Osteoarthritis (OA), a debilitating and progressive joint disease, presents major therapeutic challenges due to chondrocyte ferroptosis, chronic synovial inflammation, and the pharmacokinetic limitations of conventional intra-articular therapies, such as rapid clearance and poor retention. To overcome these barriers, we developed a dual-functional intra-articular delivery platform composed of a gelatin-hyaluronic acid hydrogel encapsulating fenofibrate-loaded, cartilage-targeting nanoparticles (FNPs-GelHA hydrogel). This system synergistically inhibits OA progression by simultaneously suppressing chondrocyte ferroptosis and modulating the inflammatory joint microenvironment. In vitro studies revealed that FNPs-GelHA hydrogel markedly attenuates chondrocyte ferroptosis, inflammation, oxidative stress, and lipid peroxidation. Furthermore, this system effectively reprograms macrophage polarization by suppressing pro-inflammatory M1 phenotypes and promoting reparative M2 phenotypes, thereby contributing to immunomodulation and cartilage repair. In addition, in vivo experiments demonstrated prolonged joint retention of this system and significant therapeutic efficacy in delaying OA progression. By integrating targeted drug delivery, ferroptosis inhibition, and immune microenvironment remodeling, this composite hydrogel-nanoparticle platform offers a synergistic and promising strategy for OA treatment.

Osteoporosis is a common disease whose primary treatment currently involves anti-osteoporosis medications. However, these drugs are often inconvenient to administer and are associated with side effects. Therefore, developing new treatments is of significant clinical importance. Puerarin (Pue) is a potential therapeutic agent for osteoporosis, but its poor solubility, low bioavailability, and instability limit its efficacy. In this study, we synthesized a tetrahedral framework nucleic acids(tFNAs)-puerarin complex (TPC) by loading puerarin onto tFNAs. TPC demonstrates enhanced cellular uptake and stability, and shows superior osteogenic activity and anti-osteoporosis effects compared to Pue alone, mediated through the FXR/Runx2 pathway. In summary, we have developed a novel nanocomplex, TPC, with promising therapeutic potential for osteoporosis.

Abstract Chronic bone and joint diseases severely affect the functional status of bone, cartilage, and soft tissues, thus leading to pain and dysfunction in the affected areas. Patients with these diseases can be treated by conservative methods such as oral medications in the early stages, while surgical interventions are commonly required for those in the advanced stage. As conventional anti-osteoporosis (OP) drugs, anti-inflammatory drugs, painkillers, and immunomodulators may induce side effects and drug resistance in the treatment process, it is necessary to explore new therapeutic drugs for the adjuvant treatment of chronic bone and joint diseases at an early or advanced stage. Epimedium is an herbal medicine in traditional Chinese medicine (TCM) and has been used for more than 2,000 years. As the main active ingredient in this herbal medicine, icariin (ICA) is effective in the treatment of chronic bone and joint diseases. This ingredient can be involved in the pathophysiological process of these diseases via modulating the osteogenic and chondrogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), inhibiting osteoclastogenesis, resisting inflammation, protecting the extracellular matrix (ECM), regulating oxidative stress (OS), and participating in immunomodulation. In this study, the role of Epimedium in the prevention and treatment of chronic bone and joint diseases was systematically reviewed. The results demonstrated that Epimedium can be used as a complementary and alternative medicine for the treatment of chronic bone and joint diseases. In this paper, the mechanism of action and potential application of Epimedium in the prevention and treatment of chronic bone and joint diseases were summarized. These findings may lay a foundation for the further development and clinical application of Epimedium as a medicinal food source.

