Search Results (3,224)

Rheumatoid arthritis (RA) is a systemic rheumatic disease. Its most prominent characteristic is synovitis, which manifests clinically as arthritis, resulting in joint damage. Interstitial lung disease (ILD) is an extraarticular manifestation of RA that hinders therapeutic goals, affects life prognosis, and can be worsened by the administration of disease-modifying antirheumatic drugs (DMARDs). Therefore, proper management of ILD, including consideration of risk factors such as the systemic disease activity of RA and autoantibodies, and early detection with high-resolution computed tomography are required at the introduction of DMARDs. Methotrexate, a class of DMARD used as the anchor drug for RA treatment, has been recognized as likely to worsen RA-ILD. However, there are currently reports suggesting that methotrexate may have beneficial effects on RA-ILD. Conversely, several studies have also shown exacerbations of ILD with the administration of biological DMARDs, which are thought of as tolerable for patients with RA-ILD. Rheumatologists should be wary of emergence or changes in the activity of ILD and arthritis during treatment of any kind with DMARDs. Further studies are warranted to clarify underlying ethnic factors, such as the possible effects of antimelanoma differentiation-associated gene 5 antibodies on RA-ILD. Full article

Rheumatoid arthritis (RA) management via conventional monotherapy is often limited by poor transdermal flux and suboptimal articular accumulation. This study seeks to bridge a critical gap in monotherapy by engineering chitosan-coated nanobilosomal gel co-encapsulated with thymol and silibinin (CH-TH+SB-BG) in a 3:1 stoichiometric ratio. Compared with monotherapeutics, the CH-TH+SB-BG showed the highest drug content and a sustained drug release profile, accompanied by higher skin permeation and deposition, indicating the fluidizing effect of thymol and the dermal reservoir of silibinin. Interestingly, CH-TH+SB-BG was cytocompatible, owing to its higher IC50 than that of the pure drugs. A marked reduction in the paw volume and arthritic score and significant normalization of hematological, biochemical, and inflammatory biomarkers, compared with the monotherapeutics, indicate the synergistic anti-inflammatory potential of the developed gel. Furthermore, the dual loading effectively reduced oxidative stress, confirmed by a significant decrease in malondialdehyde level along with the restoration of glutathione and superoxide dismutase levels. The Bliss independence model mathematically validated pharmacological synergy. Radiographic and histopathological analysis confirmed the near-complete articular restoration and marked reduction in pannus formation. In conclusion, the developed transdermal gel can be a more effective and safer alternative to long-term oral administration, opening the way for novel topical management of RA. Full article

Osteoarthritis (OA) is a disabling joint disease characterised by cartilage degradation, synovial inflammation, and subchondral bone remodelling. Furthermore, catabolic inflammatory processes as well as dysregulated cellular signalling and oxidative stress are central to OA pathogenesis. Despite its growing global burden, currently available therapies primarily provide symptomatic relief and fail to target underlying molecular mechanisms and halt disease progression. Cold atmospheric plasma (CAP), a partially ionised, non-thermal gas that generates controlled reactive oxygen and nitrogen species (RONS), has emerged as a promising therapeutic modality capable of modulating redox-sensitive signalling pathways. CAP has demonstrated the capacity to suppress pro-inflammatory cytokine expression, enhance antioxidant defence mechanisms, influence macrophage polarisation, and stimulate tissue repair processes in rheumatoid arthritis, diabetic and dermal wound healing models. However, its potential as a disease-modifying therapy for the treatment of OA is not yet fully understood and warrants further experimental investigation. This review explores current pre-clinical evidence from different disease models, which may have implications for the potential application of CAP as a therapeutic intervention for OA, either as a disease-modifying therapy or as an adjuvant therapy for intra-articular drug delivery. Furthermore, key translational challenges including plasma parameter standardisation, interactions with synovial fluid and optimisation of joint-specific delivery strategies are discussed, identifying gaps that require further experimental investigation. Collectively, the findings of this review highlight CAP as a promising multimodal therapy with translational potential for the treatment of OA warranting further experimental validation and may open innovative avenues for future research. Full article

