Due to their unique physicochemical, optical, and electronic properties, traditional quantum dots (QDs) have been used for various optoelectronic applications, including semiconductor lasers, photodetectors, transistors, and solar cells. However, unlike other traditional QDs, graphene quantum dots (GQDs), nanosized graphene sheets that possess edge effects and quantum confinement along with a collective structural feature of graphene, have shown less toxicity and desirable biocompatibility, making them an appropriate part of the carbon family for use in biomedical applications. This review article highlights the recent advances and roles of GQDs in healthcare, with a particular focus on their applications involving bioimaging and drug delivery. Furthermore, we provide an overview of the different synthesis methods for GQDs, including the top-down and bottom-up approaches, and discuss the modifications that enhance their functionality, such as the incorporation of heteroatoms (e.g., nitrogen, sulfur, and phosphorus) to improve their properties. This review further considers the biological, optical, and toxicological attributes of GQDs, followed by recent developments involving the use of GQDs for drug delivery and bioimaging applications. Last, we describe the challenges, future prospects, and potential directions for advancing the real-time bioimaging and drug delivery applications of GQDs, including platforms for therapeutic agent release and medical diagnosis.

Despite the tremendous amount of basic knowledge in cancer immunity gained and many transitional approaches attempted, current cancer immunotherapies are still far from reaching universal effectiveness. Therefore, next-generation cancer immunotherapies would emerge from deepened mechanistic insights on the full spectrum of cellular and molecular interactions between cancer cells and their immune sentinels. This review embarks on an exhaustive exploration of the cardinal immunological principles that catalyze robust cancer surveillance and their potential escapes and recapitulate the state-of-art understanding of both receptors and corresponding immune cell types involved. Both tumor intrinsic and tumor microenvironmental mediators of immune escapes are outlined in the context of current clinic applications. Following emphasizing the exceptional requisites that effective cancer immunity cycle must meet, specific cellular subsets crucial for igniting tumor immunity, notably effector and helper T cells alongside antigen presentation cells are examined, focusing on their close interactions in both antigen-dependent and -independent manners. Such intricate interactions form dynamic immune hubs at the tumor site, holding promising key functionality in rendering effective cancer retreat. Grounded on these recent insights, refined immunotherapeutic strategies, especially those bolstering priming based anticancer effector functions are advocated.

Effective early prediction of acute pancreatitis (AP) severity remains an unmet clinical need due to limited molecular characterization of systemic immune responses. We performed integrated single-cell RNA sequencing with T- and B-cell receptor profiling on peripheral blood mononuclear cells from AP patients (n = 7) at days 1, 3, and 7 after admission. Immune landscape analysis revealed marked inter-patient heterogeneity, with a distinct expansion of MZB1-expressing plasma cells that were strongly associated with complicated AP and recovery. Functional validation in an independent cohort (n = 14) confirmed disease-associated plasma cell markers, alongside altered serum immunoglobulin and cytokine profiles (n = 32). From these findings, we established a nine-gene B-cell-derived transcriptomic signature (S100A8, DUSP1, JUN, HBA2, FOS, CYBA, JUNB, S100A9, and WDR83OS) predictive of AP severity. This model demonstrated high discriminative performance in internal validation (n = 114; AUROC > 0.95, superior to standard clinical scoring systems), and sustained accuracy in external validation cohorts of AP (n = 87) and AP combined with non-AP sepsis (n = 174) for predicting persistent organ failure. Our study identifies a mechanistic and predictive role for MZB1⁺ plasma cells in AP pathogenesis, offering a novel immune-based stratification strategy with potential for precision clinical management.

Tetrahedral framework nucleic acid (tFNA) efficiently treats various diseases; however, its effect on wound healing is unknown. We investigated tFNA's impact on human immortalized epidermal cells (HaCaT) cells and wound healing through in vitro and in vivo experiments. The tFNA is taken up by cells and exhibits good biocompatibility. Transmission electron microscopy and autophagic flux assays showed that tFNA substantially increased the number of intracellular autophagosomes, thus suggesting the activation of cell autophagy. Immunofluorescence and western blotting results indicated decreased microtubule-associated protein 1 light chain 3I (LC 3I) and prostacyclin (P62) levels, and increased microtubule-associated protein 1 light chain 3II (LC 3II), suggesting increased autophagic activity. Adenosine 5′-monophosphate-activated protein kinase (AMPK) and unc-51-like kinase 1 (ULK1) activation, and mechanistic target of rapamycin (mTOR) inhibition were also observed, suggesting their involvement in tFNA-induced cell activation. Autophagy-related protein (ATG) 5 and ATG7 knockdown in HaCaT cells reverse confirmed these results. Animal experiment results mirrored the cellular findings, revealing autophagy induction, wound healing promotion, and effective scar score reduction. These results suggest that tFNA promotes HaCaT cell autophagy activation through mTOR pathway inhibition, promoting wound healing and reducing scarring. Our findings expand the application of tFNA and highlight new avenues for clinical wound treatment.

Timely and accurate detection of Philadelphia chromosome–like acute lymphoblastic leukemia (Ph-like ALL)-related fusion gene is essential for treatment decisions. However, due to the complexity of possible gene fusion combinations of Ph-like ALL, current diagnostic workflows face critical limitations: prolonged turnaround (7–14 days), high costs, and deficiency in degraded specimens. In this study, we introduce Partial Anchored Capture and Long-Read Sequencing (PACLseq), a nanopore-sequencing-technology-based approach. We designed a detection panel associated with Ph-like ALL, specifically ABL2, CSF1R, PDGFRB, JAK2, ABL1, EPOR, and CRLF2 as target genes. Validated on 47 clinical samples, PACLseq achieved 93.3% sensitivity and 100% specificity in 26 degraded RNA samples (RIN > 3). Crucially, PACLseq maintained detection accuracy in nine low-RIN samples (RIN ≤ 3) with fragmented transcripts. The method requires only 10 ng of RNA input, delivers results in 3 days (vs. 7–14 days for conventional methods), and reduces costs by 50%. By offering rapid and accurate fusion detection, PACLseq has the potential to significantly improve diagnostic efficiency, facilitate timely treatment decisions, and enhance patient outcomes in the management of Ph-like ALL.