Sarcomas are aggressive, immunologically cold tumors with limited benefit from immune-checkpoint blockade (ICB). Through integrated multi-omics, functional, and clinical analyses, we identify pyruvate dehydrogenase alpha 1 (PDHA1)-a cuproptosis-linked metabolic gene-as a driver of sarcoma progression and immune evasion. PDHA1 is consistently overexpressed across TCGA/GEO/ICGC cohorts and associates with poor prognosis, stromal activation, and reduced immune scores; single-cell RNA-seq of the immune compartment shows PDHA1 expression across multiple immune populations, with higher levels in T cells and monocytes/dendritic cells. PDHA1 knockdown diminishes proliferation, invasion, clonogenicity, and PD-L1 levels while increasing apoptosis. Mechanistically, PDHA1 elevates E2F1, which binds and transactivates the PD-L1 promoter; rescue assays confirm E2F1-dependent PD-L1 induction. Copper chelation with tetrathiomolybdate lowers lipoylated DLAT and suppresses the PDHA1-E2F1-PD-L1 axis. In 3D spheroids, xenografts, and multiplex immunofluorescence, high PDHA1 aligns with larger tumors, higher Ki-67/BCL-2, lower cleaved caspase-3, increased PD-L1, and reduced CD8⁺ T-cell infiltration. PDHA1 hypomethylation correlates with worse survival. PDHA1 status also modulates sensitivity to phenformin and the E2F1 pathway inhibitor NSC-207895. Collectively, PDHA1 orchestrates a cuproptosis-associated E2F1-PD-L1 program that promotes immune exclusion yet predicts ICB responsiveness, supporting PDHA1 as a clinically actionable biomarker and metabolic-immunologic target in sarcoma.

Sarcomas are a heterogeneous group of mesenchymal malignancies with diverse histological subtypes, limited treatment options, and generally poor outcomes in advanced disease. EXT2, a glycosyltransferase involved in heparan sulfate biosynthesis, has been implicated in tumor–microenvironment interactions, but its role in sarcoma progression and immune regulation remains incompletely understood. We integrated transcriptomic, epigenomic, and immune landscape analyses across public sarcoma datasets and clinical specimens to investigate the clinical and biological relevance of EXT2. Functional effects of EXT2 were assessed using in vitro assays, in vivo tumor models, and CD8+ T-cell co-culture systems. Single-cell RNA sequencing data were analyzed to localize EXT2 expression within the tumor microenvironment. EXT2 was consistently upregulated in sarcoma tissues and associated with unfavorable survival outcomes, with particularly consistent evidence in osteosarcoma cohorts. EXT2 silencing suppressed tumor cell proliferation, migration, invasion, and in vivo growth, accompanied by reduced AKT phosphorylation, c-Myc expression, and PD-L1 levels. EXT2-high tumors exhibited features of an immune-excluded microenvironment, including reduced CD8+ T-cell infiltration and enrichment of cancer-associated fibroblasts and M2-like macrophages. Although EXT2 expression was associated with higher tumor mutational burden and microsatellite instability, EXT2-high tumors showed predicted immune exclusion and reduced responsiveness to immune checkpoint blockade. Single-cell analyses localized EXT2 predominantly to stromal and endothelial compartments. These findings identify EXT2 as a clinically relevant regulator of sarcoma progression and immune modulation. By engaging an AKT/c-Myc/PD-L1 signaling axis and shaping an immune-excluded tumor microenvironment, EXT2 may serve as a prognostic biomarker and a potential therapeutic target in selected sarcoma subtypes, warranting further subtype-specific and mechanistic investigation.

Arthritis is an inflammatory condition that affects the joints and surrounding tissues, triggered by factors such as inflammation, infection, degeneration, and trauma. The major forms of arthritis include osteoarthritis (OA), rheumatoid arthritis (RA), and gouty arthritis (GA). Its pathogenesis primarily involves synovial inflammation, cartilage degradation, and subchondral bone remodeling, with pro-inflammatory cytokines, collagenases, and other mediators playing central roles in disease onset and progression. The bromodomain and extraterminal (BET) protein family-a subclass of the larger bromodomain protein superfamily-comprises BRD2, BRD3, BRD4, and BRDT. The regulatory functions of BET proteins in inflammation highlight their considerable potential for mitigating arthritis-related pathology. This review provides a comprehensive overview of recent research on the role of BET proteins in OA, RA, and GA, aiming to deepen our understanding of the protective mechanisms of BET inhibitors, underscore their potential as therapeutic targets, and emphasize their relevance in the development of novel treatment strategies.

