Objective. The E74-like ETS transcription factor 3 (ELF3) plays a vital role in cell development and differentiation. However, its role in ovarian cancer (OC) infiltrating CD8+T cell exhaustion was unexplored. Here, we aim to investigate the role and the underlying molecular mechanisms of ELF3 in OC infiltrating CD8+T cells. Methods. The expression of ELF3, cytokines, and surface inhibitory receptors in OC infiltrating CD8+T cells was measured via RT-qPCR, bioinformatic analysis, flow cytometry, or correlation analysis. The function of ELF3 in CD8+T cells exhausting was detected by flow cytometry in vitro. Transcriptome sequencing analysis was performed in ELF3-overexpressing CD8+T cells and OC infiltrating CD8+T cells. The underlying mechanism was studied by CUT-RUN, dual-luciferase reporter assay, flow cytometry and WB. For clinic, the function of succinate was searched by flow cytometry in vitro and vivo. Also, serum succinate was measured by a assay kit and under gone ROC analysis.Results. ELF3 was significantly upregulated in OC infiltrating CD8+T cells, positively correlating with PD1, but negatively with IFNγ and GZMB. In vivo and vitro, ELF3-overexpression was confirmed to promote CD8+T cell exhaustion, and up-regulated SUCNR1 expression. Furthermore, the succinate-SUCNR1-ERK signaling axis were identified as a key pathway mediating this process. Additionally, serum succinate levels were elevated in OC patients and showed potential value for early diagnosis. Conclusion. ELF3 drives CD8+T cell exhaustion in the OC micro-environment, potentially through the SUCNR1 associated pathway. ELF3 and the related metabolic axis represent promising therapeutic targets for OC.

Cuproptosis, defined as copper-dependent cell death driven by mitochondrial protein lipoylation and aggregation[1], has emerged as a metabolic vulnerability in cancers with intact respiratory function. However, two fundamental questions remain unanswered: (1) Does plasma membrane potential influence susceptibility to cuproptosis? (2) Can cuproptosis propagate intercellularly, analogous to the recently characterized ferroptosis wave[2][3]? We propose a unifying hypothesis: plasma membrane depolarization serves both as a cell-autonomous sensitizing factor for cuproptosis and as a potential intercellular propagation medium, mediated through alterations in copper's electrochemical gradient and gap junction coupling. This hypothesis generates quantifiable, falsifiable predictions that are mechanistically distinct from ferroptosis.

Background: The Xiao Zhong Zhi Tong Patch (XZZTP) has been extensively utilized in China to alleviate many diseases associated with bacterial inflammation. However, its pharmacological mechanism and active components remain unclear. Methods: The anti-inflammatory effects of XZZTP were evaluated in vivo and in vitro models. The characterization of XZZTP and its transdermal components was performed using LC-MS/MS. The underlying pharmacological mechanism was predicted through network pharmacology using the identified transdermal components and verified by Western blotting. Molecular docking and molecular dynamics simulations were performed on key targets to screen active components. Results: XZZTP showed a swelling inhibition rate of 45.96% in xylene-induced ear edema mice in vivo. In vitro, the inflammatory mediators NO, TNF-α, and PGE2 were concentration-dependently reduced by XZZTP in the LPS-induced RAW 264.7 macrophages model, with inhibition rates of 56.53%, 53.75%, and 48.49% at 200 µg/mL, respectively. LC-MS/MS identified 126 chemical components (97 newly reported) in XZZTP, including 52 transdermal potential active components, among which a new iridoid and its isomer were reported for the first time. Network pharmacology analysis demonstrated that XZZTP mainly downregulated the PI3K/AKT/HIF-1 signaling pathway to alleviate bacterial inflammation. The protein expression of core targets p-PI3K, p-AKT, and HIF-1α in the LPS-induced RAW 264.7 macrophages was significantly reduced after XZZTP intervention. Eight active components were screened via molecular docking, and molecular dynamics simulations of three representative complexes validated stable binding interactions, supporting their therapeutic potential. Conclusions: These findings provide a theoretical basis for XZZTP as a potential agent to ameliorate bacterial inflammation-related diseases, serving as a reference for its further application.

