

How fibroblast heterogeneity orchestrates tissue regeneration by remodeling tissue mechanical properties that guide stem cell function is not well understood. Although fibroblasts are increasingly recognized as key regulators of tissue homeostasis, the specific subpopulations and molecular pathways through which they remodel the mechanical niche during hair follicle regeneration are not fully defined. Here, we identify that Hmmr fibroblasts located beneath the dermal papilla (DP) of the hair follicle promote hair follicle regeneration by secreting extracellular matrix (ECM) components to activate hair follicle stem cells. Single-cell RNA-sequencing and immunostaining mapped spatially distinct fibroblast subpopulations in the dermal microenvironment and showed that regional ECM viscoelastic remodeling occurs prior to hair regeneration and coincides precisely with the emergence of Hmmr fibroblasts. Functional studies in vivo and in skin organoids demonstrate that Hmmr fibroblasts act as mechanical sensors that engage DP cells via NCAM1–FGFR1 signaling to stimulate hair regeneration. We propose a tripartite biomechanical module comprising ECM viscoelastic remodeling (effector), Hmmr fibroblasts (sensor), and DP cells (executor) that cooperatively drives hair regeneration. Together, our work identifies a heterogeneous fibroblast-defined mechanical niche as a central regulator of tissue renewal, highlighting the role of fibroblast diversity in coordinating regeneration and advancing our understanding of the mechano-molecular basis of tissue repair.

纤维母细胞异质性如何通过重塑组织机械特性来指导干细胞功能，从而调控组织再生，这一过程尚不明确。尽管纤维母细胞被越来越多地认为是组织稳态的关键调节因子，但它们在毛囊再生过程中通过哪些特定亚群和分子途径重塑机械微环境尚不明确。在此，我们确定位于毛囊真皮乳头（DP）下方的Hmmr纤维母细胞通过分泌细胞外基质（ECM）成分来激活毛囊干细胞，从而促进毛囊再生。单细胞RNA测序和免疫染色在真皮微环境中定位了空间上不同的纤维母细胞亚群，并显示区域ECM粘弹性重塑发生在毛囊再生之前，并与Hmmr纤维母细胞的出现精确吻合。体内和皮肤类器官的功能研究证明，Hmmr纤维母细胞作为机械传感器，通过NCAM1-FGFR1信号通路与DP细胞相互作用，刺激毛囊再生。我们提出一个由ECM粘弹性重塑（效应器）、Hmmr纤维母细胞（传感器）和DP细胞（执行者）组成的三角生物力学模块，共同驱动毛囊再生。总之，我们的研究确定了异质性纤维母细胞定义的机械微环境作为组织更新的中心调节因子，突出了纤维母细胞多样性在协调再生中的作用，并深化了我们对于组织修复的机械-分子基础的理解。

Restoration of the blood–spinal cord barrier (BSCB) is required for substantial neurological improvement after spinal cord injury (SCI). Astrocytes are integral to this barrier and, after injury, undergo glycolytic adaptation accompanied by lactate accumulation. Whether a lactate-linked modification program in astrocytes participates in BSCB repair has remained unresolved. Here, we identify astrocytic delactylation as a brake on BSCB repair. Sirtuin2 (Sirt2), a delactylase, was strongly induced in astrocytes at the lesion border, and its expression paralleled the pathological expansion of microvessels. Selective deletion of in astrocytes increased lactylation, produced a lactate-rich metabolic state, attenuated inflammatory astrocyte programs, enhanced repair-associated features, and reinforced BSCB repair. These changes further reduced inflammatory infiltration and promoted neuronal retention, increased 5-hydroxytryptamine-positive fiber density, and improved locomotor recovery. Pharmacological Sirt2 inhibition produced similar vascular and locomotor benefits. Mechanistically, loss elevated H4K8la occupancy at the hepatocyte growth factor () locus and promoted transcription, thereby facilitating BSCB repair. Astrocyte-specific ablation also weakened CD8 T-cell-related inflammatory activity after SCI. Collectively, our findings position astrocytic -dependent delactylation as a negative epigenetic–metabolic regulator of BSCB reconstruction and support astrocytic delactylation as a therapeutic target for SCI.

