Head and neck squamous cell carcinoma (HNSCC) presents a significant global health challenge, characterized by late-stage diagnosis and high rates of locoregional recurrence. Traditional tissue biopsy, while considered the gold standard, is invasive and often fails to capture the spatial and temporal heterogeneity of the tumor. Liquid biopsy has emerged as a transformative, noninvasive paradigm for molecular diagnostics, leveraging circulating biomarkers found in blood and saliva. This systematic review critically evaluates current evidence regarding the diagnostic accuracy, prognostic value, and molecular validity of circulating tumor cells, circulating tumor DNA (ctDNA), and the transcriptomic landscape of coding and noncoding RNAs (miRNAs, lncRNAs, and circRNAs) in HNSCC. Our review highlights the specificity of ctDNA for monitoring minimal residual disease, particularly in human papillomavirus- and Epstein-Barr virus-driven malignancies, where viral kinetics serve as sensitive biomarkers for recurrence. Furthermore, we explore the utility of "Saliva-Exosomics," suggesting that salivary exosomes may offer high sensitivity for early-stage oral cavity lesions due to anatomical proximity. The review also synthesizes data on novel RNA species, such as tumor-educated platelets and circular RNAs, which act as stable systemic biosensors. Despite promising results, significant heterogeneity in isolation protocols and detection platforms (e.g., next-generation sequencing vs. digital PCR) remains a barrier to widespread clinical implementation. We conclude that integrating multianalyte liquid biopsies into clinical practice holds the potential to personalize therapeutic strategies, improve survival outcomes, and redefine the standard of care in head and neck oncology.

Replacement therapy is an advanced therapeutic approach for diseases caused by molecular deficits. It aims to restore normal physiology by replacing deficient molecules such as enzymes, proteins, genes, or other molecules. Here, we discuss different modalities, including protein replacement, gene therapy, messenger RNA (mRNA) replacement, noncoding RNA (ncRNA) therapies, cell replacement, and gene editing, aimed at addressing and treating the fundamental genetic defects underlying a range of diseases. These therapies could have potentially curative and disease-modifying effects when used to directly replace deficient or dysfunctional components, addressing the inherent limitations of conventional therapies, such as off-target effects and control of disease-related symptoms. Some replacement therapies, such as protein therapy, gene therapy, and cell therapy, are already approved for clinical use, while emerging approaches-including mRNA therapy, ncRNA therapy, and gene editing-remain primarily in the preclinical or clinical trial stages. To achieve broad clinical translation of these emerging approaches, key challenges, including delivery, safety, specificity, and ethical concerns, must be addressed. This review provides an overview of the existing modalities of replacement therapies, their mechanisms of action, and future directions for improving clinical translation, efficacy, and accessibility.

The advent of single-cell RNA sequencing (scRNA-seq) has fundamentally transformed biological research, converting our understanding of cellular diversity from a purely conceptual idea into a quantifiable, applicable, and observable reality. Early efforts successfully created catalogs of cell types across diverse tissues and species, delivering an effective inventory of the components that make up complex animal systems. Yet the field now stands at a crossroads; rather than bringing clarity, the ever-growing number of cellular atlases threatens to flood and overwhelm it. In this review, we argue that the next evolution of scRNA-seq must integrate three essential pillars: temporal dynamics, spatial information, and evolutionary conservation. We have entered the era of predictive biology, moving beyond simple inventories to build dynamic, multispecies, spatially resolved comparative meta-atlases. This new approach seeks not only to understand the fundamental processes of development, physiology, and disease but also to predict cellular behaviors and their evolutionary trajectories, ultimately achieving a mechanistic understanding of life's complexity.