Background/Objectives: Only substantial quantities of xeno-free human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs) (hiPSC-CMs) with stable quality and structural and functional maturity can meet the demand for cardiac cell therapy. The use of xeno-free microcarriers can significantly increase cell yield. Co-culturing with hematopoietic stem cells (HSCs) simulates the environment in vivo and has a necessary impact on the development of CMs. However, no microcarrier-based protocol for xeno-free hiPSC-CM culture has yet been established, and the effects of HSCs on CM development and their underlying mechanisms remain unclear. Therefore, this study aims to investigate these issues. Methods: We used a xeno-free microcarrier (plastic) culture system coated by a defined xeno-free matrix (MatriClone) to expand hiPSCs and hiPSC-CMs with human hematopoietic stem cells (hHSCs). Using RNA sequencing (RNA-seq), cytokine assay, and various cellular molecular techniques, we investigated the role of hHSCs in cardiac differentiation and maturation, and underlying mechanisms. Results: hiPSCs were evenly distributed on the surface of plastic coated with 1 μg/cm2 MatriClone (MatriClone-Plastic), increasing and sustaining pluripotency marker levels. Directed differentiation of hiPSCs on 1 μg/cm2 MatriClone-Plastic induced a larger number of CMs, and the level of cardiac differentiation was also significantly improved. When hHSCs were co-cultured with cells at the cardiac progenitor cell stage, results from electron microscopy, electrophysiology, and qPCR showed that hiPSC-CMs significantly promoted cardiac structural and functional maturation. The co-cultured hHSCs released multiple cytokines that were changed dynamically at different time points, and that were highly likely to activate the epidermal growth factor receptor (EGFR)/mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling pathway to promote cardiac development and maturation. Conclusions: hHSCs can efficiently promote differentiation and maturation of xeno-free hiPSC-CMs on MatriClone-Plastic via the EGFR/MAPK/ERK signaling pathway.

Radiation-induced heart disease (RIHD) is a significant late complication of radiotherapy for thoracic malignancies, limiting cancer control and patient well-being. Although RIHD has been extensively studied, its precise molecular mechanisms remain poorly defined, and effective therapeutic agents are lacking. Herein, we demonstrate that circNCX1, a circular RNA of SLC8A1 that regulates cytoplasmic calcium levels and muscle excitation-contraction coupling, was inhibited by radiation. To investigate this in vitro, human cardiomyocyte AC16 cells exposed to 4 Gy X-ray irradiation were used as a model. In irradiated AC16 cells, circNCX1 functions as a miR-133a-3p-sequestering competing endogenous RNA (ceRNA) that derepresses PIK3C2A, thereby augmenting PI3K/AKT/mTOR signaling and limiting radiation-induced apoptosis. Building upon this observation, a cardiac-targeted circNCX1-nanogel is assembled by incorporating circNCX1 expression plasmid into a polyethylene glycol-sodium alginate (SA) nanogel matrix, and subsequently modified with targeting PCM and TAT peptides to augment cardiac accumulation. For the in vivo study, male C57BL/6J mice receiving a single localized 20 Gy heart dose were used as a model for evaluating RIHD for 12 weeks. Intravenously administered circNCX1 nanogel rapidly accumulated in the heart prior to irradiation and conferred robust cardiac protection, evidenced by preserved cardiac function and reduced myocardial fibrosis and apoptosis. Histological analyses and serum biochemical markers of major organs demonstrated undetectable off-target injury. Collectively, these findings demonstrate that circNCX1 nanogel, particularly when administered prior to radiation, mitigates RIHD by improving ventricular function, reducing myocardial fibrosis and cardiomyocyte apoptosis, and reactivating the PI3K/AKT/mTOR survival pathway.