脊髓损伤（SCI）后，血-脊髓屏障（BSCB）的恢复对于神经功能的显著改善是必需的。星形胶质细胞是这一屏障的重要组成部分，损伤后，星形胶质细胞会经历伴随乳酸积累的糖酵解适应。星形胶质细胞中乳酸相关修饰程序是否参与BSCB修复尚无定论。在这里，我们确定星形胶质细胞去乳酸化是BSCB修复的制动因素。去乙酰化酶Sirtuin2（Sirt2）在损伤边缘的星形胶质细胞中强烈诱导，其表达与微血管的病理性扩张平行。在星形胶质细胞中选择性删除Sirt2增加了乳酸化，产生了富含乳酸的代谢状态，减轻了炎症性星形胶质细胞程序，增强了修复相关特征，并加强了BSCB修复。这些变化进一步减少了炎症浸润，促进了神经元保留，增加了5-羟色胺阳性纤维密度，并改善了运动恢复。Sirt2的药理抑制产生了类似的血管和运动恢复益处。机制上，Sirt2的缺失提高了肝细胞生长因子（HGF）位点的H4K8la占用，并促进了转录，从而促进了BSCB修复。星形胶质细胞特异性消除也减弱了SCI后的CD8 T细胞相关炎症活动。总之，我们的发现将星形胶质细胞依赖性去乳酸化定位为BSCB重建的负表观遗传-代谢调节器，并支持将星形胶质细胞去乳酸化作为SCI的治疗靶点。

The hypoxic microenvironment in gliomas critically contributes to malignant progression. This study investigates the functional role and molecular mechanisms of long noncoding RNAs derived from hypoxic endothelial cell exosomes in reprogramming tumor-associated macrophages and driving glioma progression. We identified a novel long noncoding RNA, lnc-DKK3, enriched in exosomes secreted by hypoxic endothelial cells. Nuclear-localized lnc-DKK3 suppresses PD-L1 ubiquitination in macrophages by binding to USP47, promoting M2-like polarization and immunosuppression. Additionally, the lnc-DKK3/USP47 axis stabilizes RelA, augmenting its transcriptional activity and collectively accelerating glioma progression. Thus, hypoxic endothelial-cell-derived lnc-DKK3 drives M2 polarization via the USP47/PD-L1 pathway and promotes glioma progression via the USP47/RelA axis, highlighting its therapeutic potential. To translate these insights, we developed a macrophage-specific CRISPR interference–liquid nanoparticle platform targeting the lnc-DKK3 super-enhancer and demonstrated its synergistic sensitization to anti-PD-1 therapy in preclinical models.

缺氧性微环境在胶质瘤的恶性进展中起着至关重要的作用。本研究调查了缺氧内皮细胞外泌体来源的长非编码RNA在重编程肿瘤相关巨噬细胞和驱动胶质瘤进展中的功能作用和分子机制。我们鉴定了一种新的长非编码RNA，lnc-DKK3，在缺氧内皮细胞分泌的外泌体中富集。核定位的lnc-DKK3通过结合USP47抑制巨噬细胞的PD-L1泛素化，促进M2样极化和免疫抑制。此外，lnc-DKK3/USP47轴稳定RelA，增强其转录活性，共同加速胶质瘤进展。因此，缺氧内皮细胞来源的lnc-DKK3通过USP47/PD-L1途径驱动M2极化，并通过USP47/RelA轴促进胶质瘤进展，突显其治疗潜力。为了将这些见解转化为实际应用，我们开发了一种针对lnc-DKK3超增强子的巨噬细胞特异性CRISPR干扰-液体纳米颗粒平台，并在临床前模型中证明了其对抗PD-1疗法的协同敏感性。

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(-lactide--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(-lactide--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.

尽管目前硬脑膜修补片能够通过机械密封防止脑脊液泄漏，但它们未能解决创伤性脑损伤的关键病理级联反应，包括脑膜淋巴管的解剖结构破坏和神经免疫反应失调。在这里，我们通过使用雷帕霉素缓释聚(-乳酸-ε-己内酯)纳米纤维进行淋巴-免疫微环境工程，打破了这种治疗僵局。这种生物活性补片通过以下三种机制发挥其治疗作用：(a)通过调节辅助性T细胞17/调节性T细胞平衡来恢复免疫稳态；(b)形态上正常化脑膜淋巴网络；(c)通过抑制成纤维细胞增殖来防止脑组织粘连。在创伤性脑损伤大鼠模型中，与对照相比，4%雷帕霉素载体的聚(-乳酸-ε-己内酯)纳米纤维实现了更高的功能恢复和显著减少的脑组织损失。关键的是，它重建了免疫微环境并正常化了脑膜淋巴系统的形态。这项研究代表了从被动硬脑膜闭合到主动神经免疫调节的范式转变，为创伤性脑损伤提供了一种神经保护性治疗策略。