Background/Objectives: The interplay between oral and systemic diseases is highlighted by the shared inflammatory mechanisms and epidemiological associations between periodontitis and rheumatoid arthritis (RA). Building on previous syntheses of the effect of periodontal therapy on RA disease activity, we sought to refine the evidence base through strict restriction to randomized controlled trials (RCTs), separate analysis of the two non-interchangeable formulations of the Disease Activity Score on 28 joints (DAS28-CRP and DAS28-ESR, based on either C-reactive protein or erythrocyte sedimentation rate, respectively), and inclusion of recent randomized trials. We aimed to determine whether the first two steps of periodontal therapy (steps 1 and 2 of the 2020 EFP S3-level clinical practice guideline), delivered through supragingival professional mechanical plaque removal and subgingival instrumentation, reduce DAS28 in adults with concurrent RA and periodontitis. Methods: The review protocol was registered in PROSPERO (CRD420261400735). Five databases were searched in accordance with PRISMA 2020. Only RCTs were eligible. Risk of bias was assessed with RoB-2. DAS28-CRP and DAS28-ESR were analyzed in separate random-effects forest plots. Sensitivity analyses addressed adjunctive antibiotics and high baseline disease activity. Results: Ten trials (n = 430 randomized patients) were included. At 3 months, DAS28-CRP was significantly reduced (between-group MD = −0.84, 95% CI −1.38 to −0.29; change-from-baseline MD = −0.55, −0.92 to −0.19). On DAS28-ESR at 3 months, the change-from-baseline estimate was significant (MD = −1.27, −2.22 to −0.31) and the follow-up estimate concordant in direction but not significant (MD = −0.89, −1.85 to 0.07), with substantial heterogeneity. Conclusions: Periodontal therapy may be associated with short-term reductions in RA disease activity, particularly DAS28-CRP at 3 months, with directionally concordant but less certain effects on DAS28-ESR. The evidence remains limited by small sample sizes, risk of bias, substantial heterogeneity of the DAS28-ESR estimates, and sparse follow-up beyond 3 months. As no trial reported individual responder categories, these group-level findings support periodontal therapy as a possible adjunctive measure in RA rather than a predictable, clinically meaningful benefit at the individual patient level. Full article

Background: Rheumatoid arthritis (RA) is associated with increased cardiovascular risk beyond traditional risk factors. Carotid intima–media thickness (IMT) is a marker of subclinical atherosclerosis and may be influenced by chronic inflammation in RA. Objectives: This study aimed to compare carotid IMT between women with RA and age-matched controls, and to investigate the associations between IMT and RA-related factors, including disease duration, menopausal status, anti-cyclic citrullinated peptide (anti-CCP) antibodies and the CD4/CD8 T-cell ratio. Methods: This cross-sectional study included 59 women with RA and 55 age-matched controls. All RA patients received methotrexate and had no recent biologic DMARD exposure. Carotid IMT was measured by B-mode ultrasonography. Clinical, laboratory, and immunologic parameters, including anti-CCP antibodies and CD4/CD8 ratio, were analyzed. Results: Mean carotid IMT was significantly higher in RA patients than in controls (0.85 ± 0.09 vs. 0.63 ± 0.08 mm, p < 0.0001). Within the RA group, IMT correlated positively with disease duration (r = 0.48, p < 0.001), years since menopause (ρ = 0.44, p = 0.001), anti-CCP titers (r = 0.31, p = 0.018) and CD4/CD8 ratio (r = 0.42, p < 0.001), and inversely with CD8 T-cell counts (r = −0.34, p = 0.009). In multivariable analysis, RA duration and CD4/CD8 ratio remained independently associated with IMT after adjustment for age, lipids and blood pressure. Conclusions: Women with RA had greater carotid IMT than age-matched controls. Longer disease duration and a higher CD4/CD8 ratio were independently associated with IMT, supporting a link between cumulative disease burden, T-cell imbalance and subclinical carotid atherosclerosis in RA. These findings support routine cardiovascular risk assessment and consideration of vascular imaging in high-risk RA subgroups. Full article