In recent years, China's new round of institution reform has further optimized the drug regulatory system. Relevant departments and institutions involved in traditional Chinese medicine (TCM) regulation have been strengthened. TCM regulatory science, as an emerging interdisciplinary field, has received high regard and experienced rapid development, significantly enhancing TCM regulatory capabilities. Simultaneously, accelerated progress in emerging technologies and production innovation for TCM drug discovery, coupled with the implementation of the National Major Scientific and Technological Special Project for ''Significant New Drugs Development'' and its translational achievements, have led to a historic turning point in the development of innovative natural TCM drugs over the past five years. Driven by the dual engines of ''regulatory science'' and ''policy restructuring'', the development of new TCM drugs has entered a fast lane. Both the quantity and quality of investigational new drug (IND) and new drug application (NDA) registrations and approvals for new natural TCM drugs have shown rapid growth, effectively meeting the public's health demands for TCM products and unmet clinical needs of patients. This study focuses on the development of new TCM drugs during the significant historical phase from 2021 to 2025. It provides a comprehensive overview of new TCM and natural drug applications and regulatory reviews over the past five years, delves into the implementation of the National Drug Regulatory Science Action Plan, and highlights the importance of TCM regulatory science as an emerging interdisciplinary field in accelerating the creation of new TCM drugs. It systematically summarizes the effects of regulatory policies and regulations, the reform of TCM registration classification, specialized TCM registration provisions, and incentive measures such as the National Major Scientific and Technological Special Project for ''Significant New Drugs Development''. Based on an international perspective, it provides a focused review of recent highlights in TCM new drug development and regulation. This holds significant importance for promoting breakthroughs in TCM new drugs across more disease areas and advancing the international coordination of TCM regulation. The challenge faced in managing the registration of new TCM drugs lies in resolving the conflict between TCM theory and modern drug attributes, while balancing the rapid advancement of traditional medical theory and emerging technologies with the robustness of the drug regulatory framework. In the future, actively advancing research and translation in TCM regulatory science, innovatively establishing benefit-risk assessment systems and standards for new TCM drugs, and accelerating the development of a globally leading regulatory system with Chinese characteristics that aligns with the unique nature of TCM will be particularly crucial for global coordination of TCM regulatory policies, and the modernization and internationalization of TCM.

Psoralea corylifolia(PF) is widely utilized for the treatment of conditions such as kidney yang deficiency, frequent urination, and cold pain in the waist and knees. However, both basic research and clinical reports indicate that it induce hepatotoxicity. Our preliminary research has confirmed that PF has hepatotoxicity and in vitro research indicated that psoralidin is hepatotoxic. but it remains unclear whether psoralidin is the hepatotoxic component of PF and the mechanism of psoralidin induces hepatotoxicity. This study aimed to investigate the hepatotoxicity induced by psoralidin and its toxic mechanisms. Kunming mice were used to conduct long-term toxicity experiments. Liver function indices, organ coefficients, and histopathological observations were employed to assess the hepatotoxicity of psoralidin. Non-targeted metabolomics and proteomics analyses were conducted to elucidate the potential pathways and targets associated with psoralidin-induced hepatotoxicity. Furthermore, immunofluorescence staining, molecular docking and Western blotting analyses were utilized to validate the mechanisms underlying psoralidin hepatotoxicity. The elevation of ALT and AST, accompanied by hepatic steatosis and lipid droplet aggregation were observed after psoralidin treatement. Psoralidin affected biosynthesis of unsaturated fatty acid, fatty acid metabolism, arachidonic acid metabolism, phospholipid metabolism, and oxidative phosphorylation. Further validation research found that psoralidin induced the expressions of Acot4 and Plin5, which in turn caused up-regulations of TGs and FFA in mice, and increased the HSD17B12 level, thereby promoting the synthesis of long-chain fatty acids and facilitating lipid synthesis. And psoralidin catalyzed the conversion of phosphatidylcholine into LPC by enhancing Pla2g6 and Pla2g12b levels, which promoted the synthesis and accumulation of TGs, ultimately inducing disorders in glycerophospholipid metabolism. Furthermore, psoralidin caused upregulation of ROS and mitochondrial damage, leading to a decrease in FA oxidation. Psoralidin is one of the hepatotoxic components of PF, which induced hepatotoxicity via promoting lipid synthesis and inhibiting lipid oxidative degradation.

