Abstract The oral microbiome is increasingly recognized as an upstream ecological interface with systemic relevance beyond oral disease. Emerging evidence links oral dysbiosis to skeletal pathology through an oral–gut axis involving salivary microbial transfer, gut remodeling, barrier dysfunction, and microbiota-derived metabolites. In this review, we summarize current evidence supporting the oral–gut–bone axis in systemic bone-related diseases and propose an integrated framework in which oral ecological disturbance may contribute to skeletal vulnerability through gut-dependent metabolic and inflammatory relay mechanisms. We highlight three major mechanistic architectures: metabolite-centered osteoimmune regulation, barrier dysfunction with inflammatory amplification, and oral-derived microbial signaling. Across rheumatoid arthritis, osteoarthritis, and osteoporosis, these pathways are associated with distinct downstream phenotypes, including inflammatory bone erosion, degenerative joint remodeling, and systemic bone loss. Short-chain fatty acids, valeric acid, bile acid derivatives, and tryptophan-derived indoles emerge as key intermediates linking microbial ecology to osteoclastogenesis, osteoblast activity, immune polarization, and joint homeostasis. We also discuss translational opportunities involving metabolite restoration, microbiota-targeted intervention, host-pathway modulation, and mechanism-guided biomarker development. Despite recent progress, most current evidence remains associative, and major gaps persist in causal inference and functional validation.
Abstract Craniofacial development is a complex process shaped by the coordinated work of multiple embryonic lineages, including cranial neural crest cells (CNCCs), surface ectoderm, mesoderm, and pharyngeal endoderm. CNCCs make major contributions to craniofacial skeletal and connective tissues, but craniofacial morphogenesis cannot be explained by one lineage alone. This process depends on active interactions among different cell lineage populations, which provide both structural components and regulatory signals. Recent advances in single-cell and spatial omics technologies have shown that lineage specification and differentiation are controlled by intrinsic gene regulatory programs and extrinsic cues, including morphogen signaling, extracellular matrix remodeling, and biomechanical forces. These interactions are especially critical during neural crest migration, epithelial-mesenchymal communication, and organogenesis of craniofacial structures, including teeth and glands. In this review, we summarize how multiple lineages contribute to craniofacial formation and highlight the coordinated mechanisms that bring these lineages together during development. We combine classical embryological concepts with recent molecular findings to show that craniofacial morphogenesis is a systems-level process. This view helps explain craniofacial disorders and supports regenerative strategies that recreate complex tissue architecture and function.
Abstract Diabetic cutaneous wounds, particularly diabetic foot ulcers, are among the most severe chronic complications of diabetes mellitus and remain a major clinical challenge because of persistent inflammation, oxidative stress, impaired angiogenesis, and delayed tissue regeneration. Although conventional therapies such as debridement, infection control, and growth factor application can partially improve wound conditions, their overall efficacy remains limited. Mesenchymal stem cell-derived small extracellular vesicles (MSC-sEVs) have recently emerged as a promising cell-free therapeutic strategy for diabetic wound repair. Increasing evidence indicates that MSC-sEVs can regulate multiple pathological processes involved in diabetic wounds, including macrophage polarization, neutrophil extracellular trap formation, oxidative stress, ferroptosis, cellular senescence, and autophagy dysfunction. Through these mechanisms, MSC-sEVs promote angiogenesis, collagen deposition, fibroblast proliferation, keratinocyte migration, and re-epithelialization, thereby accelerating wound closure and tissue regeneration. This review summarizes recent advances in MSC-sEV-based diabetic wound therapy by linking major pathological barriers with specific cellular targets and molecular mechanisms, thereby highlighting the mechanistic basis and potential advantages of MSC-sEVs over conventional cell-based strategies. Current limitations, including heterogeneity of MSC sources, insufficient standardization of sEV isolation and characterization, limited retention at wound sites, and incomplete clinical validation, are also discussed. Future research should focus on standardized production, functional engineering, carrier-based delivery systems, and well-designed preclinical and clinical studies to facilitate the cautious and evidence-based translation of MSC-sEVs for chronic diabetic wound management.
