Frontiers in Molecular Biosciences最新文献

{"title":"Therapeutic reprogramming of natural killer cells for solid tumors: expanding frontiers into rare and ultra-rare malignancies.","authors":"Francesca Rosato, James W Hodge","doi":"10.3389/fmolb.2026.1955532","DOIUrl":"10.3389/fmolb.2026.1955532","url":null,"abstract":"<p><p>Rare and ultra-rare solid tumors collectively account for approximately one-quarter of all cancer diagnoses yet remain associated with poor clinical outcomes. Delayed diagnosis, limited biological characterization, few therapeutic options, and the logistical challenges of conducting adequately powered clinical trials underscore the potential for adaptable cellular immunotherapies that can be applied across diverse tumor histologies. Natural killer (NK) cells have emerged as a promising platform for adoptive cell therapy because of their ability to recognize and eliminate malignant cells independently of major histocompatibility complex restriction, their favorable safety profile, and their suitability for standardized allogeneic, off-the-shelf manufacturing. This review examines the progression of NK cell-based therapies from their biological and therapeutic foundations in solid tumors to their emerging application in rare and ultra-rare malignancies. Recent advances in NK cell engineering are enabling multifunctional cell products designed to enhance tumor recognition, trafficking, persistence, and resistance to the immunosuppressive tumor microenvironment. We also review emerging clinical evidence demonstrating the feasibility and safety of these approaches while highlighting the major biological and translational barriers that continue to limit durable responses. Building on these advances, attention is given to the unique challenges of rare and ultra-rare cancers, where small patient populations, tumor heterogeneity, limited therapeutic targets, and logistical constraints pose unique challenges to conventional drug and cellular therapy development. Finally, we discuss how scalable off-the-shelf manufacturing, rational combination strategies, innovative clinical trial designs, and next-generation technologies, including multiplex gene editing, armored NK cells, and <i>in vivo</i> engineering, may facilitate this translation. Collectively, progress in NK cell therapy across solid tumors provides a framework for extending increasingly adaptable and scalable immunotherapeutic platforms to rare and ultra-rare malignancies, with the potential to expand treatment opportunities for patient populations that have historically had limited therapeutic options.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"13 ","pages":"1955532"},"PeriodicalIF":4.4,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13644166/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149135515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Blood-based proteomics for schizophrenia: candidate biomarkers for risk assessment and precision psychiatry.","authors":"Alexey S Kononikhin, Anna E Bugrova, Arina S Foliforova, Maria I Indeykina, Polina A Strelnikova, Natalia V Zakharova, Anna Y Morozova, George P Kostyuk, Evgeny N Nikolaev","doi":"10.3389/fmolb.2026.1882675","DOIUrl":"10.3389/fmolb.2026.1882675","url":null,"abstract":"<p><p>Schizophrenia (SCZ) is a severe mental disorder where diagnosis remains subjective, and treatment efficacy is limited by high heterogeneity, particularly for negative and cognitive symptoms. There is an urgent need for objective molecular biomarkers, especially for early diagnosis and for identifying individuals at clinical high risk (CHR) for psychosis. This review analyzes blood proteomic studies in SCZ, CHR states, and related disorders (2019-2025), categorizing them into mass-spectrometry (MS)-based approaches (panoramic and targeted) and affinity-based methods (Olink, SOMAscan). It synthesizes findings from global discovery projects, targeted validation studies, critical risk prediction models, and large-scale Mendelian randomization analyses using UK Biobank data. The field is transitioning from cataloging differentially expressed proteins to identifying causal biomarkers with therapeutic potential (druggability). We propose a consolidated panel of high-priority protein markers, including the ITIH family, CRP, DNER, CTSS, and complement proteins. A critical gap remains in the incomplete coverage of these markers in commercial assays for targeted MS. The future lies in integrating validated