Environmental exposure to polycyclic aromatic hydrocarbons (PAHs) has been associated with cardiovascular disease, yet the specific metabolites and cell-type-resolved mechanisms underlying stroke risk remain poorly defined. Here, we applied an integrated multilevel framework combining population-based exposure analysis with network toxicology, transcriptomics, and single-cell validation to investigate how PAH exposure, using 2-naphthol (2-NAP) as a representative metabolite, may contribute to stroke. PAH metabolites were analyzed in relation to stroke using logistic regression and restricted cubic splines, while mixture effects were evaluated using weighted quantile sum regression and machine-learning models. Network toxicology combined with transcriptomic and machine-learning analyses was used to identify candidate genes and prioritize four putative core genes (DPP4, IFIH1, KAT6A, and LAMP2). Single-cell RNA sequencing further resolved the cell-type-specific expression of these genes, highlighting endothelial cell and macrophage subsets and implicating TGF-β-related signaling pathways. Molecular docking suggested a direct interaction between the key metabolite 2-NAP and LAMP2, which was further examined in vitro. Functional experiments demonstrated that 2-NAP exposure increased LAMP2 expression, induced endothelial DNA damage, impaired microglial migration, and enhanced the production of pro-inflammatory cytokines. Together, these findings suggest that 2-NAP may represent an important contributor linking PAH exposure to stroke and that LAMP2-associated pathways may participate in PAH-related cerebrovascular injury. This study provides mechanistic insight by bridging epidemiological associations with defined molecular pathways and cerebrovascular cell populations, strengthening the biological plausibility of PAH-related stroke risk.

Gouty arthritis is an autoinflammatory joint disease caused by the deposition of monosodium urate crystals, which activate innate immune responses and elicit acute episodes of joint pain and inflammation. Although macrophages are key players in recognizing monosodium urate (MSU) crystals and initiating the inflammatory cascade, the specific contribution of tissue-resident macrophages and their mechanosensory machinery remains unclear. Here, we identify the mechanosensitive ion channel PIEZO1 as a critical mediator of inflammation and pain in MSU-induced acute gout. We show that synovial CX3CR1+ tissue-resident macrophages are enriched and activated in both patient samples and a murine model of gout. PIEZO1 is highly expressed in these cells and responds to mechanical stress with calcium influx, which is further amplified in MSU-treated joints. Pharmacological inhibition or genetic ablation of PIEZO1 in CX3CR1+ macrophages significantly attenuated joint swelling, inflammatory cytokine expression, mechanical hypersensitivity, and motor dysfunction. In contrast, Piezo1 deletion in CCR2+ monocytes, MRP8+ neutrophils, or Col1a2+ fibroblasts did not affect gout-associated symptoms, indicating a non-redundant role for resident macrophage-expressed PIEZO1. These findings define a PIEZO1-dependent mechanotransduction pathway in tissue-resident macrophages that drives gout-related inflammation and nociception and suggest that targeting PIEZO1 may offer therapeutic benefit in acute gout flares.

Myocardial ischemia-reperfusion injury (MIRI) limits the success of reperfusion therapies. Identifying potential biomarkers within the nuclear factor kappa-B (NF-κB) pathway is critical for developing new treatments. Transcriptomic data from mouse MIRI models were combined with NF-κB pathway-related genes. Candidate genes were identified from the overlapping differentially expressed genes. Potential biomarkers were selected via protein-protein interaction network analysis and validated with independent datasets. We performed functional analysis, built transcription factor and competing endogenous RNA (ceRNA) networks, and conducted drug prediction and molecular docking. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) validation was performed in a MIRI mouse model. Nine candidate genes were identified, with Nfkbia and Icam1 emerging as potential biomarkers. Functional analysis connected Nfkbia to mitochondrial metabolism and Icam1 to extracellular matrix processes/nuclear processes. A regulatory network involving mmu-miR-706 and seven lncRNAs was constructed. Drug prediction identified Tosyllysyl Chloromethyl Ketone (TLCK) as exhibiting favourable binding affinity for both targets. Experimental validation confirmed significant upregulation of Nfkbia and Icam1 in MIRI. This study established Nfkbia and Icam1 as key NF-κB-associated genes in MIRI and constructed a ceRNA network. These findings advance our understanding of MIRI mechanisms and support future therapy development. However, these findings were based on bioinformatics analysis and preliminary experimental validation, and required further functional experiments for confirmation.

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.