Chemoresistance constitutes a major cause of poor prognosis in advanced cervical cancer. Our previous studies have confirmed that Siglec-15 affects the progression of cervical cancer, whereas its role in regulating cervical cancer chemoresistance remains unexplored. This study investigates the role of Siglec-15 in cervical cancer chemoresistance and explores its mechanism. Siglec-15 expression and mitochondrial retrograde signaling levels were compared between parental and cisplatin-resistant cervical cancer cells. Lentiviral transfection was used to assess the functional effects of Siglec-15 modulation on the proliferation, apoptosis, and chemosensitivity of resistant cells. Further investigations were conducted to examine the effects of Siglec-15 on the mitogen-activated protein kinase (MAPK) signaling pathway, mitochondrial membrane potential, reactive oxygen species levels, and the expression of retrograde-related proteins. These in vitro findings were subsequently validated in vivo using a xenograft tumor model through immunohistochemistry, Terminal-deoxynucleotidyl transferase-mediated dUTP-nick-end labeling (TUNEL) assays, and western blotting. The results showed that Siglec-15 was markedly upregulated in cisplatin-resistant cervical cancer cells, correlating with enhanced mitochondrial retrograde signaling. Siglec-15 overexpression promoted cisplatin resistance and mitochondrial retrograde signaling, driving proliferation while inhibiting apoptosis. Mechanistically, Siglec-15 regulated mitochondrial retrograde signaling through activation of the MAPK pathway, thereby enhancing chemoresistance in drug-resistant cells. Elevated Siglec-15 expression enhances cisplatin resistance in cervical cancer cells by activating the MAPK pathway to promote mitochondrial retrograde signaling.

RNA-binding motif 47 (RBM47), a hub gene in atherosclerosis, induced oxidative stress in macrophages in atherosclerosis progression by enhancing ENC1 stability via binding to the AU-rich elements (AREs). However, RBM47 promoted C-to-U editing of multiple genes, such as acyl-CoA synthetase family member 2 (ACSF2), apoB, CD36, CD170, IL-10, oxysterol binding protein like 9, and transmembrane protein 30a (TMEM30A). These genes play important roles in atherosclerosis. Thus, the role of RBM47 in atherosclerosis may be complex. Notably, ACSF2 and HECT and RLD domain containing E3 ubiquitin protein ligase 2 promoted ferroptosis. TMEM30A exhibited a "don't eat me" signal. CD170 decreased ADAMTS13 activity. Recombinant ADAMTS-13 was undergoing phase 3 clinical trials. However, the biological significance of these genes after RNA editing, except for apoB and tight junction protein 1, is unclear. RBM47 also stabilized Axin1, Cullin 3, IL-8, Dickkopf WNT signaling pathway inhibitor 1, Kelch-like ECH-associated protein 1, and IL-10 expression by recognizing the GAUSAW (S = G/C, W = A/U) motif and AREs/GU-rich elements (GREs). However, the role of RBM47 in other genes that contain AREs and GREs, such as apoA-II, ABCA1, HMGCR, IFN-γ, IL-15, low-density lipoprotein receptor, oxidized low-density lipoprotein receptor 1, and programmed cell death 1 ligand 1, is unclear. This review focuses on the role and mechanism of RBM47-mediated genes in atherosclerosis to provide knowledge for new targets.

Ulcerative colitis (UC) is a chronic immune-mediated disorder of the gastrointestinal tract underpinned by dysregulated mucosal immune responses. Although biological therapies targeting individual cytokines have improved clinical outcomes, most patients fail to achieve durable remission, highlighting the limitations of single-target approaches. Emerging evidence suggests that cytokines function not in isolation but within highly interconnected signaling networks. Systems-level analyses using single-cell transcriptomics and network-based reconstruction reveal that UC phenotypes are characterized by specific rewiring of cytokine communication. Longitudinal multi-omics data, ex vivo perturbation models, and spatial transcriptomics offer opportunities to extend this framework by resolving the spatiotemporal dynamics of cytokine communication across disease states. Integration with systems genomics and microbial-metabolic networks could further refine patient-specific cytokine models. Together, this multi-layered framework supports a paradigm shift away from reductionist, single-cytokine approaches toward a dynamic, spatially organized, and genetically constrained systems immunology perspective of mucosal inflammation, informing novel precision medicine strategies.