Aspartame is a widely used artificial sweetener, but its possible relationship with rheumatoid arthritis (RA) remains insufficiently understood. This study aimed to explore, rather than prove, potential molecular links between aspartame-related targets and RA-associated gene networks. Three public RA transcriptomic datasets (GSE55235, GSE55457, and GSE77298) from the Gene Expression Omnibus (GEO) database were integrated as discovery/training data. Because these datasets included different tissue origins, batch correction was used to reduce dataset-level technical variation, whereas tissue-origin-related biological variation was not assumed to be fully removable. After differential expression analysis, RA-associated differentially expressed genes (DEGs) were identified. The single-cell dataset GSE200815 was used for cell annotation and cellular expression visualization; because its comparator group consists of psoriatic arthritis (PsA) samples rather than healthy controls, single-cell results were interpreted as RA-vs-PsA observations and were not treated as disease-versus-healthy-control evidence. Potential targets of aspartame were retrieved from ChEMBL, SwissTargetPrediction, and the Similarity Ensemble Approach (SEA), and were intersected with RA-related DEGs to construct an aspartame-gene-RA regulatory network. Diagnostic models were developed using 113 machine-learning algorithm combinations to determine an optimal multigene model and its core genes. HLA-DRB1 was selected for exploratory scTenifoldKnk-based virtual knockout mainly because it was included in the optimal model and has a well-established role in RA immunogenetics; the single-cell analysis was used only to describe cellular distribution in the RA/PsA dataset. Molecular docking was then used to evaluate the possible interaction between aspartame and HLA-DRB1. Forty-four intersected genes linked the predicted aspartame targets with RA DEGs. The random forest plus partial least-squares generalized linear model (RF + plsRglm) identified 16 core genes. Network-level interpretation indicated that these genes were distributed across immune/antigen-processing, inflammatory-signaling, protease/extracellular-matrix-remodeling, adhesion, metabolic, and proliferation-related modules; therefore, HLA-DRB1 was treated as a prioritized immune-module candidate rather than as the sole driver of the network. Following virtual knockout of HLA-DRB1, affected genes were enriched in extracellular matrix organization, extracellular structure organization, extracellular matrix, collagen trimer, extracellular matrix structural constituent, and collagen binding. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways included integrin signaling, focal adhesion, proteoglycans in cancer, cytoskeleton in muscle, and phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling. Molecular docking showed a minimum binding energy of −6.7 kcal/mol, which was more negative than the preset stability criterion of −5.0 kcal/mol, and the docking pose suggested contacts around ARG-146. This integrative analysis suggests a hypothesis-generating association between aspartame-related predicted targets and RA-relevant molecular networks involving HLA-DRB1 and other core genes. The findings do not establish causality and require experimental, epidemiological, biophysical, and tissue-stratified validation before any causal or clinical inference can be made. Full article

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterised by persistent synovitis, progressive cartilage destruction and bone erosion. Recent advances in single-cell and spatial omics, together with immunometabolic studies, have revealed marked state heterogeneity among synovial macrophages in RA. Their metabolic reprogramming appears to sustain pathogenic cellular states, drive aberrant intercellular communication and impair the resolution of inflammation. Rather than acting as an independent initiating factor, it more likely operates as a downstream amplifier of disease. In this review, we outline the principal functional states and metabolic features of synovial macrophages in health and RA. We focus on how the rewiring of glucose, lipid and amino acid metabolism links inflammatory transcription, tissue remodelling and bone destruction. These connections are mediated by metabolic enzymes, metabolic intermediates, redox regulation and epigenetic modifications. We further summarise the immunometabolic effects of currently available antirheumatic drugs. We also appraise the preclinical evidence and translational limitations of metabolic pathway inhibitors, natural products and nanodelivery systems. It should be noted that most existing evidence still relies on in vitro polarisation systems and rodent models. Validation of metabolic flux, cell-state specificity and causal relationships in human synovium remains limited. As a narrative review focused on recent studies of synovial macrophage metabolism in health and inflammation, this work aims to delineate how metabolic reprogramming shapes the phenotypic heterogeneity and pathogenic functions of macrophages in RA. It also seeks to appraise the potential value and current boundaries of evidence for therapeutically targeting macrophage metabolism. Full article