ABSTRACT Cutaneous bacterial infections frequently elicit severe pruritus, prominently featuring alloknesis, a pathological state where innocuous touch provokes intense itch. However, the peripheral mechanisms translating microbial cues into touch-evoked pruritus remain unresolved. Here, we establish an epicutaneous Pseudomonas aeruginosa infection model that robustly isolates mechanical alloknesis from spontaneous scratching. We identify bacterial flagellin as the critical virulence factor driving this specific sensory modality via Toll-like receptor 5 (TLR5) activation exclusively within Calb1 + Aβ rapidly adapting low-threshold mechanoreceptors (RA-LTMRs). Mechanistically, pathogen-driven TLR5 signaling depletes intracellular PIP2, which suppresses KCNQ4-mediated M-currents and dismantles the biophysical brake on LTMR excitability. Our findings define a distinct microbial-neuronal axis that directly converts tactile stimuli into itch at the peripheral entry point, providing an infection-based framework for dissecting pathogen-sensory neuron interactions and uncovering precise therapeutic targets for chronic, touch-evoked pruritus. TEASER A bacterial flagellin-sensing touch neuron pathway converts innocuous touch into itch during skin infection.

Objectives: IgA nephropathy (IgAN) is a common primary glomerulonephritis with limited treatment options. Gallic acid (GA) has demonstrated renal protective effects, but its precise mechanisms against IgAN remain incompletely elucidated. This study aims to reveal the molecular mechanism by which GA exerts a renal protective effect on IgAN. Methods: Transcriptomics and network pharmacology were combined in an integrative manner. The GSE175759 dataset's differentially expressed genes (DEGs) were filtered out. SwissTargetPrediction and Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) were used to forecast GA's goals. Core targets and pathways were obtained by functional enrichment analysis. Human mesangial cells (HMCs) were stimulated with polymeric IgA1 (p-IgA1) to create an IgAN model in vitro. Reactive oxygen species (ROS), glutathione/glutathione oxidized (GSH/GSSG), lipid peroxidation, malondialdehyde (MDA), Fe2+, and mitochondrial membrane potential levels were evaluated in relation to GA. Western blot analysis was used in conjunction with gainof-function (overexpression) and loss-of-function (siRNA) assays to examine the expression of the core protein and the downstream target proteins. Results: Bioinformatic analysis identified 1141 DEGs in IgAN, with mitogen-activated protein kinase (MAPK) signaling being the most significantly enriched pathway. Intersection of 109 GA predicted targets with DEGs yielded 8 candidate genes, including dual-specificity phosphatase 1 (DUSP1), which was the most downregulated gene. In vitro, GA treatment significantly alleviated p-IgA1-induced oxidative stress and ferroptosis in HMCs. These protective effects were dependent on DUSP1. Mechanistically, GA upregulated DUSP1 expression, thereby inhibiting p38 MAPK phosphorylation and subsequently increasing the protein levels of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11). Conclusion: This study demonstrates that GA may attenuate IgAN progression by inhibiting oxidative stress and ferroptosis in HMCs via the DUSP1/p38 MAPK signaling axis.

Members of the clade A protein phosphatase 2 C (PP2C) family serve as critical negative regulators of abscisic acid (ABA) signaling pathways and mediate plant adaptation to abiotic stresses. However, systematic genome-wide characterization of clade A PP2C members in Populus trichocarpa remains limited. In this study, we identified 16 clade A PtrPP2C genes through a comprehensive genome-wide analysis. Additionally, their evolutionary relationships, cis-acting elements, and expression patterns were investigated. Phylogenetic reconstruction revealed significant evolutionary conservation of the poplar clade A PtrPP2Cs with Arabidopsis homologs. Moreover, promoter analysis identified abundant ABA-responsive elements (ABREs) and stress-related elements, suggesting conserved regulatory mechanisms in stress adaptation. Transcriptomic profiling demonstrated that most of clade A PtrPP2Cs exhibited significant upregulation under both drought stress and ABA treatment, with PtrPP2C-9 as a representative example. Additionally, functional validation through osmotic stress assays using mannitol revealed that PtrPP2C-9-overexpressing (PtrPP2C-9-OE) transgenic plants displayed enhanced sensitivity to osmotic stress compared to wild-type controls, as evidenced by reduced root elongation and compromised stress tolerance. Furthermore, PtrPP2C-9 may influence poplar tolerance to drought stress by mediating a transcriptional regulatory network centered on ABF3 and GBF3. This study provides the first systematic investigation of clade A PP2Cs in poplar, establishing their critical roles in osmotic stress responses and offering potential molecular targets for improving stress resilience in woody plants.