Guanine nucleotide exchange factors (GEFs) and their small GTPase substrates constitute a fundamental regulatory system that governs diverse cellular processes, including cytoskeletal dynamics, membrane trafficking, and transcriptional regulation. Since their discovery, GEFs have been recognized as molecular switches that activate small GTPases by catalyzing GDP-to-GTP exchange, thereby playing pivotal roles in cellular signaling and homeostasis. Despite extensive research, key gaps remain in understanding the spatiotemporal regulation of GEF isoforms, their functional redundancy in disease, and the development of isoform-specific drugs. This review examines the regulatory mechanisms and physiological roles of GEFs, highlighting their growing potential as therapeutic targets. We explore the phylogenetic classification of GEFs into major families (Ras, Rho, Rab, and ArfGEFs) and their regulatory networks, which encompass subcellular localization, posttranslational modifications, and scaffolding interactions. Special emphasis is placed on GEF–H1, a microtubule-regulated RhoGEF, and its roles in cytoskeletal remodeling, cancer metastasis, and immune responses. We also examine GEF dysregulation in diseases like cancer, neurodegeneration, and cardiovascular disorders, and assess current therapies, such as small-molecule inhibitors and emerging PROTAC technology. This review connects GEF biology with clinical applications by combining basic research with translational insights, providing guidance for precision medicine and novel therapeutic strategies targeting GEF-related diseases.

The era of targeted therapies has significantly advanced our understanding of cancer growth and metastasis. Intrinsic or acquired drug resistance remains a major challenge, rendering clinically overt metastatic disease incurable in most patients. This review first examines key clinical trials and their primary outcomes involving targeted therapies in the most common advanced solid tumors, along with the main mechanisms underlying drug resistance. Recently, micrometastatic disease has emerged as a novel focus of investigation aimed at definitively curing advanced solid tumors. Accordingly, this review explores the biology of micrometastases, current challenges in their detection and monitoring, and the main strategies proposed to prevent their progression. The potential roles of nanotechnology and artificial intelligence-driven predictive models are also discussed. Furthermore, we highlight specific characteristics of micrometastatic disease that favor immune modulation, and we evaluate the effectiveness of an immunotherapy regimen that inhibits immune suppression. The lead time provided by serum tumor markers, used experimentally to better track the progression of otherwise undetectable micrometastatic disease, also forms the mechanistic basis for a novel protocol we propose to prevent relapse in high-risk cancer patients. This innovative protocol holds scientific relevance being supported by an appropriate mathematical model and ready for immediate application in clinical practice.

G protein-coupled receptors (GPCRs) are the largest and most diverse class of membrane proteins, mediating cellular responses to a wide range of extracellular stimuli. GPCRs initiate complex intracellular signaling networks that regulate vital physiological functions and are associated with numerous diseases, including various types of cancer. Their conserved seven-transmembrane (7TM) structure enables these signaling networks by allowing interactions with multiple ligands and intracellular effectors. In several types of tumors, abnormal GPCR signaling promotes carcinogenesis by supporting immune evasion, cell proliferation, and therapeutic resistance. A significant research gap exists in fully understanding the molecular mechanisms behind pathway-specific activation and biased ligand discovery of GPCRs, which could lead to the development of more effective therapies. This review examines the complexity of GPCRs, with a focus on their role in signaling through the differential activation of pathways regulated by β-arrestin and G proteins. It discusses how targeted modulation of signaling outcomes by receptor mutants might offer therapeutic benefits in cancer treatment. The review also highlights emerging technologies, such as aptamers, PROTACs, and nanobodies, that more precisely target GPCRs. In addition to exploring receptor structure–function relationships and pathway selectivity, this review provides valuable insights into GPCR-biased signaling and its implications in cancer biology.

Intracerebral hemorrhage (ICH) is a serious neurological disease, characterized by a high incidence rate, a high mortality rate, and long-term neurological dysfunction. Due to the complexity of the pathological mechanism, traditional treatment methods, including surgical intervention and drug therapy, are limited in repairing nerve damage and restoring function. It is necessary to explore innovative treatment strategies. Here, we propose three different pathophysiological stages of ICH, namely, primary injury, secondary injury, and chronic remodeling, and comprehensively discuss the precise targeted treatment of each stage according to the different pathological characteristics. Recent advances in regenerative medicine offer tremendous potential for neurological recovery. This review deeply discusses the emerging biomedical strategies for treating ICH through the integration of cell therapy, intelligent biomaterial platforms, and neuroelectronic interfaces. Furthermore, this review outlines the key clinical translation pathways for emerging therapeutic approaches. By using advanced biomarkers to stratify patients, optimizing combined treatment strategies and overcoming regulatory challenges are of great significance for accelerating the transition of these technologies into clinical practice. This review aims to provide a new perspective for the precise treatment of ICH to improve the neurological prognosis of patients by comprehensively discussing the current research progress and future development directions.