proteomic panels with genetic data to enable personalized therapeutic strategies. However, significant hurdles related to reproducibility, cohort heterogeneity, and the lack of standardized validation protocols must be overcome before these biomarkers can be translated into routine clinical practice. Ongoing debates include the choice between MS-based and affinity-based platforms for clinical translation, the interpretation of complement and inflammatory markers as either core pathophysiological drivers or non-specific epiphenomena, and the predictive value of proteomic signatures for psychosis transition. Recent large-scale studies provide a crucial methodological framework, demonstrating the power of rigorous validation and the importance of harmonized, multi-cohort analyses for advancing the field toward clinical implementation.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"13 ","pages":"1882675"},"PeriodicalIF":4.4,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13643384/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149135835","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ferroptosis nanomedicine for cancer therapy: strategies and challenges.","authors":"Yanpin Ma, Ziyi Xu, Hudabia Akram, Tiancheng Yang, Jiachun Sun, Xinyu Gu","doi":"10.3389/fmolb.2026.1950781","DOIUrl":"10.3389/fmolb.2026.1950781","url":null,"abstract":"<p><p>Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation, and it has become an attractive strategy for cancer therapy because it can target redox and metabolic vulnerabilities that differ from those exploited by apoptosis-based treatments. Small-molecule ferroptosis inducers have clarified the therapeutic logic of this pathway, but their use in cancer treatment requires control over pharmacokinetics, tumor selectivity, local activation and systemic safety. Nanomedicine offers a programmable route to address these requirements. Engineered nanoplatforms can supply catalytic iron, remodel the tumor redox state, deplete antioxidant defenses, carry ferroptosis inducers, respond to tumor microenvironmental cues and combine ferroptosis with phototherapy, sonodynamic therapy, chemotherapy, radiotherapy or immunotherapy. Yet the field remains largely preclinical, and translation will depend on biodistribution, degradability, metal-related toxicity, manufacturing reproducibility, pharmacodynamic biomarkers and rational patient selection. This review summarizes the biological rationale for ferroptosis-targeted cancer therapy, analyzes major translational barriers, and synthesizes nanomedicine strategies that may move ferroptosis induction from experimental proof of concept toward clinically interpretable intervention.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"13 ","pages":"1950781"},"PeriodicalIF":4.4,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13644005/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149134543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of an application for colorectal cancer prediction using SDC2 and TFPI2 methylation: an opportunity for early and noninvasive diagnosis in Latin-America.","authors":"Fernando Hernandez-Medina, Alejandro Cornejo, Andrea Orue","doi":"10.3389/fmolb.2026.1922606","DOIUrl":"10.3389/fmolb.2026.1922606","url":null,"abstract":"<p><p>Colorectal cancer remains a major public health challenge globally and within Latin-America, where expanding mortality rates are compounded by heterogeneous access to screening programs, healthcare infrastructure. While early detection is critical to improving survival rates, conventional fecal tests and colonoscopies face significant financial, logistical, and patient-adherence barriers in resource-limited settings. Epigenetic alterations, specifically promoter hypermethylation of CpG islands, occur early during the adenoma-carcinoma sequence and provide stable, highly sensitive targets for noninvasive molecular diagnostics. In this Perspective, we discuss the molecular rationale and complementary diagnostic value of combining two robustly validated epigenetic biomarkers, Syndecan-2 (SDC2), which modulates epithelial integrity and signaling, and Tissue Factor Pathway Inhibitor-2 (TFPI2), a critical serine protease inhibitor regulating extracellular matrix remodeling. Transcriptional silencing of these genes through aberrant hypermethylation reflects distinct yet commentary pathways of colorectal carcinogenesis, providing the molecular foundation for the implementation