Hypertrophic scarring (HTS) represents a common clinical challenge characterized by excessive fibroblast activation and tissue fibrosis. However, the upstream signals driving pathological fibroblast proliferation remain poorly understood. Here, we identify the G protein-coupled receptor MrgprX2 (human)/MrgprB2 (mouse), traditionally restricted to mast cells, as an inducible pro-fibrotic receptor in dermal fibroblasts during HTS progression. MrgprX2 is markedly upregulated in dermal fibroblasts from HTS, and pharmacological inhibition of MrgprX2 significantly reduces fibrosis in humanized skin organoid models. In mouse studies, the endogenous peptide LL37 emerged as an MrgprX2/B2 activator in fibroblasts, triggering calcium influx, transforming growth factor β1 (TGF-β1) secretion, and proliferation. Genetic ablation of MrgprB2 in fibroblasts significantly reduced fibrosis in vivo, establishing the LL37-MrgprX2/B2-TGF-β1 axis as a key mediator of fibroblast activation and fibrotic remodeling. Together, our findings position MrgprX2/B2 as a critical molecular link between tissue injury-associated signals and fibrotic pathology, offering a promising therapeutic target for fibroblast-driven fibrosis in HTS.

Post-translational modifications (PTMs) play a critical role in cancer radioresistance, yet how they regulate ferroptosis to influence radiotherapy response remains poorly understood. Here, we show that HDAC4 promotes radiation resistance in lung cancer by inhibiting ferroptosis. Through a CRISPR screen in patient-derived organoids, we identify HDAC4 as a key mediator. Mechanistically, HDAC4 acts as an E3 SUMO ligase that SUMOylates MBD1, preventing its ubiquitination and degradation. Stabilized MBD1 represses TP53 and CYP1A1 transcription, thereby suppressing lipid reactive oxygen species formation and ferroptosis. To target HDAC4, we develop a proteolysis-targeting chimera (PROTAC), TP1, based on tasquinimod, which binds and degrades HDAC4 specifically, as confirmed by surface plasmon resonance and proteomics. TP1 exhibits stronger radiosensitizing effects than tasquinimod in lung cancer organoids and xenograft models. Our findings uncover HDAC4 as a suppressor of ferroptosis in radioresistance and present a PROTAC-based strategy to enhance radiotherapy efficacy.

Keratinocytes actively contribute to somatosensory signaling in chronic skin diseases, yet the mechanotransduction mechanisms involved in atopic dermatitis (AD)-associated itch remain unclear. Here we identify keratinocyte-expressed mechanosensitive ion channel Piezo2 as a critical driver of chronic itch in AD. While Piezo1 was constitutively expressed and dispensable for chronic itch in the MC903-induced AD model, Piezo2 expression was markedly upregulated in keratinocytes of lesional AD skin. Keratinocyte-specific Piezo2 deletion attenuated spontaneous scratching and spontaneous C fiber activity, while having minimal impact on skin inflammation. Mechanistically, Piezo2 suppressed the neurorepulsive factor Semaphorin 3A (Sema3a), a key regulator of sensory nerve architecture. Loss of Piezo2 restored Sema3a expression in the epidermis, reduced nerve fiber branching, and dampened C fiber hyperexcitability. Furthermore, keratinocyte-specific ablation of Sema3a exacerbated AD-related itch and nerve fiber outgrowth. These findings establish a non-neuronal epithelial mechanism wherein keratinocyte Piezo2 modulates sensory nerve remodeling and pruritus in chronic skin inflammation, offering potential targets for therapeutic intervention.