Background/Objectives: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease in which senescence-associated secretory phenotype (SASP)-related transcriptional programs may contribute to synovial inflammation and fibroblast activation. This study aimed to integrate bulk transcriptomic cohorts with the gene-expression component of a single-nucleus multimodal dataset to identify reproducible SASP-related candidate biomarkers and prioritize fibroblast-associated signals in RA. Methods: SASP-score correlation analysis, differential expression analysis, cross-cohort evaluation, logistic regression, gene set enrichment analysis, single-nucleus transcriptomic characterization, predicted regulatory network analysis, and RT-qPCR assessment were performed. GSE89408 was used as the discovery bulk transcriptomic cohort, GSE77298 as the external evaluation cohort, and GSE243917 as the single-nucleus gene-expression dataset. Results: Fibroblasts showed relatively high SASP-related transcriptional scores within the RA single-nucleus dataset. The cross-cohort evaluation retained RCAN1, IRF1, CFB, and TIMP1 as reproducibly elevated candidates. Among all 15 non-empty panels derived from these four genes, the RCAN1/IRF1/CFB panel achieved the highest five-fold cross-validated AUC in GSE89408 and tied for the highest external AUC in GSE77298. Adding TIMP1 did not improve the external AUC or the 95% confidence interval. Among the retained genes, CFB showed the strongest fibroblast-associated expression pattern and SASP-score correlation. The RT-qPCR analysis provided preliminary mRNA-level support for the increased expression of RCAN1, IRF1, and CFB in the RA-related cell samples. Conclusions: RCAN1, IRF1, and CFB form a reproducible SASP-related candidate panel in RA, with CFB prioritized as a fibroblast-associated marker. Further protein-level, functional, and controlled single-cell validation studies are required. Full article

Background/Objectives: Teriflunomide is an active metabolite of leflunomide and acts as a selective and reversible inhibitor of dihydroorotate dehydrogenase, a key enzyme in de novo pyrimidine biosynthesis. It exhibits immunomodulatory activity by reducing the proliferation of activated T and B lymphocytes and is widely used in the treatment of rheumatoid arthritis and relapsing multiple sclerosis. This study aimed to develop a rapid, accurate, and simple high-performance liquid chromatography (HPLC) method with fluorometric detection for quantifying teriflunomide in human plasma. Methods: Plasma samples were prepared by liquid–liquid extraction followed by pre-column derivatization with NBD-Cl. Teriflunomide was derivatized with 4-chloro-7-nitrobenzofurazan (NBD-Cl) and separated using a reversed-phase C18 column (5 µm, 4.6 × 150 mm) at 30 °C with isocratic elution. The mobile phase consisted of acetonitrile and 0.1% orthophosphoric acid (80:20, v/v) at a flow rate of 1.1 mL/min. Fluorescence detection was performed at λex = 465 nm and λem = 535 nm. The method meets European Medicines Agency (EMA) guidelines for bioanalytical validation and was successfully applied to pharmacokinetic studies, including AUC_0–t, AUC_0–∞, C_max, T_max, and t_½. Results: Teriflunomide showed a retention time of 2.55 ± 0.01 min. The method exhibited linearity in the range of 0.01–30 ng/mL (r² = 0.9998), with a limit of detection and quantification of 0.003 and 0.01 ng/mL, respectively. The relative standard deviation was 3.27%. Conclusions: This work introduces a novel, cost-effective, and highly sensitive HPLC with fluorescence detection (HPLC-FL) method for the determination of teriflunomide in human plasma, providing an efficient alternative to LC-MS/MS for routine pharmacokinetic and bioequivalence studies. Full article

Background/Objectives: Inheritance classification in rare diseases remains challenging because curated knowledge is incomplete, heterogeneous, and imbalanced across inheritance categories. Disease-level inheritance modeling can support knowledge organization, annotation review, and hypothesis generation in rare-disease resources. This paper introduces RareFusion-Net, a multimodal benchmark framework for disease-level inheritance classification, and evaluates whether integrating ontology-enriched disease text, structured epidemiological metadata, and gene-association information improves prediction in curated rare-disease knowledge bases. RareFusion-Net is intended for knowledge modeling, not individual patient diagnosis. Methods: We developed RareFusionBalanced, a gated multimodal fusion model that combines biomedical disease descriptions, structured metadata, and gene-related information using auxiliary supervision. Ontology-enriched disease text was treated as the dominant semantic modality, while tabular and gene modalities were incorporated as complementary evidence when available. Robustness was improved using balanced regularization, selective transformer fine-tuning, dropout, weight decay, label smoothing, early stopping, and prediction aggregation across random seeds. Evaluation included accuracy, macro-F1, micro-F1, macro-AUC, mean average precision, calibration metrics, class-wise analysis, statistical testing, and ablation experiments. Results: RareFusionBalanced achieved 0.7382 test accuracy, 0.6284 macro-F1, 0.7382 micro-F1, 0.9183 macro-AUC, and 0.6686 mean average precision. Calibration was favorable, with an expected calibration error of 0.0395 and a Brier-OVR of 0.0528. The multimodal model slightly outperformed TextOnly-TransformerBalanced, but improvement over the best TF-IDF baseline was not statistically significant. Ablation showed ontology-enriched text as the strongest modality, with gene associations adding complementary value. Conclusions: RareFusion-Net provides a practical benchmark for ontology-aware rare-disease inheritance modeling. Results suggest selective multimodal benefit while highlighting minority-class difficulty, limited statistical superiority, need for external validation, and improved biological interpretability. Full article