strategy proposed herein. To overcome technical barriers that currently limit the broader adoption of methylation-based screening, we present the integration of validated quantitative real-time PCR (qPCR) methylation assays with ColoGuardIA, an open-source, lightweight, Shiny-based digital application developed by our group as an implementation-oriented proof-of-concept platform. ColoGuardIA facilitates the standardized interpretation of qPCR-derived cycle threshold (Ct) values generated by previously validated methylation tests. By helping bridge the gap between molecular oncology and decentralized clinical implementation, this framework represents a scalable strategy to support the adoption of noninvasive methylation-based screening approaches and improve access to early colorectal cancer detection in Latin-America.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"13 ","pages":"1922606"},"PeriodicalIF":4.4,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13639266/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149106651","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated microarray-based and single-cell transcriptomic analyses reveal cell adhesion-related fibrotic remodeling signatures in heart failure.","authors":"Shun Zhang, Le Li, Zuohua Li, Xiaojun Wang, Juan Zhou, Qing Lyu","doi":"10.3389/fmolb.2026.1929610","DOIUrl":"10.3389/fmolb.2026.1929610","url":null,"abstract":"<p><strong>Background: </strong>Heart failure (HF) is characterized by impaired cardiac pumping function and progressive remodeling. Cell adhesion is essential for tissue integrity and the regulation of inflammation and fibrosis. This study aimed to identify key cell adhesion-related genes (CARGs) and explore their roles in HF.</p><p><strong>Methods: </strong>HF-related transcriptomic datasets (GSE1621, GSE5500, GSE36074, GSE18224, GSE308859, and GSE116250) were obtained from GEO. Differentially expressed genes were intersected with cell adhesion-related genes from MSigDB to identify CARGs. Functional enrichment and protein-protein interaction analyses were performed. A CARG-based CelladhesionScore was constructed to evaluate its discriminatory value and associated pathways. Key CARGs were identified using CytoHubba. Single-cell transcriptomic analysis was conducted to assess fibroblast states and gene dynamics. GSE36074 and a transverse aortic constriction (TAC) mouse model were used for validation by qPCR, Western blotting, and immunohistochemistry.</p><p><strong>Results: </strong>Forty-five differentially expressed CARGs were identified and were mainly enriched in cell adhesion, extracellular region, and ECM-receptor interaction pathways. The CelladhesionScore distinguished HF samples from controls, while the high-CelladhesionScore group showed enrichment of fibrosis-related pathways. <i>Col5a1</i>, <i>Col6a1</i>, and <i>Fbn1</i> were identified as key CARGs. Single-cell analysis showed that these genes were predominantly expressed in fibroblasts and associated with fibroblast-state changes and ECM remodeling. Their upregulation was consistently validated in external datasets and the TAC mouse model.</p><p><strong>Conclusion: </strong><i>Col5a1</i>, <i>Col6a1</i>, and <i>Fbn1</i> are key CARGs associated with HF and fibroblast-mediated ECM remodeling. These findings provide new insights into cell adhesion-related molecular alterations in HF and may facilitate the identification of candidate biomarkers and therapeutic targets.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"13 ","pages":"1929610"},"PeriodicalIF":4.4,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13640610/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149106740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-omics analysis unveils inflammatory and metabolic alterations between the synovium and cartilage in patients with knee osteoarthritis.","authors":"Wenlong Xu, Shao Cheng, Zhen Wang, Shang Ma, Xiaokun Dong, Jinxin Ma, Bowen Zheng, Bingqi Wei, Shangzeng Wang","doi":"10.3389/fmolb.2026.1855139","DOIUrl":"10.3389/fmolb.2026.1855139","url":null,"abstract":"<p><strong>Background: </strong>KOA (knee osteoarthritis) is a degenerative disease affecting the entire joint, involving synovial inflammation and cartilage degeneration, but their molecular interplay remains unclear. This study integrated proteomics and metabolomics to investigate cross-tissue alterations in KOA.