Bones can fulfill functions in movement, attachment, and protection of internal organs. Bone diseases caused by ageing, trauma, infection, and other reasons may seriously affect the daily life of patients. Magnesium ions are closely associated with the maintenance of bone health. Integrating magnesium ions into delivery systems and hydrogels can improve their application, thus directly acting on the osteoblast cell lineage and influencing the proliferation and differentiation of relevant cells. The slow release of magnesium ions allows for their effects on the target site for a long time, reducing the clearance of magnesium ions in the body, which significantly contributes to bone repair. Magnesium-based bioalloy scaffolds have received widespread attention for their favourable biocompatibility, degradability, and bone-forming properties and play an important role in bone regeneration and repair. This article presents a review on the role and mechanism of magnesium-containing materials in bone repair and regeneration. By discussing the current challenges and future directions for magnesium-containing biomaterials, new insights are provided into the development of these materials in the field of orthopaedics. In conclusion, magnesium-containing biomaterials have great application value in orthopaedics.

Artificial intelligence (AI) has garnered increasing attention in the medical field. As the core technology of AI, deep learning (DL) has been extensively applied to the imaging-based screening of orthopedic diseases, primarily including image classification, segmentation, and risk prediction. This review systematically summarizes recent research advances, methodologies, and clinical applications of AI-assisted diagnostic technologies in orthopedic imaging, highlighting the practical value and development trends of DL in this field. By retrieving literature published over the past five years in PubMed and the Web of Science Core Collection, this study emphasizes the application of DL-based techniques in the screening of orthopedic conditions, such as osteoarthritis (OA), osteoporosis (OP), and bone tumors. The results demonstrate that DL-based methods exhibit excellent diagnostic performance and considerable clinical potential. However, despite the rapid increase in research output, there are still several challenges in this field, including the lack of high-quality datasets, the limited cross-institutional generalizability of models, the absence of standardized quality control protocols, and the urgent demand for multicenter clinical validation. Overall, DL holds great promise for enhancing diagnostic accuracy and improving patient outcomes in orthopedic imaging.

Background: Recent research emphasizes the significant regulatory functions of epigenetic alterations and post-translational modifications (PTMs) in the ferroptosis process. Despite the existing volume of literature, there is a remarkable shortage of comprehensive analyses that systematically trace the evolution of research, map key investigative routes, evaluate the current situation of the field, determine central themes, and predict future directions. This study intends to offer a comprehensive summary of the progress achieved during the past 12 years in comprehending how epigenetic modifications and PTMs regulate ferroptosis. Methods: The dataset originated from the Web of Science, covering the period from January 1, 2012, to May 21, 2024. By employing advanced analytical tools, we carried out an extensive scientometric assessment in combination with detailed visual data analysis. Results: The results emphasize the crucial role of China, which contributes 69.59% of the global research output, thereby demonstrating its significant influence on the research trajectory in this domain. Remarkable productivity is manifested at institutions such as Central South University, Shanghai Jiao Tong University, and Zhejiang University. Liu Shuang and Tang Daolin stand out as the most productive authors in this field. The journal Cell Death & Disease leads in terms of publication volume, having published the greatest number of articles related to this area. This study identified hepatocellular carcinoma, mitochondrial diseases, and iron overload as the most prominent diseases explored in this research domain. Conclusion: This meticulous scientometric assessment is beneficial to both experienced researchers and newcomers by providing essential information and facilitating the derivation of innovative concepts in this field.