The purpose of this work was to examine the function of fibroblast growth factor 18 (FGF18) in rat myocardial ischemia-reperfusion injury (MIRI) and elucidate its relationship to mitochondrial function through the Sirtuin 1/peroxisome proliferator-activated receptor gamma coactivator 1 (SIRT1/PGC-1α) pathway. To evaluate myocardial infarct size, pathological alterations, cardiomyocyte injury, mitochondrial state, oxidative stress, and SIRT1/PGC-1α protein expression, FGF18-knockdown and FGF18-overexpression rat MIRI models were created. H9c2 cardiomyocytes were used to create an in vitro hypoxia-reoxygenation (H/R) model, and FGF18-overexpressing H9c2 cells were given the SIRT1 inhibitor EX-527. We detected the effects of FGF18-mediated regulation of the SIRT1/PGC-1α pathway on H/R-induced alterations in H9c2 cells, including cell viability, mitochondrial reactive oxygen species (ROS) production, mitochondrial membrane potential, apoptotic rate, and the protein expression of FGF18, SIRT1, PGC-1α, and mitofusin 1 (Mfn1). Furthermore, we performed a protein immunoprecipitation (IP)-protein acetylation assay to determine whether FGF18 influences the acetylation level of PGC-1α through the regulation of SIRT1. Results showed that FGF18 overexpression upregulated SIRT1/PGC-1α/Mfn1 expression, improved mitochondrial function, reduced oxidative stress, and enhanced H9c2 survival under H/R, while FGF18 knockdown had opposite effects. Moreover, FGF18 overexpression inhibited H/R-induced PGC-1α acetylation, and SIRT1 inhibition abrogated FGF18-mediated protective effects. Collectively, FGF18 attenuates rat myocardial MIRI by alleviating oxidative stress and regulating mitochondrial homeostasis through SIRT1-mediated deacetylation of PGC-1α.

Myocardial ischemia-induced cell injury involves the concurrent occurrence of pyroptosis, apoptosis, and oxidative stress, whereas its upstream regulatory mechanism remains unclear. The present study aimed to investigate the functional association between long noncoding RNA CRNDE and the NLRP3/ASC pathway in H9c2 cardiomyocytes subjected to hypoxia-induced injury. Using H9c2 cardiomyocytes as the research model, a hypoxia-induced injury model was constructed, shRNA-mediated knockdown of CRNDE was performed, and functional rescue experiments were conducted in combination with an NLRP3 agonist. Results showed that hypoxia treatment significantly upregulated the expression level of CRNDE in H9c2 cells, and this upregulation was significantly positively correlated with the activation of the NLRP3/ASC pathway. Knockdown of CRNDE specifically inhibited the mRNA and protein expression of key molecules in the NLRP3/ASC pathway (NLRP3, ASC, Caspase-1, GSDMD); reduced the secretion of inflammatory factors IL-1β and IL-18; decreased the cell apoptosis rate; and improved oxidative stress imbalance. RNA FISH assay confirmed that CRNDE was localized in the cytoplasm of H9c2 cells; knockdown of CRNDE alleviated hypoxia-induced mitochondrial damage, G1/S phase cell cycle arrest, and impairment of cell membrane integrity, and the above protective effects could be reversed by the NLRP3 agonist. In conclusion, CRNDE is closely associated with hypoxia-induced cardiomyocyte injury, and its effects in mediating pyroptosis, apoptosis, and oxidative stress rely on activation of the NLRP3/ASC pathway. Targeting CRNDE may provide a supplementary strategy for the treatment of myocardial ischemia-related diseases.