</p><p><strong>Methods: </strong>Paired synovial and cartilage tissues from 12 KOA patients and 12 controls were analyzed using DIA proteomics and untargeted metabolomics. The major molecular abnormalities in OA synovium and cartilage were evaluated through differential expression analysis, GO and KEGG functional enrichment analyses, protein-protein interaction network analysis, protein-metabolite integrated analysis, and cross-tissue integrative analysis. TIAM1, Rac1, and MRPS7 were validated by Western blot.</p><p><strong>Results: </strong>Proteomic analysis showed that proteins related to inflammation and cytoskeletal remodeling were significantly upregulated in OA synovial tissue, including increased expression of TIAM1. In cartilage tissue, proteins related to mitochondrial translation and energy metabolism were significantly downregulated, including decreased expression of MRPS7. Metabolomic analysis indicated enhanced arachidonic acid metabolism in synovial tissue, with significantly increased levels of inflammation-related metabolites such as PGE2 and 12-HETE. In cartilage tissue, metabolites related to the tricarboxylic acid cycle and pyrimidine metabolism were decreased, suggesting impaired energy supply and nucleotide metabolism. Protein-metabolite integrated analysis further showed that the differential molecules in OA synovium were mainly involved in inflammatory signaling, nucleotide metabolism, carbohydrate metabolism, and lipid mediator output, whereas those in OA cartilage were mainly associated with mitochondrial function, basal metabolism, cellular stress, and matrix homeostasis-related processes. Integrated analysis suggested that the synovial TIAM1/Rac1-related pathway may be involved in the inflammatory microenvironment and cytoskeletal remodeling, whereas the downregulation of MRPS7 in cartilage indicates suppressed mitochondrial translation. Western blot results further validated the upregulation of TIAM1 and Rac1 in OA synovium and the downregulation of MRPS7 in OA cartilage.</p><p><strong>Conclusion: </strong>This multi omics study revealed the cross tissue molecular characteristics of KOA, manifested as synovitis metabolic activation and cartilage energy metabolism dysfunction, suggesting that it may be closely related to the regulation of TIAM1-Rac1 signaling axis and mitochondrial damage. These findings provide a new perspective for a deeper understanding of the pathogenesis of KOA and point out potential therapeutic intervention targets.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"13 ","pages":"1855139"},"PeriodicalIF":4.4,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13639140/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149106806","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"H⁺ exchange and pH profiling of select non-glycolytic cytosolic phosphate transfer and oxidation-reduction reactions.","authors":"Robert Robergs, Marek Nalos, Petr Kelbich, Adela Jizerová, Ivana Mervartová, Michal Vostrý, Milan Štengl, Vaclav Babuška","doi":"10.3389/fmolb.2026.1816622","DOIUrl":"https://doi.org/10.3389/fmolb.2026.1816622","url":null,"abstract":"<p><strong>Background: </strong>Despite animal research of cellular and systemic acidosis for more than 100 years, there is no dominant evidence-based understanding of the cause of metabolic acidosis. Embedded in this crisis state is the understanding that the hydrogen ion (H⁺) involved in some chemical reactions, either as a substrate or product (H⁺ exchange (H⁺ _e)), does not change the pH of biological solutions. This research documents the direct roles of the H⁺ _e of a selection of non-glycolytic cytosolic chemical reactions in changing the pH of an unbuffered aqueous solution.</p><p><strong>Methods: </strong>Reagents were prepared using deionized water, substrates at known concentrations, enzymes and needed activator chemicals. The chemical reactions studied were creatine kinase (CKase) (to ATP and CrP), ATPase, hexokinase (HKase), and glucose-6-phosphate dehydrogenase (G₆PDHase). Each reaction was started by addition of the enzyme, and reagent pH was measured intermittently using a pH electrode. Samples of reagent (200 μL) were acquired for product measurement by spectrophotometry.