NEDDylation is a crucial post-translational modification wherein the ubiquitin-related molecule NEDD8 is added to lysine residues in substrate proteins via a stepwise enzymatic cascade with the participation of the NEDDylation activating enzyme (NAE, E1), E2 conjugating enzymes, and E3 ligases. Many significant proteins in the NEDDylation process are highly expressed in several human diseases, and suppression of NEDDylation is an attractive strategy to develop novel therapeutic drugs for these diseases. Although a variety of small-molecule inhibitors targeting NEDDylation have been discovered, pevonedistat (also known as MLN4924) is the only NEDDylation inhibitor to date to enter phase III clinical trials. Moreover, many preclinical studies and over 40 clinical trials have fully investigated the potential therapeutic effects of pevonedistat, which has been proven safe for human diseases. A literature search was conducted in X-mol, Web of Science and PubMed, and the keywords to retrieve the literature were pevonedistat and MLN4924. Stepwise enzymatic cascades involved in the NEDDylation process and specific mechanisms underlying pevonedistat binding to NAE were investigated. Crucially, this review also details the research progress of pevonedistat, including the discovery process and design strategies. Through the inhibition of NEDDylation pathway, pevonedistat can alleviate various human diseases, including cancers, metabolic diseases, viral diseases, neurological disorders, cardiac diseases, and autoimmune diseases. Review offers new perspectives for the future research on pevonedistat. By a systematic understanding of relevant findings, this review highlights the immense potential of pevonedistat for human diseases and facilitates the promotion of targeting NEDDylation as a new and effective therapeutic strategy.

Hepatocellular carcinoma (HCC) is a lethal malignancy with limited diagnostic biomarkers. The present study aims to comprehensively investigate the expression, clinical prognostic significance, and potential mechanisms of PSMD6 in HCC through comprehensive bioinformatics analyses and in vitro experimental validation. PSMD6 expression in HCC was analyzed using data from the UALCAN, SANGERBOX and TIMER databases. The association between PSMD6 expression and clinicopathological features, patient prognosis, and immune cell filtration was evaluated. Functional enrichment analyses (Gene Ontology and Kyoto Encyclopedia of Genes and Genomes) were performed to identify PSMD6-related signaling pathways, and a protein-protein interaction (PPI) network was constructed using the BioGRID and STRING databases. Key findings from bioinformatics analyses were validated in vitro using reverse transcription-quantitative (RT-qPCR) and western blotting in HCC cell lines. PSMD6 expression was significantly upregulated in HCC compared with adjacent normal tissues (P<0.001), which has been consistently validated by various databases and confirmed by in vitro experiments using RT-qPCR and western blotting. High PSMD6 expression was significantly associated with advanced tumor grade and patient age and served as an independent predictor of poor overall survival (P<0.001). In addition, PSMD6 demonstrated high diagnostic accuracy for HCC (area under the curve=0.877). Moreover, PSMD6 expression showed a positive correlation with the infiltration levels of CD4+ T cells and B cells in HCC (P<0.05), independent of tumor purity (P>0.05). Functional enrichment analysis indicated that PSMD6 was involved in critical oncogenic pathways, including the cell cycle. PPI network analysis revealed that PSMD6 interact with several key proteins, such as PSMC3, PSMD7 and UCHL5 to achieve a regulatory function in HCC. In conclusion, PSMD6 is significantly overexpressed in HCC and is strongly associated with tumor progression and poor prognosis. It represents a promising diagnostic biomarker and a potential therapeutic target for HCC.

Passive radiative cooling is a promising technology for mitigating global warming by reflecting sunlight and radiating heat into the supercooled outer space. This approach has attracted increasing attention. However, achieving efficient light scattering typically depends on high-refractive-index inorganic materials, such as titanium dioxide. Despite its widespread application, recent research reveals that titanium dioxide may pose a potential carcinogenic risk. As a sustainable alternative, cellulose offers renewability, biodegradability, and biocompatibility. Inspired by the scale structure of the Calothyrza margaritifera beetles, all-cellulose-based highly scattering films are developed to overcome the intrinsic low refractive index of cellulose. These films consist of ethyl cellulose microspheres with optimized size and filling fraction as scattering centers and cellulose nanofibers as a supporting network to anchor these microspheres. Despite their ultrathin thickness (10 mu m), these films achieved a reflectivity of 70%. When applied for passive radiative cooling, 300-mu m-thick all-cellulose-based films reduced temperature by 8 degrees C during the day and 2 degrees C at night. The use of cellulose to achieve thinner, more efficient scattering materials while minimizing material usage, offering a sustainable and safer alternative to titanium dioxide as a scattering material. Such all-cellulose-based highly scattering films hold great promise for the fields of functional coatings, foods, and personal care products.