Membrane contact sites enable organelles to interact closely, thereby coordinating cellular homeostasis and functional regulation. Among diverse subcellular membrane architectures, mitochondria-associated endoplasmic reticulum membranes (MAMs) assume a crucial role in the physiological and pathological environments. A plethora of cellular processes are intertwined with MAMs, such as Ca²⁺ translocation, lipid metabolism, endoplasmic reticulum (ER) stress response, mitochondrial dynamics, and mitophagy. In the event of improper modulation of MAMs components, the incidence of diseases would surge remarkably. This review endeavors to expound upon the functions of key MAMs proteins in healthy state and decipher their regulatory mechanisms under physiological and pathological circumstances. In addition, we try to probe into the specific contribution of MAMs within the occurrence and development of diseases, and subsequently collate drug compounds and clinical trials that target MAMs components. Finally, we proffer our insights regarding the contentious perspectives and prospective research directions of MAMs. Understanding the roles and mechanisms of MAMs may potentially offer novel diagnostic biomarkers and treatment targets in clinical practice, paving the way for more precise and effective clinical interventions for common diseases.

Wound healing is a complex, multicellular process that is essential for restoring tissue integrity after injury. In a subset of individuals, however, this process becomes dysregulated, culminating in hypertrophic scars or keloids—fibroproliferative disorders marked by excessive extracellular matrix deposition and prolonged inflammation. Although these lesions differ clinically, both share overlapping molecular mechanisms involving aberrant activation of the TGF-β, Intergrin-FAK, and Wnt/β-catenin pathways. Recent insights from single-cell and multiomics technologies have revealed profound heterogeneity within scar-forming fibroblast populations and highlighted the modulatory roles of immune cells, genetic predispositions, and anatomical tension. However, despite increasing mechanistic understanding, current interventions—including surgery, corticosteroids, and laser therapy—are limited by high recurrence rates and variable efficacy. Emerging strategies now target fibroblast plasticity, inflammatory circuits, and biomechanical feedback via tools such as gene editing, immune modulation, and smart biomaterials. This review integrates advances across epidemiology, molecular signaling, and therapeutic innovation, underscoring the need for personalized, multitargeted approaches. Ultimately, transforming pathological scarring from a persistent clinical burden into a regenerative opportunity will depend on interdisciplinary collaboration and the continued translation of benchside discovery into bedside care.

Gene editing and RNA editing technologies are advancing modern medicine by enabling precise manipulation of genetic information at the DNA and RNA levels, respectively. The third-generation gene editing tools, particularly Clustered regularly interspaced shortpalindromic repeats (CRISPR)/CRISPR-associated (Cas) system, have transformed genetic disease treatment with high efficiency, precision, and cost effectiveness, while RNA editing, via adenosine deaminase acting on RNA (ADAR) enzymes and CRISPR–Cas13, offers reversible regulation to avoid genomic integration risks. Despite advancements, challenges persist in delivery efficiency, tissue specificity, and long-term safety, limiting their clinical translation. This review systematically discusses the molecular mechanisms and technological evolution of these tools, focusing on their promising applications in treating nervous system disorders (e.g., Alzheimer's, Parkinson's), immune diseases (e.g., severe combined immunodeficiency, lupus), and cancers. It compares their technical attributes, analyzes ethical and regulatory issues, and highlights synergies between the two technologies. By bridging basic research and clinical translation, this review provides critical insights for advancing precision medicine, reshaping disease diagnosis, prevention, and treatment paradigms.

Neutrophils, constituting a predominant subset of innate immune cells in mammalian systems, play pivotal roles in pathogenic clearance and homeostatic maintenance. In the progressive development of cancer, neutrophils exert dual roles in both anticancer and procancer processes through their heterogeneity. In recent years, research into the role of neutrophils in cancer and various nontumor diseases has been continuously deepening. However, current research in this area remains incomplete. This review comprehensively summarizes the tissue homing dynamics, lifespan regulation, and physiological functions of neutrophils, starting from their development and heterogeneity. Furthermore, we delineate the dual regulatory functions of neutrophils in carcinogenesis, encompassing both tumor-suppressive mechanisms and protumor mechanisms. This section further synthesizes recent advancements in neutrophil-targeted therapeutic platforms and biomimetic delivery systems, while critically evaluating persistent methodological and translational challenges in clinical applications. In addition, we systematically analyze the role of neutrophils in non-neoplastic diseases and list several typical diseases, including infectious diseases. Finally, we also discuss current controversies and research perspectives on neutrophils. It is hoped that this review will deepen insights into the role of neutrophils in homeostasis and disease, while exploring their potential in disease treatment.

Ubiquitin is a highly conserved small molecule that exists in large quantities in eukaryotic cells and plays a crucial role in protein quality control by phagocytosis and degradation of ubiquitin-modified proteins. The abnormal expression of the ubiquitin–proteasome system (UPS) in cancer leads to the abnormal expression of ubiquitin ligases and ubiquitin-binding enzymes, resulting in the abnormal accumulation of ubiquitinated proteins. Consequently, UPS dysregulation can contribute to tumor initiation, progression, and resistance to therapy. While proteasome inhibitors have shown clinical success, comprehensive reviews integrating upstream UPS components and their therapeutic potential are lacking. This paper reviews the composition of the UPS, its tumor-promoting mechanisms, as well as the small molecule inhibitors and proteasome inhibitors based on this system, including their mechanisms of action and adverse effects, and explores their clinical advances in the treatment of cancer. This review provides a valuable framework for developing next-generation anti-cancer therapies and establishes the UPS as a critical therapeutic target for precision oncology.