</p><p><strong>Results: </strong>Results are presented as start pH:end pH; [Product], mmol·L^-1; pH:[Product] slope, pH.mmol^-1.L^-1: CKase to ATP (7.49:9.51; [1.95]; 1.289); CKase to CrP (8.29:7.89; [0.64]; -1.35); ATPase (8.94:8.23; [0.84]; -0.9385); HKase (8.59:6.55; [2.36];-1.596), G₆PDHase (7.53:6.89; [1.46]; -0.8006). All chemical reactions that produced carboxylic acids did so as anions, and all resulted in pH responses consistent with the role of the H⁺ as a substrate or product. The sequencing or summing of the CKase, ATPase, HKase and G6PDHase reactions revealed potential for summative computational modelling.</p><p><strong>Conclusions: </strong>The evidence opposes traditional theories as the sole cause of cellular or systemic acidosis.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"13 ","pages":"1816622"},"PeriodicalIF":4.4,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13634964/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149106622","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immune-modulating copper-doped bioactive glass-based injectable hydrogel for periodontitis therapy.","authors":"Huiqin Lv, Onaza Ali, Ting Tu, Zhe Liu, Yunyan Zhan","doi":"10.3389/fmolb.2026.1843490","DOIUrl":"10.3389/fmolb.2026.1843490","url":null,"abstract":"<p><strong>Background: </strong>Periodontitis, a chronic inflammatory disorder driven by microbial dysbiosis and aberrant host immune responses, poses a significant challenge to periodontal tissue regeneration owing to persistent infection and impaired osteogenesis.</p><p><strong>Objective: </strong>Herein, we engineered an injectable hydrogel (denoted Cu@BG-HA) via borate ester crosslinking of copper-doped mesoporous bioactive glass nanoparticles (Cu@BG, 480 nm) with hyaluronic acid, aiming to concurrently address antibacterial, immunomodulatory, and osteogenic deficits in the periodontal microenvironment.</p><p><strong>Methods: </strong>The Cu@BG-HA hydrogel was synthesized through dynamic borate ester bond formation between Cu@BG nanoparticles and HA polymer networks. The physicochemical properties, ion release kinetics, and therapeutic efficacy were systematically characterized using <i>in vitro</i> models of bacterial infection, macrophage polarization, and osteoblast differentiation.</p><p><strong>Results: </strong>The Cu@BG-HA hydrogel demonstrated sustained Cu²⁺ release over 24 days, achieving eradication rates of 99.8% ± 3.2% against <i>Staphylococcus aureus</i> and 98.6% ± 1.7% against <i>Porphyromonas gingivalis</i>. Under lipopolysaccharide/interferon-γ (LPS/IFN-γ) stimulation, the hydrogel effectively orchestrated macrophage phenotype switching from pro-inflammatory M1 toward anti-inflammatory M2 states in RAW264.7 cells. Furthermore, Cu@BG-HA markedly potentiated osteogenic differentiation of MC3T3-E1 pre-osteoblasts, evidenced by 1.8- and 1.7-fold enhancements in alkaline phosphatase activity and mineralized nodule formation, respectively, relative to control conditions.</p><p><strong>Conclusion: </strong>Collectively, these findings establish Cu@BG-HA as a multifunctional, minimally invasive therapeutic platform that integrates potent antibacterial, immunomodulatory, and pro-osteogenic functionalities. This strategy offers substantial translational potential for periodontitis management and may be extendable to other inflammatory osteolytic pathologies.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"13 ","pages":"1843490"},"PeriodicalIF":4.4,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13673140/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149215498","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Heterogeneous mechanisms, risk stratification, and translational advances in the malignant transformation of oral potentially malignant disorders to oral squamous cell carcinoma.","authors":"Zijing Yu, Hutao Peng, Xiaobo Cheng, Wenpin Xu, Yupei Wang, Yinhu Xiao, Ting Wei, Zhizhen Huang, Yang He, Jian Wang","doi":"10.3389/fmolb.2026.1948915","DOIUrl":"https://doi.org/10.3389/fmolb.2026.1948915","url":null,"abstract":"<p><p>Oral potentially malignant disorders (OPMDs) represent important precursor conditions in the development of oral squamous cell carcinoma (OSCC) and provide a critical window for early prevention, risk assessment, and precision intervention of oral cancer. Oral leukoplakia, proliferative verrucous leukoplakia, oral erythroplakia, oral lichen planus, and oral submucous fibrosis are among the most common and clinically significant OPMDs. Although these disorders may contribute to malignant transformation through shared mechanisms, including chronic inflammation, oxidative stress, genetic and epigenetic alterations, immune dysregulation, epithelial-mesenchymal crosstalk, and microbiome dysbiosis, their