Abstract The functional interdependence between type 2 immunity and the nervous system plays a critical role in maintaining tissue homeostasis and promoting repair across multiple organs. These systems act in concert through bidirectional crosstalk to preserve systemic physiological equilibrium. The nervous system, including its peripheral components, releases neuropeptides and neurotransmitters in response to signals from type 2 immune cells, such as T helper 2 (Th2) cells and group 2 innate lymphoid cells (ILC2s), thereby inducing cytokine production and immunomodulatory effects. Conversely, type 2 immune cells and their cytokines can sensitize peripheral nociceptors and regulate neurotransmitter release, forming a reciprocal feedback loop. This review summarizes the molecular mechanisms underlying type 2 neuroimmune interactions and their roles in physiological homeostasis and tissue repair across multiple organ systems, including the nervous system, skin, gastrointestinal tract, respiratory tract, and oral cavity. In addition, we highlight current controversies and knowledge gaps to identify critical molecular targets that confer specificity to type 2 neuroimmune interactions, and to propose emerging conceptual frameworks and research directions for the clinical management of related disorders.
Abstract Metabolic reprogramming is a hallmark of human cancers, including prostate cancer (PCa), yet its genomic drivers remain poorly understood. Unlike most cancers, which exhibit the Warburg effect, PCa usually possesses elevated oxidative phosphorylation (OXPHOS). This study investigates whether and how the loss of ZFHX3, a tumor suppressor frequently inactivated in advanced PCa, modulates cellular metabolism. Whereas ZFHX3 deep deletion in human PCa correlated with much worse patient overall survival than somatic mutations, it also correlated with enriched mitochondrial pathways. Analyses of ZFHX3-knockout PCa cells demonstrated a bioenergetic shift toward higher OXPHOS, characterized by enlarged mitochondria, increased tricarboxylic acid (TCA) cycle activity, enhanced ATP production, reduced reactive oxygen species, and improved redox homeostasis. Mechanistically, ZFHX3 loss elevated protein levels of Complex II subunits and their assembly without increasing their gene transcription. Functionally, inhibiting mitochondrial respiration or the SDHB subunit of Complex II abolished the ZFHX3-loss-enhanced cell proliferation, whereas inhibiting Complex II enzymatic activity did not. These findings uncover a novel ZFHX3 function in maintaining mitochondrial metabolic homeostasis, establish its loss as a driver of the OXPHOS shift during PCa progression, and highlight the ZFHX3 loss-Complex II disruption as a potential therapeutic opportunity for targeting PCa with ZFHX3 loss.
Abstract X-linked hypophosphatemia (XLH) is a hereditary disorder caused by dysregulation of the FGF23-kidney-bone/teeth axis, leading to chronic hypophosphatemia and impaired mineralization. As target organs highly sensitive to phosphate homeostasis, the teeth and jaw often exhibit pathological changes that precede skeletal deformities, offering early diagnostic value. This article elucidates the damaging effects of hypophosphatemia on dental hard tissues and craniofacial development. Hypophosphatemia-induced impaired dentin mineralization results in interglobular dentin retention and abnormal pulp morphology, which, together with enamel microcracks, constitute the pathological basis for spontaneous pulp infections and periapical lesions. Craniofacial manifestations also include jaw abnormalities, periodontal bone loss, and craniosynostosis. A diagnostic framework for XLH-related oral manifestations integrating imaging, biochemical markers, and genetic testing is proposed, with key differential diagnoses clarified. The article emphasizes the paradigm shift in managing XLH-associated oral complications from conventional phosphate/vitamin D supplementation to anti-FGF23 targeted therapy. It advocates for life-cycle oral management coordinated with systemic homeostatic reconstruction for XLH encompassing prevention, infection control, and multidisciplinary care. By integrating systemic etiological intervention with local precision therapy, this review aims to provide a basis for early identification and standardized management of XLH.
Mucosal barrier tissues, including the nasal, respiratory, oral, gastrointestinal, and urinogenital tract, constitute the largest interface between the host and the external environment. These surfaces are continuously exposed to pathogen infection and environmental pollutants. Disruption of mucosal barrier integrity leads to various inflammatory and infectious diseases. Emerging evidence suggests that programmed cell death (PCD) plays a crucial role in shaping the integrity of barrier and local immune responses. In recent years, rapid advances have led to the identification of multiple newly characterized PCD, including apoptosis, necroptosis, autosis, pyroptosis, PANoptosis, ferroptosis, cuproptosis, parthanatos, NETosis, disulfidptosis, entosis, anoikis, methuosis, alkaliptosis, oxeiptosis, lysozincrosis, NECSO (necrosis by sodium overload), and mitoxyperiosis. In this review, we summarize recent advances in PCD, emphasizing their morphological features, activation cascades, and regulatory mechanisms, and discuss their implications in mucosal barrier homeostasis. We further examine how dysregulated PCD contributes to epithelial dysfunction, chronic inflammation, and pathogen infection.