Heart failure (HF), characterized by maladaptive cardiac fibrosis and progressive functional deterioration, remains a therapeutic challenge. In this study, we established a cardiac organoid HF model derived from human-induced pluripotent stem cells (hiPSCs) and observed a significant downregulation of the desmosomal protein plakophilin-2 (PKP2) in this model. Reduced PKP2 expression was detected in both HF rat and mouse. Subsequent in vivo studies on Pkp2-knockout (Pkp2-KO) rats demonstrated that adeno-associated virus serotype 9 (AAV9)-mediated restoration of PKP2 not only restored cardiac PKP2 expression but also attenuated the progression of fibrosis. Administration of AAV9-PKP2 could also inhibit myocardial fibrosis and slow down disease progression in HF mouse. Single-cell RNA sequencing analysis in rats revealed enriched pathological profibrotic cardiac fibroblasts (CFs) in PKP2-deficient myocardium. Mechanistically, AAV9-PKP2 administration induced the phenotypic conversion of activated CFs into quiescent antifibrotic states. Integrated bioinformatics identified that protein tyrosine phosphatase receptor type C (Ptprc) was a pivotal regulator orchestrating this cellular reprogramming. Our findings thus unveil PKP2 as a master regulator of fibroblast activation and propose AAV9-PKP2 gene therapy as a promising novel therapeutic strategy targeting pathological fibrosis in HF.

Meniere disease (MD) is a chronic inner ear disorder with significant heritability. This study compares the burden of rare high- and moderate-impact coding variants in an MD cohort to determine whether genetic burden in sporadic MD (SMD) overlaps familial MD (FMD), potentially revealing hidden inheritance in SMD. Exome sequencing identified rare variants in unrelated FMD (N = 93) and SMD (N = 287) patients. Gene Burden Analysis (GBA) was performed, and candidate genes were prioritized using the number of variant carriers, inner-ear expression, and hearing/balance-related phenotypic annotations. FMD patients showed higher accumulation of missense and loss-of-function variants than SMD, especially in genes linked to auditory and vestibular function. GBA identified 269 enriched genes in SMD, with 31 annotated for inner ear phenotypes, while FMD had 432 with 51 pinpointed. Sporadic and FMD overlapped in 28.1% of enriched genes, with ADGRV1, MEGF8, and MYO7A most commonly shared. Auditory brainstem responses from knockout mouse models supported hearing loss of three novel MD candidate genes (NIN, CCDC88C, and ANKRD24), consistent with patient hearing profiles. In conclusion, SMD and FMD have a divergent genetic architecture. The enrichment of missense variants in stria vascularis and hair cell stereocilia genes supports distinct pathogenic mechanisms and a multiallelic-recessive inheritance pattern in MD.

Salivary metabolomics is increasingly recognized as a powerful, noninvasive approach for studying human health and disease. Unlike blood or urine, saliva is easily accessible, minimally invasive, and suitable for repeated sampling. Advances in nuclear magnetic resonance, mass spectrometry, capillary electrophoresis, and bioinformatics have improved the sensitivity and reproducibility of salivary metabolite profiling, enabling its use across diverse systemic diseases such as cancer, cardiovascular disorders, diabetes, viral infections, autoimmune diseases, and neurodegenerative conditions. Despite this progress, clinical translation is limited by variability in sampling, lack of standardized protocols, and insufficient large-scale validation. This review synthesizes recent developments in human salivary metabolomics, emphasizing disease-specific biomarkers and key applications in systemic disease diagnosis and monitoring. We also examine methodological and biological factors that influence data reliability, including collection methods, storage conditions, circadian rhythms, age, and host–microbiome interactions. Furthermore, integration of multiomics strategies, machine learning, and clinical registry data is discussed as a means to enhance biomarker discovery and translational potential. By addressing these challenges, salivary metabolomics can evolve into a reliable platform for noninvasive diagnosis, longitudinal disease monitoring, and personalized medicine, providing a valuable complement to blood-based diagnostics in precision healthcare.

Free radicals, molecules with unpaired electrons, are double-edged swords. While they may cause damages to cells and threaten human health, they play essential roles in cellular signaling toward mitochondrial and immune homeostasis. Overproduction or insufficient supply of free radicals can both lead to health concerns and disease syndromes by causing oxidative or reductive stress to cells. Current redox therapies frequently fail clinically due to imprecise dosing and targeting, causing therapeutic futility or paradoxical harm by disrupting redox homeostasis, necessitating integrated frameworks linking redox biology to precision interventions alongside therapeutic innovation. This review explores free radicals’ generation sources, characterizes mitochondrial oxidative phosphorylation and pathological hyperglycemia as pivotal endogenous sources, and proposes oxygen and transition metals as fundamental regulators. This paper synthesizes multidimensional molecular mechanisms and pathologies arising from redox dysregulation and establishes reductive stress as a critical pathogenesis driver alongside oxidative stress. This review discusses free radical approaches and proposes cold atmospheric plasma as a transformative redox-modulating technology capable of bridging therapeutic dichotomies through calibrated interventions. By integrating mechanistic insights with innovative methodologies, this work underscores the imperative to innovatively harness the dual nature of free radicals for precision health and disease management.

The prognostic value of baseline bone mineral density (BMD) and posttreatment BMD decrease (BMDD) in non-small cell lung cancer (NSCLC) patients receiving immune checkpoint inhibitor (ICI) treatment remains unclear. We assembled data of 2096 patients with advanced NSCLC from five institutions to develop a combined model incorporating BMD/BMDD and clinical characteristics for noninvasive prognosis prediction. BMD was automatically assessed using a deep learning-based method. Compared with the physiological BMD group and the non-severe BMDD group, the pathological BMD group and the severe BMDD group had shorter progression-free survival (PFS) (hazard ratio [HR]: 1.19, p = 0.003; and HR: 1.19, p = 0.002, respectively) and overall survival (OS) (HR: 1.31, p < 0.001; and HR: 1.30, p < 0.001). Compared with the single BMD/BMDD model, the combined model had higher Harrell's concordance indexes (c-indexes) (PFS: 0.580 and OS: 0.654). Transcriptomic analysis of 130 patients from the NSCLC radiogenomic cohort revealed upregulation of epithelial–mesenchymal transition, inflammatory, and hypoxia pathways, and increased macrophage infiltration in tumors of patients with pathological BMD. This study showed that lower baseline BMD and more severe BMDD are associated with poorer prognosis. BMD in combination with clinical characteristics can help to improve risk stratification and prognosis prediction.