Osteoarthritis (OA) is recognized as the most common joint disease with serious public health implications. Cardiovascular health (CVH) is also an issue that is frequently emphasized in public health and has an impact on a variety of diseases and mortality rates. This study aims to investigate the association of CVH with the morbidity of OA. And explore the association of CVH with both all-cause and cardiovascular disease (CVD) mortality among US adults with OA. This study utilized data from the National Health and Nutrition Examination Survey 2005–2018, which included 21,289 adults aged ≥ 20, representing 137,912,968 Americans. CVH was assessed by Life’s Essential 8 (LE8) includes 4 behavior and 4 factor metrics. Total LE8 scores were calculated from the unweighted average on a 0–100 scale and were categorized as high (80–100), moderate (50–79), and low (0–49) CVH. Multivariable logistic regression explored the association of OA with CVH. Cox proportional hazards regression examined LE8 associations with mortality. Adjusting for confounding variables, per 10 points LE8 increase, the OR was 0.82 in association with OA, while OA morbidity were decreased by 30

Articular cartilage injury is a significant concern in osteoarthritis (OA), and while traditional pharmacological treatments and surgical interventions have provided some pain relief and promoted cartilage regeneration to a certain extent, long-term therapeutic outcomes remain suboptimal. The advancement of cartilage tissue engineering has introduced novel perspectives for cartilage regeneration. Hydrogel scaffolds, as crucial components in tissue functionality, have evolved from their initial role of physical coverage or single functionality to current combinations of diverse functionalities. This review thoroughly examines recent applications of functional hydrogels in cartilage regeneration. This article begins by discussing essential background information, including treatment strategies for cartilage defects and the fundamental characteristics of hydrogels. Next, within the framework of cartilage tissue engineering, we analyse five categories of functional hydrogels, emphasizing their distinctive physicochemical properties, drug delivery capabilities, and stimulus-responsive features for cartilage repair. The discussion extends to their mechanisms of action, classification, and limitations. Clinical products related to hydrogels in this field are also summarized. Finally, recommendations are offered to address current challenges and future directions in the development of functional hydrogels for cartilage regeneration.

The inflammatory microenvironment mediated by synovial macrophages, particularly the pro-inflammatory M1 subtype, plays a central role in OA progression and represents a critical therapeutic target. However, delivery strategies that enable efficient and selective targeting of M1 macrophages for modulating the inflammatory microenvironment are still limited. To address this challenge, we developed a glucose-functionalized nanoparticle system (Ber-MNPs) to deliver berberine directly to pro-inflammatory M1 subtype macrophages—via GLUT1-mediated targeting, thereby modulating the inflammatory microenvironment to alleviate OA progression. The Ber-MNPs exhibited excellent targeting specificity toward M1 macrophages in vitro. In addition, Ber-MNPs can suppress macrophage polarization toward the pro-inflammatory M1 phenotype, promote their transition to the anti-inflammatory M2 phenotype, and downregulate inflammatory cytokines, thereby protecting chondrocytes from catabolic damage. In a surgically induced OA mouse model, intra-articularly administered Ber-MNPs exhibited prolonged joint retention and mitigated OA progression by attenuating synovial inflammation and preserving cartilage integrity. Together, this study establishes a M1 macrophage-targeted nanotherapeutic platform that achieves precise inflammatory modulation, offering a new strategy for reshaping the synovial inflammatory microenvironment and achieving effective delay of OA progression.

INTRODUCTION:Existing research suggests an association between smoking and the incidence of recurrent aphthous stomatitis (RAS); however, the causal relationship remains ambiguous. We employed Mendelian randomization (MR) to clarify the potential causal association between smoking and the risk of developing RAS. METHODS:We utilized genome-wide association study (GWAS) sequencing data related to smoking from the Finnish database as instrumental variables (IVs) and GWAS data for RAS from the UK Biobank (UKB) as the outcome to perform a two-sample MR analysis. The selection of IVs was rigorously controlled according to the three principal assumptions of relevance, independence, and exclusivity. The primary analytical methods utilized were inverse variance weighting (IVW) and weighted median (WM), supplemented by MR-Egger, simple mode, and weighted mode techniques to infer causality between smoking and RAS. Sensitivity analyses were conducted using MR-PRESSO, Cochran's Q, and the MR-Egger intercept to ensure the robustness of the findings. RESULTS:The findings from the IVW and WM analyses suggest a causal association between smoking and an elevated risk of RAS (IVW: OR=1.003; 95% CI: 1.0002-1.005, p=0.033; WM: OR=1.003; 95% CI: 1.00006-1.007, p=0.044). Compared to non-smokers, smokers have a 0.3% increase in the risk of RAS. Furthermore, the sensitivity analysis did not reveal any inconsistencies that would contradict the MR results. CONCLUSIONS:Our findings provide preliminary evidence of a potential causal relationship between smoking and the risk of RAS, which may contribute to a deeper understanding of the underlying mechanisms. Further research is needed to confirm these results and explore their implications for clinical practice.