Head and neck cancer (HNC) is a highly prevalent and lethal carcinoma, with major risk factors including smoking, alcohol consumption, and HPV/EBV infection. Although immunotherapy has reshaped the treatment paradigm for HNC, patients with advanced disease still have a poor prognosis. Due to anatomical and functional complexities, patients with HNC often experience impairments in speech, swallowing, and respiration, together with appearance-related distress, resulting in severe psychosocial stress and psychological trauma. Emerging work in cancer neuroscience indicates that peripheral nerves and stress-responsive neuroendocrine pathways shape the tumor microenvironment to regulate tumor growth, angiogenesis, metastasis, immune evasion, and treatment response. Chronic stress drives cancer progression through sustained activation of the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system, elevating glucocorticoids and catecholamines that signal through glucocorticoid receptors and adrenergic receptors on tumor, stromal, and immune cells. This review explores the relationship between the nervous system and HNC, focusing on how stress affects cancer development and discussing innovative therapeutic strategies targeting neuroendocrine and neural components to improve HNC outcomes.
Oral mucosal diseases arise at a highly exposed barrier interface where microbial communities, mucosal immunity, and epithelial repair programs must remain dynamically balanced. Increasing evidence suggests that oral microbial dysbiosis is not merely a compositional shift, but a context-dependent functional state involving altered microbial localization, virulence programs, metabolic activity, and host sensing thresholds. In this Review, we examine oral candidiasis (OC), oral lichen planus (OLP), recurrent aphthous ulcer (RAU), oral leukoplakia (OLK), and oral squamous cell carcinoma (OSCC) as representative disease contexts along the continuum from oral homeostasis to barrier failure. We integrate microbial signals, immune remodeling, epithelial barrier states, and disease-stage transitions into an evidence-graded framework. We propose that dysbiosis may function as an initiating trigger, inflammatory amplifier, chronic maintenance factor, risk-associated ecological signal, or secondary colonization event, depending on disease context, stage, localization, and evidence certainty. OC currently has the strongest mechanistic and interventional support, whereas evidence in OLP, RAU, OLK, and OSCC remains more heterogeneous. This framework may guide future microbiota-informed risk stratification, prevention, adjunctive therapy, and supportive care.
The epigenome plays fundamental roles in diverse physiological processes, including the innate immune response to pathogen invasion. Dysregulation of epigenetic regulators leads to aberrant expression and activation of signaling cascades, thereby driving the development of disease. In this review, we discuss recent advances in how epigenetic regulators shape innate immune signaling networks, as well as the crosstalk between the epigenome and metabolites that have been identified as key regulatory molecules. We further highlight the critical functions of epigenetic modifiers in the pathogenesis of immune-related disorders, including sepsis and oral diseases, and summarize progress in therapeutic strategies targeting these regulatory factors.
Substantial evidence has linked the oral microbiome to various systemic diseases, but it remains unclear whether periodontal clinical trials have incorporated omics-level or systemic endpoints. We conducted a dual-modality analysis covering January 2016 to January 2026, including 2,031 Web of Science records and 1,199 interventional periodontal trials from ClinicalTrials.gov. Trial endpoints were classified into three hierarchical tiers using a standardized schema: microbiome/omics, systemic biomarkers, and local clinical parameters. The results showed that although annual publication volume on the oral-systemic axis increased approximately 7-fold, 87.2% of trials still used only local clinical endpoints, only 11.5% included systemic biomarkers, and only 1.3% included microbiome/omics endpoints, with no increase over the decade. Thus, despite substantial research growth, the endpoint structure of periodontal trials has remained largely unchanged, revealing a significant translational gap. Future trials should consider incorporating composite microbial endpoints and biobanking.