Targeted protein degradation (TPD) represents a paradigm shift in drug discovery, moving beyond traditional binding-based inhibition toward active removal of disease-driving proteins. This approach has unlocked therapeutic possibilities for previously “undruggable” targets, including transcription factors like MYC and STAT3, mutant oncoproteins such as KRAS G12C, and scaffolding molecules lacking conventional binding pockets. Among TPD strategies, proteolysis-targeting chimeras (PROTACs) have emerged as the leading clinical platform, with the first molecule entering trials in 2019 and progression to Phase III completion by 2024. This comprehensive review examines PROTAC development across diverse therapeutic areas, analyzing key targets including kinases, hormone receptors, antiapoptotic proteins, and epigenetic modulators. We evaluate clinical progression of breakthrough candidates such as ARV-110 for prostate cancer, ARV-471 for breast cancer, and BTK degraders, while discussing critical challenges including the “hook effect” and oral bioavailability limitations. The review explores future directions encompassing innovative delivery strategies, tissue-specific degrader design, and approaches for expanding E3 ligase repertoires and overcoming resistance. This review provides essential foundations for rational target selection, molecular optimization, and clinical translation strategies. By integrating mechanistic insights with clinical realities, this analysis offers perspectives on PROTAC technology advancement and identifies opportunities for transforming treatment of complex diseases resistant to conventional therapies.

Dalpiciclib, a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, has demonstrated significant clinical activity and manageable safety in advanced luminal breast cancer, yet its neoadjuvant value remains unestablished. The single-arm, phase II DANCER trial (NCT05640778) is the first to evaluate circulating tumor DNA (ctDNA)-guided neoadjuvant CDK4/6 inhibitor therapy in patients with operable human epidermal growth factor receptor 2 (HER2)-negative luminal B breast cancer, a subtype with poor chemotherapy response and unmet neoadjuvant needs. Thirty patients received dalpiciclib plus aromatase inhibitors (DAL-AI) with ctDNA monitoring and multiomics profiling. At week 2, 26 (86.7%) patients achieved complete cell cycle arrest (primary endpoint). By surgery, 60.0% had partial response; breast pathological complete response and residual cancer burden 0–I rates were 6.7 and 3.3%, respectively. Treatment was well tolerated, with the most common grade ≥3 adverse events being neutropenia and leukopenia. Candidate predictive biomarkers included ctDNA clearance, GSTM1 copy number, MammaPrint index, plasma CCL4/CCL19 levels, and tissue pRb/CDK4 expression. A novel baseline response index combining CCL4 and pRb showed excellent predictive performance and stratified patients by likelihood of clinical benefit, with ctDNA dynamics further refining stratification. These findings support DAL-AI as a promising neoadjuvant option and highlight the value of biomarker-guided strategies for treatment optimization.

Respiratory syncytial virus (RSV) is a notorious pathogen that serves as the leading cause of lower respiratory tract infections (LRTI) among infants, the elderly, and immunocompromised individuals. Its widespread prevalence exerts a considerable burden on global healthcare systems and economies, owing to the high rates of hospitalization and the potential for long-term health complications. Significant progress has been achieved in RSV prevention strategies during recent years, with three vaccines currently approved worldwide for active immunization in adults aged 60 years and older, as well as pregnant women. Furthermore, the monoclonal antibody nirsevimab has been approved for the prevention of RSV infections in infants. However, effective antiviral treatments for postinfection cases remain an unmet clinical need. This review comprehensively elaborates the molecular and cellular mechanisms of RSV infection, including viral structure, replication cycle, and pathogenic mechanisms. Meanwhile, we systematically summarize the latest advances in preventive and therapeutic agents and analyze the practical applications and existing limitations of current immunization strategies. Furthermore, we discuss and propose the challenges and future directions in drug development. The review provide insights for developing novel and effective prevention and treatment strategies against RSV infection.

Breast cancer (BC) is the most prevalent cancer in women and remains the leading cause of cancer-related mortality globally. Its development is influenced by multiple factors, including genetics, environmental, aging, and modulation of various signaling pathways. The heterogeneity of BC together with the emergence of treatment resistance and recurrence have prompted researchers to explore and develop new therapeutic approaches. Recently, oncology research has primarily focused on the development of targeted therapies against molecular abnormalities in BC. These therapies include monoclonal antibodies, tyrosine kinase inhibitors, antibody–drug conjugates, PI3K/Akt/mTOR pathway inhibitors, CDK 4/6 inhibitors, PARP inhibitors, antiangiogenic agents, and various other targeted drugs. Immunomodulatory strategies, including immune checkpoint inhibitors (anti-PD-1/PD-L1), CTLA-4 blockers, adoptive T-cell therapy, and cancer vaccines, stimulate immune response against cancer cells. Epigenetic therapies like DNMT and HDAC inhibitors have also shown promise in BC treatment. This review highlights how innovative approaches like targeting intratumoral heterogeneity, liquid biopsy for resistance mutation detection, bypass mechanisms (FGFR1 activation following CDK4/6 inhibition), artificial intelligence-based drug discovery, patient-derived organoids, and adaptive trial designs are shaping BC treatment. By combining molecular insights with precision therapeutics, these advancements offer significant potential to address resistance, improve efficacy, and enhance patient outcomes.