Idiopathic pulmonary fibrosis (IPF) is characterized by persistent fibroblast activation and progressive extracellular matrix remodeling, leading to irreversible lung architectural distortion. Although high-throughput omics approaches have advanced understanding of IPF pathogenesis, most studies have relied on single-omics analyses, limiting cross-layer functional interpretation. Here, we applied an integrated multi-omics strategy to characterize coordinated molecular alterations in IPF fibroblasts. Primary lung fibroblasts derived from patients with IPF and control subjects were analyzed using integrated transcriptomic, proteomic, and metabolomic profiling. Publicly available RNA-sequencing data deposited in the Gene Expression Omnibus (GEO; GSE301181) were used for transcriptomic analysis, while proteomic and metabolomic analyses were newly performed in a donor-matched subset of 10 IPF patients and 10 control subjects. Differentially expressed genes (DEGs), proteins (DEPs), and metabolites were identified using standardized statistical criteria, and cross-layer integration was conducted to identify molecules showing concordant regulation. Transcriptomic analysis identified 1,689 DEGs in IPF fibroblasts, whereas proteomic profiling initially quantified 6,236 proteins; after restricting analyses to peptide-supported proteins (≥2 unique peptides), 56 high-confidence DEPs were retained. Integration of transcriptomic and proteomic datasets identified 10 peptide-supported molecules exhibiting concordant regulation at both the mRNA and protein levels. Metabolomic profiling demonstrated significant reductions in metabolites involved in redox balance, lipid metabolism, glycolysis, nitrogen metabolism, and amine metabolism, indicating broad metabolic reprogramming associated with persistent fibroblast activation. Together, these findings suggest that IPF fibroblast activation is accompanied by coordinated transcriptional, translational, and metabolic reprogramming and highlight the value of integrated multi-omics analysis for interpreting regulatory features of fibrotic fibroblasts.

The mechanisms of Alzheimer's disease (AD) development are complex, and the detailed roles of neuroinflammation in AD still need to be elucidated. With various genetic and environmental risk factors, the accumulation of harmful amyloid plaques containing amyloid-β (Aβ) peptides is one of the main hallmarks of AD. Recent findings show that the innate immune protein interferon-induced transmembrane protein 3 (IFITM3) binds to γ-secretase and modulates Aβ production, providing a direct link between neuroinflammation, amyloidogenesis, and the pathogenesis of AD. In this review, we explore IFITM3-mediated modulation of γ-secretase complex activity and its pivotal role in AD pathology during neuroinflammation. Furthermore, we also provide an overview of the recent growing evidence connecting the roles of infection, the immune system, and AD pathogenesis.

Glycosylation, the enzymatic addition of sugar chains to proteins and lipids, is the most abundant and chemically diverse form of post-translational modification in eukaryotes. Despite its central role in cell biology, the glycosylation machinery has long been overlooked as a potential driver of cancer. By systematically mining large-scale cancer genomic datasets for somatic copy number alterations, we identified glycosyltransferases as a new class of oncogenic amplification targets. Here we discuss the biological rationale for why alterations in glycosyltransferase genes can drive oncogenesis, the role of the Golgi apparatus as the organizing hub of glycan biosynthesis, and the emerging therapeutic implications of these findings. Collectively, this evidence positions the glycosylation machinery not merely as a bystander altered in malignancy, but as an active and targetable driver of cancer.

X-ray repair cross-complementing protein 1 (XRCC1) protects cells from the effects of genotoxic stress by coordinating base excision repair (BER) and DNA single-strand break repair. XRCC1 phosphorylation and recruitment to sites of DNA damage are dependent on poly(ADP-ribose) polymerase-1 (PARP1) activity. As a central scaffolding protein, XRCC1 interacts with multiple components of BER pathway and also contributes to DNA double-strand break repair through the alternative nonhomologous end-joining pathway. In this regard, both established and recent studies have highlighted its critical role in spermatogenesis, extending beyond its classical association with PARP1. By integrating expression profiles with functional evidence, this review summarizes current insights into XRCC1 expression and subnuclear localization in spermatogenic cells, as well as its cooperative interaction with PARP1 in maintaining genomic integrity through efficient recombination and repair of genotoxic damage.