Three-dimensional (3D) epithelial models are widely used to investigate epithelial biology, host-pathogen interactions, and topical therapeutics. However, many existing models rely on primary keratinocytes or specific cell lines, limiting accessibility, reproducibility, and scalability. Besides, reliable oral epithelial models based on stable keratinocyte cell lines remain limited, as most current systems depend on primary cells or organotypic cultures. In this study, we established simplified and reproducible 3D epithelial models using an optimized air-liquid interface (ALI) culture system with two human keratinocyte cell lines, HaCaT (epidermal) and HOK (oral). After culture condition optimization, both cell types maintained stable stratification and differentiation across multiple passages. Histological analysis showed well-organized epithelial architectures with distinct basal and suprabasal layers. Immunofluorescence staining confirmed spatially distinct expression of epithelial differentiation markers closely resembling native epithelia. Functionally, the reconstructed epithelia robust barrier integrity and responded to Candida albicans infection. Moreover, the models allowed evaluation of drug permeability across epithelial layers. Collectively, this simplified 3D culture platform provides a reproducible, accessible strategy for constructing epithelial models using standardized keratinocyte cell lines without primary cells. The system offers a practical tool for oral and cutaneous epithelial research, with potential in infection studies, disease modeling, and preclinical drug screening.
Triggering receptor expressed on myeloid cells 1 (TREM-1) is a critical amplifier of innate immune responses, orchestrating pathophysiology across diverse inflammatory conditions. In the oral cavity, TREM-1 activation promotes the development of periodontitis, peri-implantitis, and oral lichen planus by polarizing myeloid cells toward a pro-inflammatory state, enhancing pro-inflammatory cytokine release, and accelerating tissue degradation and bone resorption. Notably, this TREM-1-driven myeloid dysregulation also underpins severe systemic comorbidities, including atherosclerotic cardiovascular disease (ASCVD), diabetic kidney disease (DKD), and Alzheimeru2019s disease (AD). This review synthesizes current knowledge to delineate the TREM-1 axis as a pathogenic hub in oral-systemic crosstalk, specifying three dissemination routes: systemic leakage of local mediators after barrier disruption, peripheral migration of epigenetically primed TREM-1+ cells, and synergy with metabolic risks. We further highlight soluble TREM-1 (sTREM-1) as a promising biomarker reflecting cumulative inflammatory burden. Ultimately, combining established oral therapies with emerging TREM-1-targeted strategies offers a mechanistically grounded framework to disrupt the oral-systemic disease continuum, providing novel therapeutic avenues for inflammatory comorbidities.
Targeting regulatory T (Treg) cells represents a promising strategy for reshaping peripheral immune homeostasis and treating inflammatory diseases, such as inflammatory bowel disease and multiple sclerosis. However, the two main strategies used for targeting Treg cells, which include adoptive Treg cell therapy and low-dose interleukin (IL)-2 treatment, have not achieved satisfactory clinical outcomes. Multiple studies have indicated that targeting Treg cells alone cannot effectively restore immune homeostasis. Here, we showed that the combination of low-dose IL-2 therapy and inhibition of IL-6/STAT3 signaling exhibits better therapeutic effects in the treatment of inflammatory bowel disease and experimental autoimmune encephalomyelitis. This combination therapy restored immune homeostasis and alleviated inflammation by significantly increasing Treg cells and suppressing effector T cells, such as T helper 1 and T helper 17 cells. Overall, our data indicate that the combination of low-dose IL-2 therapy and inhibition of IL-6/STAT3 signaling warrants further investigation as a means of remodeling immune homeostasis to treat mucosal inflammation and autoimmune disorders.
Type 2 diabetes (T2D) is associated with alterations in the oral microenvironment, including microbial dysbiosis and host transcriptional changes. Whether antidiabetic therapies such as semaglutide modulate these alterations in a coordinated manner remains unclear. To investigate the association between semaglutide treatment and coordinated changes in oral microbiota and host transcriptional programs. 16S rRNA sequencing and bulk RNA-seq were performed on oral samples from WT, db/db, and semaglutide-treated db/db mice. Microbial diversity, taxonomic composition, gene expression, and integrative analyses were conducted. u03B2 diversity revealed clear separation between WT and db/db groups, with treated samples partially shifting toward the WT state, while u03B1 diversity showed no significant difference. The dysbiosis index was increased in db/db mice and reduced following treatment. At the genus level, Bacillus and Delftia decreased, whereas Streptococcus increased in db/db mice, with opposite trends after treatment. Transcriptomic analysis identified interferon-enriched and metabolic-associated gene clusters, with modulation of interferon- and antiviral-response pathways following treatment. Integration analyses demonstrated reorganization of gene-microbiota networks and significant correlations between cluster-specific transcriptional programs and dysbiosis. T2D is associated with coordinated alterations in oral microbiota and host transcription, and semaglutide treatment is accompanied by partial remodeling of these features.