Vascular dysfunction is implicated in the pathogenesis of osteoarthritis (OA). Herein, we utilized smooth muscle specific human Sirt1 transgenic (smSirt1-Tg) mice characterized by vascular homeostasis to prepare an OA model to validate vasculature-derived articular cartilage protective factors. The OA of smSirt1-Tg mice exhibited significantly reduced cartilage destruction and pain sensitivity, accompanied by increased proteoglycans content and collagen type II (Col2ɑ) expression and decreased matrix metallopeptidase 13 (MMP13) and p53 expression. Vascular smooth muscle cell-derived cZFP609 was highly enriched in the articular cartilage and plasma of smSirt1-Tg mice. Overexpression of cZFP609 abrogated TNFα-induced endoplasmic reticulum (ER) stress and fine-tuned the mitochondrial homeostasis in chondrocytes. Mechanistically, cZFP609, located in the cytoplasm, interacted with binding immunoglobulin protein (BiP) to stabilize the BiP oligomeric form. This interaction reduced the level of active BiP monomer that induced not only ER stress via activating IRE1α (inositol-requiring enzyme 1α) signaling but also mediated the formation of ER–mitochondria contacts (ERMCs). Increased oligomeric BiP by overexpression of cZFP609 suppressed ERMC-driven aberrant ER–mitochondria communication and diminished lipid peroxidation and ferroptosis, which contributed to maintaining mitochondrial homeostasis and alleviating cartilage degeneration in OA. Taken together, these results elucidate a beneficial cZFP609-driven feed-forward circuit that can be effectively targeted to stem the progression of OA.

Diabetic wound healing, characterized by persistent inflammation, impaired angiogenesis, and dysfunctional cellular responses, remains a major clinical challenge due to its complex pathophysiology. This challenge is most evident in diabetic foot ulcers (DFUs), which carry high risks of infection, recurrence, and amputation, contributing substantially to patient morbidity, mortality, and healthcare costs. Despite multidisciplinary care, debridement, and advanced dressings, healing outcomes are often suboptimal, highlighting an urgent need for deeper pathophysiological insights and more effective therapeutic strategies. This review synthesizes current understanding of DFU pathogenesis, emphasizing how sustained metabolic dysfunction disrupts fibroblast and immune cell function, thereby perpetuating chronic wounds. We also critically examine commonly used animal models and their limitations in replicating the complexity of human DFUs and discuss emerging therapeutic approaches with translational promise. Advancing our understanding of these mechanisms and validating innovative interventions may ultimately reduce DFU-related amputations and mortality, improve healing outcomes, and enhance patient quality of life. This review aims to catalyze future research and therapeutic innovation in diabetic wound care.

The substantial loss of cardiomyocytes resulting from myocardial infarction leads to pathological remodeling of the heart and the onset of heart failure. Promoting heart regeneration is therefore a critical therapeutic goal for repairing damaged cardiac tissue. Over the past two decades, the utilization of cardiac stem cells for heart regeneration has emerged as a focal point of research. However, the related mechanisms and efficacy remain constrained by poor integration and survival. Concurrently, genetic lineage tracing has definitively shown that the adult mammalian heart lacks significant endogenous stem cells. It is now widely accepted that heart regeneration primarily arises from the proliferation of pre-existing adult cardiomyocytes. This review systematically summarizes the physiological and microenvironmental changes during the developmental process of cardiomyocytes, elucidates the intrinsic and extrinsic molecular biological mechanisms that regulate cardiomyocyte proliferation, and discusses exogenous cell transplantation therapy, potentially endogenous pharmacological and genetic approaches, as well as promising bioengineering and cross-disciplinary methods. By synthesizing these multifaceted advances, this review aims to clarify important issues that require further elucidation in this field, thereby advancing the depth of research on heart regeneration and its clinical translational applications.

F-Box Protein 32 (FBXO32), a F-box protein family member, exhibits oncogenic and tumor-suppressive roles in various carcinomas. However, its function and underlying molecular mechanisms in hepatocellular carcinoma (HCC) are still unknown. We observed that FBXO32 was overexpressed in HCC tissues than normal tissues, which is pertaining to poor prognosis in HCC patients. Functional tests demonstrated that FBXO32 enhanced HCC cell proliferation, invasion, and metastasis, which was confirmed in vivo using mouse models. Proteomics-based approaches and computational analyses reported a positive correlation between FBXO32 and PI3K–AKT pathway, identifying pleckstrin homology domain leucine-rich repeat protein phosphatase 2 (PHLPP2) as an interacting protein. Mechanistically, DNA promoter hypomethylation elevated FBXO32 expression in HCC cells, promoting K48-linked PHLPP2 polyubiquitination at the K592 and K942 sites through direct interactions. Notably, targeting FBXO32 significantly inhibited tumor growth in both an orthotopic HCC model and an organoid model derived from HCC patients. To sum up, this work emphasizes the part of FBXO32 in propelling HCC progression via facilitating PI3K–AKT pathway activation via PHLPP2 degradation.

Myeloid-derived suppressor cells (MDSCs) represent a significant immunosuppressive population within the tumor microenvironment of colorectal cancer (CRC). Their activity has been strongly associated with the reprogramming of cholesterol metabolism, although the underlying mechanisms remain unclear. To investigate this, we generated myeloid-specific cholesterol 25-hydroxylase (CH25H) knockdown mice and differentiated bone marrow cells from wild-type (WT) or Ch25h^f/f Lyz2^Cre mice into MDSCs, subsequently treating them with 25-hydroxycholesterol (25HC). Immune function was evaluated using flow cytometry, Western blotting, and real-time polymerase chain reaction (PCR). Our findings indicated that CH25H and its metabolite 25HC were significantly upregulated in CRC-associated MDSCs. The loss of CH25H impaired their immunosuppressive capacity by reducing arginase-1 (ARG1) expression, an effect that was restored by 25HC supplementation. Mechanistically, 25HC suppressed the activation of the cyclic guanosine monophosphate–adenosine monophosphate synthase–stimulator of interferon genes (cGAS–STING) pathway and the downstream tank-binding kinase 1 (TBK1). TBK1 formed a complex with receptor-interacting protein kinase 3 (RIPK3), thereby repressing ARG1 expression through phosphorylation-dependent signaling. Collectively, these findings reveal a previously unrecognized CH25H–25HC–STING axis in MDSC-mediated immune regulation and suggest that targeting cholesterol metabolism may provide a promising therapeutic strategy for CRC immunotherapy.