Background: Skeletal muscle atrophy is a common musculoskeletal disorder that significantly reduces patient quality of life. Long non-coding RNA (lncRNA) XLOC_015548 has been identified as a pivotal regulator of C2C12 myoblast proliferation and differentiation. However, its role in mitigating denervation-induced muscle atrophy and the underlying mechanisms remain unclear. Methods: We employed lentiviral-mediated stable expression of XLOC_015548 in C2C12 myoblasts and skeletal muscle-specific XLOC_015548-edited mouse models to investigate the function of this lncRNA. Muscle atrophy models were established in vitro by glucocorticoid-induced atrophy with dexamethasone (DEX) and in vivo by sciatic nerve transection-induced denervation. The MEK inhibitor U0126 was used to assess the role of the growth arrest and DNA damage-inducible 45 gamma/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (Gadd45g/MEK/ERK) signaling pathway. Results: Overexpression of XLOC_015548 significantly activated the MEK/ERK signaling pathway (p < 0.05) by downregulating Gadd45g expression (p < 0.05) and promoting its cytoplasmic localization, thereby enhancing cell proliferation and myotube formation. Furthermore, XLOC_015548 reduced the level of reactive oxygen species (ROS) (p < 0.01), stabilized the mitochondrial membrane potential, and alleviated DEX-induced oxidative stress. These protective effects were partially reversed by U0126, confirming the involvement of the MEK/ERK pathway. Skeletal muscle-specific overexpression of XLOC_015548 in vivo significantly reduced denervation-induced muscle atrophy (q < 0.05) and increased the muscle fiber cross-sectional area. Conclusion: XLOC_015548 plays a critical role in promoting myogenic differentiation and protecting against muscle atrophy by regulating Gadd45g expression, activating the MEK/ERK signaling pathway, and reducing oxidative stress. These findings underscore the therapeutic potential of XLOC_015548 in skeletal muscle atrophy, and provide a foundation for lncRNA-based treatment strategies.

Osteoarthritis (OA) is a prevalent degenerative joint disease predominantly affecting the elderly and is characterized by cartilage degradation, synovitis, and subchondral bone sclerosis. Despite its widespread occurrence, no effective pharmacological interventions currently exist to halt or reverse disease progression. Polyphenolic compounds, a diverse class of plant-derived substances, have attracted considerable attention for their potent anti-inflammatory and antioxidant activities. This review summarizes recent advances in understanding the multifaceted roles of polyphenols in OA. Specifically, polyphenols protect chondrocytes and preserve the extracellular matrix by mitigating oxidative stress, suppressing inflammation, regulating autophagy and cholesterol metabolism, and inhibiting programmed cell death pathways, including apoptosis, pyroptosis, and ferroptosis. Furthermore, they exert protective effects on synovial tissue by regulating macrophage polarization and inhibiting pathogenic fibroblast activation, while also contributing to the maintenance of subchondral bone homeostasis. Recent progress in nanotechnology-based delivery systems, designed to overcome the poor solubility and limited bioavailability of polyphenols, is also highlighted. Collectively, this review integrates mechanistic insights with emerging therapeutic strategies, underscoring the potential of polyphenolic compounds as disease-modifying agents for OA.