Heparanase 1 (HPSE1) is the only mammalian endoglycosidase that cleaves heparan sulfate (HS), a glycosaminoglycan (GAG), and is frequently upregulated in cancers, thereby promoting tumor progression. Despite extensive efforts to develop inhibitors of its HS-degrading activity, its non-enzymatic functions limit therapeutic efficacy and pose a major challenge for therapeutic development. Thus, inhibiting HPSE1 expression is critical for controlling its enzymatic and non-enzymatic functions; however, no FDA-approved inhibitors are currently available. Here, we identify auranofin (AUF), an oral gold-containing drug used to treat rheumatoid arthritis, as a potent inhibitor of HPSE1 promoter activity. High-throughput screening revealed that an atypical protein kinase C (aPKC)–NF-κB signaling axis is a key regulator of HPSE1 expression. Notably, AUF treatment reduced HPSE1 expression and significantly suppressed the invasive capacity of MDA-MB-231 cells in a Transwell migration assay. We then investigated the role of HPSE1 in the invasive activity of MDA-MB-231 cells, which produce higher levels of hyaluronan (HA) and HS than non-invasive cells. Neither HS degradation, HA supplementation in Matrigel during Transwell migration, nor HPSE1 overexpression alone was sufficient to drive invasion, suggesting that invasive capacity depends on mesenchymal features and coordinated induction of HPSE1 and GAGs rather than HS degradation. Collectively, our findings demonstrate that AUF-mediated inhibition of aPKC suppresses HPSE1 expression, thereby inhibiting both its enzymatic and non-enzymatic functions and limiting cancer progression, metastasis, and angiogenesis. These results highlight the therapeutic potential of AUF for targeting HPSE1-driven tumor progression and support its repurposing for cancer treatment. Full article

Autoimmune and immune-mediated inflammatory diseases (IMIDs) develop when genetically and environmentally susceptible hosts lose stable immune tolerance. The gut ecosystem is increasingly recognized as a biologically active interface in this process. Its bacterial, fungal, and viral components may shape mucosal and systemic immunity through antigenic stimulation, barrier regulation, and metabolite-dependent signaling, although the strength of evidence is uneven: bacteriome data are currently the most mature, whereas mycobiome, virome, and phageome findings remain more disease-specific and emerging. Dysbiosis may influence autoimmunity through overlapping routes, including epithelial barrier failure, altered short-chain fatty acid, bile acid, and tryptophan metabolism, molecular mimicry, and cross-kingdom microbial interactions. Nutrition is central to this network because dietary substrates determine microbial growth, metabolic output, epithelial integrity, and immune-cell differentiation. In this narrative review, we integrate evidence on disease-associated bacteriome, mycobiome, and virome patterns in systemic autoimmune diseases, with emphasis on rheumatoid arthritis, systemic lupus erythematosus, Sjögren’s syndrome, systemic sclerosis, spondyloarthritis, vasculitides, and idiopathic inflammatory myopathies. COVID-19 is considered not as a proven causal driver of autoimmunity, but as an example of an environmental and infectious insult capable of perturbing microbiome–barrier–immune communication. Finally, we discuss diet-based and microbiome-targeted approaches, including probiotics, prebiotics, synbiotics, and postbiotics, as adjunctive strategies that may help restore microbial resilience and immune balance. A better understanding of the diet–microbiome–host immunity axis may support more personalized preventive and therapeutic concepts in autoimmune disease. Full article