The rapid development of immune checkpoint inhibitors has fundamentally changed the landscape of cancer treatment. These agents restore T cell-mediated antitumor immune responses by targeting key immune checkpoint molecules, thereby suppressing or eliminating tumors. However, their clinical application still faces multiple challenges, mainly including efficacy heterogeneity, drug resistance, immune-related adverse events. Furthermore, there is still a lack of reliable biomarkers for predicting efficacy and toxicity. More critically, there is absence of precise predictive models that can systematically integrate multiomics features, dynamic tumor microenvironment evolution, and patient individual differences to comprehensively address the above issues. This review systematically summarizes the latest advancements in this field. The main contents include emerging targets like lymphocyte activation gene 3, T cell immunoreceptor with immunoglobulin and tyrosine-based inhibitory motif domain, and mucin-domain-containing-3, combination strategies, and the current research status and limitations of various predictive biomarkers. Moreover, it focuses on the potential of microbiome regulation, metabolic reprogramming, and artificial intelligence-driven multiomics analysis technologies in achieving dynamic patient stratification and personalized treatment. By integrating the frontier research results and clinical insights, the review aims to provide a systematical theory framework and future directions for advancing precision immunotherapy.

Lactate, once dismissed as a mere by-product of cancer metabolism, has emerged as a pivotal factor in tumor progression, exerting diverse effects on metabolic reprogramming and immune modulation. Lactate enhances tumor cell adaptability through sustained glycolysis and concurrently shapes the tumor microenvironment by modulating immune, stromal, and endothelial cell function. This review highlights the evolving understanding of lactate's role, extending beyond the Warburg effect to its regulatory capacity via lactylation, a recently identified post-translational modification. The complex interaction between lactate and tumor biology is examined, emphasizing its influence on the tumor microenvironment and immune dynamics. Additionally, potential therapeutic strategies targeting lactate metabolism and transport are explored, along with lactylation regulation by histone-modifying enzymes. Inhibitors targeting lactate production and transport, especially those against lactate dehydrogenase (LDH) and monocarboxylate transporters (MCTs), have shown considerable potential in preclinical and early clinical studies. Recent advancements are discussed, underscoring the potential of integrating metabolic regulation with immunotherapies, thereby offering a dual pathway in cancer treatment. These insights establish lactate and lactylation as pivotal modulators of tumor biology and highlight their potential as targets in precision oncology.

Messenger RNA (mRNA) vaccines have revolutionized infectious disease prevention and cancer immunotherapy due to their rapid development, potent immunogenicity, and flexible design. Central to the clinical success of mRNA vaccines, lipid nanoparticles (LNPs) function as efficient, nonviral delivery systems capable of protecting mRNA and facilitating its uptake by target cells. Recent advances have demonstrated that LNP-formulated mRNA vaccines and therapeutics elicit robust immune responses and confer effective protection against a broad spectrum of pathogens, including viruses and bacteria. Moreover, LNP-based therapies have shown promising therapeutic efficacy in various cancers and rare diseases, as evidenced by both preclinical models and clinical trials. This review provides a comprehensive overview of the key components, structural features, and preparation technologies of LNPs. It further discusses ongoing challenges in LNP design, such as delivery efficiency, tissue targeting, and safety, and proposes rational strategies to address these limitations. Additionally, recent progress in the analytical methods used to characterize the critical quality attributes of LNPs is highlighted. This review aims to guide the rational design of next-generation LNPs and to support the broader application of mRNA-based vaccines and therapeutics.

Acute myocardial infarction (AMI) is a cardiovascular disease characterized by myocardial necrosis resulting from acute coronary artery occlusion. Although standardized diagnostic and therapeutic protocols have markedly reduced its mortality, AMI remains a leading cause of death and disability worldwide. Contemporary AMI research has evolved from an initial focus on local myocardial injury to a broader perspective encompassing the entire disease course, including tissue damage, remodeling, and multi-organ interactions. This review systematically delineates the key molecular mechanisms underlying AMI and subsequent ventricular remodeling, while also exploring the complex interplay between the heart and other organs such as the gut, brain, kidney, and liver. From a clinical standpoint, we summarize the historical evolution of AMI diagnostic criteria and management strategies, highlighting current classification systems, novel diagnostic technologies, and the integration of artificial intelligence tools. Furthermore, we present recent evidence-based advances in established therapeutic approaches, along with emerging strategies ranging from cellular to genetic interventions. Future directions aim to integrate mechanistic insights with interdisciplinary clinical strategies to establish a systematic and precision-based framework for AMI prevention and management.

The triglyceride-glucose (TyG) index is related to various cardiovascular diseases, but its relationship with stroke and all-cause mortality (ACM) in individuals with coronary artery disease (CAD) is still not well understood. This research sought to analyze the interaction between the TyG index and the occurrence of stroke and ACM in CAD participants. The dataset was derived from the National Health and Nutrition Examination Survey (NHANES), with 809 CAD patients included from 1999 to 2018. TyG index was determined by ln[fasting triglycerides (mg/dL) × fasting glucose (mg/dL)/2]. Findings showed that heightened TyG index values were markedly associated with a greater risk of stroke; a U-shaped interconnection was detected between the TyG index and stroke risk, with the threshold at 8.14. Individuals with a TyG index exceeding this threshold exhibited a markedly higher rate of stroke occurrence. Additionally, a J-shaped correlation was observed between the TyG index and ACM, with the threshold at 9.25, above which the risk of death increased. These findings indicate that the TyG index could act as a practical indicator for predicting stroke and ACM among CAD patients, particularly when considering threshold values.