Osteoporotic bone defects remain a major clinical challenge due to impaired osteogenesis, insufficient angiogenesis, excessive osteoclast activity, and increased susceptibility to infection. To address these issues, we developed an injectable phosphocreatine-grafted gelatin hydrogel (GGP) incorporating hierarchically structured Zn-Cu particles functionalized with a teriparatide (PTH)/strontium–zinc phosphate (SrZnP) hybrid coating. This multifunctional hydrogel was fabricated via enzymatic and ionic coordination crosslinking, yielding improved mechanical properties and sustained release of Zn2+, Sr2+, and PTH. In vitro evaluations demonstrated that the hydrogel enhanced BMSC proliferation, osteogenic differentiation, and mineralization, promoted HUVEC migration, tube formation, and angiogenic marker expression, and simultaneously inhibited osteoclastogenesis and bacterial growth. Transcriptomic analysis and inhibitor experiments revealed a dual paracrine mechanism mediating bone–vascular coupling: BMSC-derived HIF-1α–VEGF signaling facilitated angiogenesis, while HUVEC-derived PI3K–Akt–BMP-2 signaling enhanced osteogenesis. In vivo, the PTH/SrZnP@ZnCu-GGP hydrogel significantly accelerated bone regeneration and neovascularization in an ovariectomized rat calvarial defect model, accompanied by upregulated expression of BMP-2, RUNX2, p-Akt, and CD31. Collectively, this injectable hydrogel system offers a robust and translationally feasible strategy for coordinated osteogenesis–angiogenesis coupling, osteoclast suppression, and antibacterial defense, thus holding strong potential for the regeneration of osteoporotic bone defects.

This review examines the therapeutic potential of resveratrol (RES) in managing degenerative musculoskeletal diseases (DMDs), including osteoarthritis (OA), osteoporosis, and sarcopenia. With the rising incidence of these diseases in aging populations, effective interventions are increasingly urgent. RES, a polyphenolic compound found in foods such as grapes and peanuts, has shown promise due to its antioxidant and anti-inflammatory properties. Acting within the framework of medicine and food homology, RES holds dual roles as both a dietary supplement and therapeutic agent. RES exerts its effects by modulating various signaling pathways, which collectively reduce inflammation, oxidative stress, and cellular apoptosis, thereby slowing the progression of DMDs. Clinical trials suggest that RES improves bone mineral density, alleviates OA symptoms, and helps preserve muscle mass. However, challenges like limited bioavailability and targeted delivery remain. Future research should focus on optimizing RESu2019s bioavailability and exploring its synergistic effects with other natural compounds to enhance its therapeutic impact. Overall, RES exemplifies a holistic approach to DMDs management by integrating dietary and pharmacological benefits, offering a sustainable strategy for disease management and prevention.

Introduction: Hydrogels, owing to their excellent biocompatibility, tunable physicochemical properties, and ability to mimic the extracellular matrix, have emerged as promising materials for the treatment of musculoskeletal disorders, including osteoarthritis, intervertebral disc degeneration, and bone injuries. Recent advancements in smart hydrogels and multifunctional composites have further broadened their applications in drug delivery, tissue engineering, and regenerative medicine. However, despite growing interest in this field, current reviews often lack systematic, data-driven insights into the evolving research landscape. Methods: To address this gap, we conducted a bibliometric analysis using CiteSpace and VOSviewer to quantitatively map the development of hydrogel-related research in musculoskeletal disorders over the past two decades. Key parameters analyzed included publication trends, influential countries and institutions, collaborative networks, keyword evolution, and research hotspots. Results: Our analysis revealed a steady growth in publications, with China and the United States emerging as leading contributors. Prominent institutions and authors were identified, along with landmark publications that have shaped the field. Keyword co-occurrence analysis highlighted emerging themes such as injectable hydrogels, 3D bioprinting, and osteochondral regeneration. The most frequently studied disease targets included osteoarthritis, intervertebral disc degeneration, and bone defect repair. Conclusions: This comprehensive bibliometric overview offers valuable insights into the current status and future directions of hydrogel research in musculoskeletal disorders. It highlights key trends, influential contributors, and emerging hotspots, providing a solid foundation for advancing interdisciplinary collaborations and accelerating the clinical translation of hydrogel-based therapies.