Lipid metabolism is abnormal in patients with atopic dermatitis (AD). This study aimed to screen lipid metabolism-related gene (LMRG) in AD, providing insights into the underlying mechanisms of lipid metabolism abnormalities in AD. Gene expression profiles from the Gene Expression Omnibus were analyzed to identify a hub LMRG in AD through an integrative approach combining weighted gene co-expression network analysis, differential expression analysis, and machine learning. The diagnostic value of the hub gene was assessed by receiver operating characteristic curve analysis. Its biological functions and associations with immune cells were investigated using Gene Set Enrichment Analysis (GSEA)/GSVA and ssGSEA/correlation analysis, respectively. The expression of ganglioside GM2 activator (GM2A) in clinical samples was measured using reverse transcription quantitative polymerase chain reaction and an ELISA assay. We identified 14 LMRGs that were differentially expressed between AD and normal samples and were correlated with AD onset. By three machine learning algorithms, GM2A was identified as a robust LMRG in AD. GM2A expression was observed to be elevated in AD samples across transcriptomic analyses and clinical validation. Moreover, GM2A might be effective in distinguishing between individuals with AD and those without. We further discovered that GM2A was associated with immunomodulation, inflammatory response, and biosynthesis of unsaturated fatty acid pathways. GM2A expression was positively correlated with follicular helper T cells, Activated CD4+ T cells, and natural killer T cells. Besides, there was a significant relationship between GM2A and multiple drugs. This study highlighted the significant up-regulation of GM2A as an efficient biomarker for AD, linking it to immune and inflammatory responses as well as immune cell infiltration.

Neurodegenerative diseases (NDDs) represent a growing global health burden, particularly in aging populations. These disorders primarily affect neurons and are characterized by progressive neuronal dysfunction and loss within specific regions of the central nervous system. Major NDDs include Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, and stroke. Although each disorder exhibits distinct genetic backgrounds and pathological protein aggregates, they share common pathogenic mechanisms, including chronic neuroinflammation, impaired autophagy and mitophagy, disrupted proteostasis, telomere instability, and epigenetic alterations. A hallmark feature across NDDs is the accumulation of misfolded proteins, leading to synaptic dysfunction and neuronal degeneration. Small ubiquitin-like modifiers (SUMOs) are a family of ∼100 amino acid proteins, including SUMO1 and the closely related SUMO2/3 isoforms. SUMOylation is a dynamic posttranslational modification that regulates protein function through the covalent attachment or removal of SUMO moieties. This reversible process is mediated by SUMO-specific E1 activating, E2 conjugating, and E3 ligating enzymes and is counterbalanced by SUMO/Sentrin-specific proteases. The SUMOylation status of target proteins depends on the tightly controlled balance between conjugation and deconjugation systems. Acting as a molecular switch, SUMOylation modulates diverse cellular processes such as DNA damage repair, RNA metabolism, transcriptional regulation, and protein quality control, all of which are essential for maintaining cellular homeostasis. Accumulating evidence links dysregulated SUMOylation to the pathogenesis of multiple neurological disorders, including polyglutamine and synucleinopathies. SUMOylation influences neuroinflammation, oxidative stress, protein aggregation, neuroangiogenesis, ischemic injury, and demyelination. This review highlights recent advances in understanding the role of SUMOylation in NDDs and explores its potential as a promising therapeutic target.

During final cell division, the cleaved midbody is either released or asymmetrically retained as a midbody remnant (MBR). MBRs play critical roles in cell communication, signal transduction, and translation regulation, influencing cellular fate. Here, we synthesize their functions as RNA-processing granules, polarity regulators, and signaling platforms, emphasizing their role in primary cilia formation. In polarized epithelial cells, the MBR moves along the apical surface to the centrosome, delivering membrane components to permit ciliogenesis. In ductal carcinoma cells, MBR-localized Shc1-binding protein (SHCBP1) interacts with TBC1 domain family member 30 (TBC1D30 to antagonize Ras-related protein Rab-8 (Rab8) GTPase activity, blocking MBR-centrosome proximity and silencing ciliogenesis. Beyond ciliary regulation, MBRs integrate Wnt, PDGF, TGF-β, and genomic stability networks, acting as dynamic signaling hubs during cancer development. Regarding therapeutic strategies targeting MBRs, High SHCBP1 expression correlates with ciliary loss and poor prognosis in breast, pancreatic, and cholangiocarcinoma. Targeting the SHCBP1/Rab8 axis to restore ciliogenesis by reestablishing MBR-centrosome proximity offers a potential therapeutic strategy. In addition, secreted MBRs are enriched in signaling components and transcripts, serving as intercellular carriers of oncogenic cargoes and promising liquid biopsy biomarkers. In summary, by tracing MBRs from their postmitotic origin to their pathogenic roles, we highlight vulnerabilities within MBR regulatory networks and provide novel insights for cancer therapeutics.