Hydrogel microspheres (HMs) are versatile biomaterials with biocompatibility and controlled release properties, widely applied in drug delivery, cell carriers, and tissue engineering. Their tunable material compositions (natural, synthetic, or composite polymers) and diverse fabrication techniques (e.g., microfluidics, electrohydrodynamic spraying) allow precise regulation of size, morphology, and functionality, supporting applications from musculoskeletal repair to dermatological therapy. Despite rapid advancements, a comprehensive understanding of HM design, manufacturing, and biomedical applications is still lacking, as existing reviews mainly focus on single fields or specific scenarios. This review systematically summarizes HMs construction strategies (material selection and property modulation), fabrication technologies (batch emulsion, microfluidic chips, and emerging Artificial Intelligence (AI)-assisted methods), and multifunctional applications (drug and cell delivery, nanoparticle integration, and lubrication modification). It highlights the cross-system therapeutic potential of HMs and discusses challenges in clinical translation. By integrating these aspects, this review aims to bridge the gap between material design and clinical translation, providing researchers with an overview from basic research to clinical application, while exploring approaches to cross-system synergistic therapy and addressing bottlenecks in clinical translation.

UFMylation, a novel ubiquitin-like modification, plays a critical role in various intertwined cellular processes, such as the immune response, DNA damage repair, unfolded protein response (UPR), autophagy, endoplasmic reticulum (ER)-phagy, stem cell self-renewal, apoptosis, and metastasis. Dysfunction of UFMylation has been implicated in a variety of human diseases, including neurogenesis, hematopoiesis, liver development, and cancer. While this field is just emerging, research on UFMylation has escalated rapidly in recent years, with great advances having been made. However, only a few substrates of UFMylation have been identified so far, and the biological functions as well as the molecular mechanisms of the UFMylation system in tumorigenesis and the tumor microenvironment remain poorly understood. In this review, we first summarize current knowledge of the components, biochemical peculiarities, and working principles of the UFMylation system. Second, we provide a multidisciplinary review of the cellular functions, molecular mechanisms, and pathophysiological roles of the UFMylation system, with a particular emphasis on the intricate relationship between UFMylation and cancer. Finally, we discuss the potential of targeting UFMylation in cancer treatment and highlight outstanding questions for future investigation in this field.

Dysregulated copper homeostasis is implicated in inflammatory skin diseases such as psoriasis and atopic dermatitis (AD), but the role of cuproptosis remains poorly defined. This study aimed to elucidate the role and mechanism of cuproptosis in inflammatory skin diseases. Transcriptome analysis of patient lesions revealed significant alterations in cuproptosis-related genes correlating with disease-specific pathological features. These cuproptosis-related gene expression signatures demonstrated strong clinical relevance to therapeutic efficacy in both psoriasis and AD cohorts. Functional validation using disease models showed that pharmacologically inhibiting cuproptosis with the copper chelator tetrathiomolybdate (TTM), or genetically knocking down the copper importer SLC31A1, effectively alleviated chronic skin inflammation and hallmark pathological changes induced by imiquimod (IMQ) or calcipotriol (MC903). Mechanistically, we uncovered that SLC31A1-mediated cuproptosis promotes intracellular α-ketoglutarate (α-KG) accumulation, driving activation of the lysine demethylase KDM5B. Activated KDM5B specifically demethylates H3K4me3 marks at the promoter of the ferroptosis regulator ferritin heavy chain 1 (FTH1), suppressing its transcription and consequently sensitizing keratinocytes to ferroptotic cell death, thereby amplifying inflammatory tissue damage. Our findings establish a fundamental pathogenic SLC31A1/KDM5B/FTH1 molecular axis linking dysregulated copper metabolism and cuproptosis to ferroptosis execution in psoriasis and AD, providing significant mechanistic insights and pinpointing promising therapeutic targets for these refractory skin disorders.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease that is frequently associated with inflammatory bowel disease (IBD). However, the precise mechanisms linking these conditions remain unclear. In this study, we established a murine model of experimental sclerosing cholangitis (eSC) using a DDC (3,5-diethoxycarbonyl 1,4-dihydrocollidine) diet. We then demonstrated that eSC mice exhibited increased susceptibility to DSS-induced colitis, accompanied by severe intestinal pathology. Further integrated analyses revealed that eSC disrupted bile acid metabolism and gut microbiota composition, notably increasing Th17-inducing bacteria and altering bile acid profiles. Single-cell and bulk RNA-seq analyses identified a marked expansion of colonic Th17 cells and a loss of immune homeostasis in eSC mice. Therapeutically, rectal administration of lithocholic acid (LCA) and its derivative, 3-Oxo-5β-cholanoic acid (3-O-LCA), was found to restore farnesoid X receptor (FXR) signaling, reduce Th17 cell proportions, and alleviate liver and intestinal injury. Mechanistic studies show that LCA and 3-O-LCA modulate macrophage polarization and Th17 differentiation via FXR. These findings highlight the central role of the gut–liver axis, bile acid signaling, and Th17 responses in PSC–IBD pathogenesis, and suggest that targeting bile acid metabolism offers a promising therapeutic strategy. This work advances our understanding of PSC–IBD and provides a foundation for novel interventions in high-risk patients.