predominant pathological processes and malignant transformation trajectories exhibit substantial heterogeneity. Oral leukoplakia is characterized by marked clinical and molecular heterogeneity, genomic instability, and field cancerization effects; Proliferative verrucous leukoplakia is characterized by progressive multifocal disease, an exceptionally high risk of malignant transformation, and a pronounced propensity to develop multiple primary oral cancers; oral erythroplakia is frequently associated with high-grade epithelial dysplasia or early invasive carcinoma; oral lichen planus represents an immune-mediated chronic inflammatory microenvironment that may facilitate tumorigenesis; and oral submucous fibrosis represents a matrix-driven precancerous condition primarily characterized by areca nut exposure and fibrotic extracellular matrix remodeling. In recent years, advances in single-cell omics, spatial omics, salivary liquid biopsy, digital pathology, artificial intelligence, and local drug delivery systems have provided emerging technological platforms for dynamic risk stratification, early diagnosis, and precision prevention of malignant transformation in OPMDs. This review summarizes the epidemiological links between major OPMDs and OSCC, disease-specific and shared mechanisms underlying malignant transformation, candidate biomarkers, risk stratification strategies, and advances in translational therapies. Furthermore, it aims to establish an integrated management framework for oral potentially malignant lesions based on the \"epithelial-immune-stromal-microbial\" niche.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"13 ","pages":"1948915"},"PeriodicalIF":4.4,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13631419/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149106795","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lipid signature in X-ALD: a comparison between phenotypes.","authors":"Alessandra Di Veroli, Sara Petrillo, Caterina Torda, Federica Loia, Teresa Rizza, Rosalba Carrozzo, Gabriele Cruciani, Enrico Bertini, Francesco Nicita, Fiorella Piemonte, Marco Cappa","doi":"10.3389/fmolb.2026.1906499","DOIUrl":"https://doi.org/10.3389/fmolb.2026.1906499","url":null,"abstract":"<p><strong>Background: </strong>X-linked adrenoleukodystrophy (X-ALD) has highly variable phenotypes with no known genotype/phenotype correlation or method for predicting the course of the disease. Screening for X-ALD allows for early, potentially lifesaving treatment of adrenal insufficiency and cerebral demyelination, possibly useful to detect pre-clinical differences in patients and extend treatments to pre-symptomatic subjects. In this study, we analyzed the lipid signature in fibroblasts of patients with Adrenomyeloneuropathy (AMN), the late onset and slowly progressive form of X-ALD, and in patients with Cerebral Adrenoleukodystrophy (CALD), the cerebral inflammatory demyelinating form of early childhood, in order to identify specific lipid molecules as potential early predictors for CALD.</p><p><strong>Methods: </strong>We analyzed lipidomic profiles in fibroblasts obtained from n = 4 clinically affected (and genetically proven) X-ALD patients (two CALD and two AMN) and n = 4 age-matched controls, using a Dionex UltiMate 3000 UHPLC system, coupled to a Q-Exactive mass spectrometer.</p><p><strong>Results: </strong>Our results highlight alterations in lipid metabolism both in AMN and in CALD fibroblasts relative to controls, further confirming the role of LPC 26:0 as a potential biomarker of X-ALD. However, the extent and pattern of lipid remodeling differ substantially between the two phenotypes, with a contribution of neutral lipids in CALD patients, along with a selective involvement of gangliosides.</p><p><strong>Conclusion: </strong>Although both AMN and CALD fibroblasts share some disease-associated lipid alterations, CALD samples exhibited a broader and more pronounced perturbation in multiple lipid classes, particularly in LPCs and steryl esters. The identification of phenotype-associated lipid signatures may represent a step forward toward precision medicine in X-ALD, in order to improve patient phenotypic evaluation.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"13 ","pages":"1906499"},"PeriodicalIF":4.4,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13630669/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149106746","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}