Over the past 12 years, a significant body of evidence derived from extensive research has underscored the pivotal involvement of ferroptosis in the mechanisms underlying aging. Despite the growing body of literature on this topic, there remains a paucity of analytical and descriptive studies that explore its trajectory, key research directions, current trends, primary focal points, and future outlooks. This research endeavors to provide an exhaustive overview of the advancements in understanding the relationship between ferroptosis and aging over the past 12 years. The dataset utilized in this study was extracted from the Web of Science, encompassing records from January 1, 2012, through June 19, 2024. We conducted comprehensive bibliometric and visual analyses using advanced analytical tools. The results highlight China's dominant contribution, which accounts for 48.52 % of total publications, positioning it as a key player in this research area. Leading institutions, including Columbia University, Southern Medical University, and the Salk Institute for Biological Studies, demonstrate high research productivity. Pamela Maher and Gu Wei are identified as the most prolific researchers in this field. Free Radical Biology and Medicine is the leading journal, publishing the most articles in this field. This study identifies mitochondrial diseases, arrhythmias, Parkinson's disease, hepatocellular carcinoma, and iron-refractory iron deficiency anemia as the key diseases investigated in this field. This bibliometric evaluation offers critical perspectives for both experienced scholars and early-career researchers, enabling the identification of novel ideas and advancements within this domain.

BackgroundDisulfidptosis is a newly discovered form of cell death associated with tumorigenesis, particularly under oxidative stress and metabolic disorder conditions. Currently, the biological mechanisms of disulfidptosis-related genes (DRGs) in head and neck squamous cell carcinoma (HNSCC) remain unclear.MethodsThe study includes sections on methodologies, data sources, clinical data collection, subtype establishment, identification and analysis of differentially expressed genes, genetic variation, and the construction and validation of a DRG prognostic model. Various analyses are conducted, including the relationship between the risk scores model and clinicopathological features, immune status, immune checkpoints, tumor mutational burden (TMB), microsatellite instability (MSI), ESTIMATE, mRNAsi, and drug sensitivity. The study also covers single-cell analysis and DNA methylation analysis of DRGs, and the prediction of potential microRNA and long non-coding RNA target genes. Prognostic DRGs expression in HNSCC is validated through RT-qPCR and immunohistochemistry. The model’s predictive capability is confirmed using external validation cohorts from GEO datasets and clinical tissue samples. The role of DSTN in HNSCC is further validated through gene knockout experiments.ResultsWe identified four valuable genes (SLC3A2, NUBPL, ACTB, DSTN) and constructed a prognostic model, along with identifying two DRG-related subtypes. Analysis of the DRG risk score revealed that the low-risk group had a better prognosis compared to the high-risk group. Significant correlations were found between the DRG risk score and clinical features, immunotherapy response, drug sensitivity, and genes related to RNA epigenetic modifications. Low-risk HNSCC patients were identified as potential beneficiaries of immune checkpoint inhibitor (ICI) therapy. A regulatory axis involving DSTN, hsa-miR-181c-5p, LUCAT1, and IGFL2-AS1 was constructed for HNSCC. RT-qPCR and IHC data further validated the upregulation of prognostic DRGs in HNSCC. The prognostic model demonstrated excellent predictive performance for the prognosis of HNSCC patients. Additionally, DSTN was significantly overexpressed in tumor cells; its knockdown inhibited tumor cell proliferation, migration, and invasion.ConclusionThe prognostic model effectively predicts HNSCC outcomes, with better prognosis in the low-risk group. DSTN upregulation promotes tumor growth, and its knockout inhibits proliferation, migration, and invasion.