Rheumatoid arthritis (RA) is an autoimmune disease primarily characterized by chronic, erosive polyarthritis. It is associated with a high rate of disability, and its pathogenesis remains incompletely understood. Uncontrolled chronic inflammation, synovial hyperplasia, Pannus formation, and bone destruction in RA patients remain the core challenges facing current clinical treatment, and the inflammatory response is generally considered the initiating factor for this series of pathological processes. In an inflammatory environment, the body’s metabolic rate accelerates, leading to increased local oxygen consumption and ultimately creating a hypoxic microenvironment. Research has shown that under hypoxic conditions, glycolysis serves as the body’s primary energy pathway and is essential for sustaining the inflammatory response. Furthermore, lactate, a byproduct of glycolysis, functions not only as a metabolic byproduct but also as a precursor molecule; through lactylation, it contributes to the progression of RA. Although this metabolic–epigenetic axis is a common feature of various chronic inflammatory diseases, its effects on joint pathology may contribute to RA progression. Therefore, this article focuses on the intrinsic connections among hypoxia, glycolysis, and lactylation, and systematically reviews the immunological and inflammatory mechanisms of glycolysis in RA, the relationship between glycolysis and synovial hyperplasia, Pannus formation, and bone destruction in RA, and the role of lactate modification in promoting the pathological progression of RA. It also summarizes the latest research advances in RA therapies targeting hypoxia, glycolysis, and lactate modification, aiming to provide a theoretical basis for a deeper understanding of the pathogenesis of RA and the development of targeted treatment strategies. Full article

Per- and polyfluoroalkyl substances (PFAS) are persistent, chemically stable compounds widely used in daily life. Perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorohexanesulfonic acid (PFHxS), and perfluorooctanesulfonic acid (PFOS) were identified as the most relevant PFAS due to their prevalence and toxicity. This study aimed to investigate the immunotoxic mechanisms of a mixture of these PFAS using an in silico approach. Comparative Toxicogenomic Database (CTD), GeneMANIA, CytoHubba (Cytoscape), ToppGene Suite, and Metascape were used for the analysis. A total of 65 immune-related genes were identified as common to all four PFAS, with IFNG, TNF, IL1B, IL6, TYK2, CD3E, CASP8, VAV1, ARHGAP4, and CARD11 emerging as key hub genes. CTD phenotype analysis indicated immune dysregulation, with decreased humoral and adaptive immune responses in humans and tissue-specific modulation of B- and T-cell activity in mice, while no immune-related phenotypes were observed for PFNA. Network analysis identified functional modules associated with apoptotic and immune signaling, endothelial cell migration and angiogenesis, and shared inflammatory and viral response pathways. Disease enrichment analysis associated PFAS with autoimmune disorders (rheumatoid arthritis, asthma), metabolic conditions, and cardiovascular diseases (experimental diabetes, hypertensive disease). These results highlight PFAS involvement in immune modulation, cytokine signaling, and disease susceptibility. Full article

The A3 adenosine receptor (A3AR) is a stress-inducible G-protein-coupled receptor that is selectively upregulated in inflamed, hypoxic, and fibrotic tissues as well as in many malignancies, while remaining weakly expressed in most normal organs. This distinctive expression pattern provides a strong biological basis for pathology-selective pharmacology. Activation of A3AR by highly selective agonists, including piclidenoson (IB-MECA) and namodenoson (Cl-IB-MECA), initiates signaling through Gi proteins and phospholipase C (PLC), which in turn regulate a coordinated network of downstream intracellular pathways, including PI3K/Akt, NF-κB, MAPKs, and Wnt/β-catenin, resulting in suppression of inflammation, inhibition of pathological cell survival, and protection of metabolically stressed tissues. Over the three decades, extensive preclinical studies have demonstrated that A3AR agonism exerts anti-cancer, anti-fibrotic, immunomodulatory, neuroprotective, and organ-protective effects across diverse disease models, including hepatocellular carcinoma, pancreatic cancer, psoriasis, osteoarthritis, metabolic dysfunction-associated steatohepatitis, ischemic stroke, neurodegeneration, ophthalmic disorders, and inherited metabolic syndromes. Importantly, these mechanistic insights have been translated into clinical programs, with piclidenoson and namodenoson demonstrating favorable safety profiles and disease-modifying activity in inflammatory, fibrotic, and oncologic indications. This review integrates molecular, cellular, and translational evidence to highlight A3AR activation as a unifying therapeutic principle for diseases driven by inflammation, oxidative stress, hypoxia, and dysregulated cell survival, positioning selective A3AR agonists as first-in-class agents targeting the A3AR, with broad clinical applicability across multiple disease domains. Full article