Search Results (432)

Background: Edwardsiella piscicida is a significant intracellular pathogen of channel catfish (Ictalurus punctatus) and a major threat to U.S. aquaculture. A recently developed recombinant attenuated vaccine strain (χ16016) uses arabinose-regulated murA expression to trigger delayed cell wall lysis in vivo, ensuring biological containment while conferring strong protection against virulent challenge. Although its efficacy has been demonstrated, the host immune programs underlying protection remain incompletely defined. Methods: We used RNA sequencing to characterize tissue-specific transcriptomic responses in the intestines and kidneys of channel catfish at 7 days post-vaccination. Fish were vaccinated with χ16016 by either bath immersion or intracoelomic (IC) injection, and differentially expressed genes and enriched immune pathways were analyzed to determine how the vaccine delivery route shapes systemic and mucosal immune responses. Results: Across comparisons, 19,101 differentially expressed genes revealed pronounced route- and tissue-dependent immune remodeling. As aquaculture vaccination strategies increasingly prioritize scalability and practical deployment, understanding how the delivery route shapes immune outcomes is critical. Here, IC vaccination induced broader systemic transcriptional changes, particularly in the intestine, whereas bath immunization elicited a more focused yet coordinated mucosal response. Overall, intestinal tissue exhibited greater transcriptional responsiveness than kidney tissue, underscoring its central role in early vaccine-induced immunity. Functional enrichment analyses identified the activation of innate recognition pathways, MAPK and calcium signaling cascades, complement components, antigen processing machinery, and cell adhesion networks. Notably, bath immunization enriched the intestinal immune network for IgA production pathway, which represents an orthology-based mapping of conserved mucosal immune components, alongside the upregulation of IL-6, CXCL12–CXCR4, integrins (α4β7), MHC class II, complement C3, and polymeric immunoglobulin receptor (pIgR). Given that catfish rely primarily on IgM in mucosal immunity, these findings indicate the induction of IgM-mediated mucosal defense rather than classical mammalian IgA responses. Concurrent complement and scavenger receptor signatures suggest a transition toward efficient opsonophagocytic clearance with controlled inflammation at this subacute stage. Conclusions: This study provides the first systems-level view of host transcriptomic responses to a regulated-lysis E. piscicida vaccine in channel catfish. The findings demonstrate that immersion vaccination, although transcriptionally less expansive than injection, effectively activates coordinated mucosal innate and adaptive immune programs, supporting its practical use as a scalable vaccination strategy for aquaculture. Full article

IGF1 plays a critical role in cell proliferation and survival. Previous studies show that IGF1 binds to integrin αvβ3 and induces αvβ3-IGF1-IGF1R ternary complex formation. However, how IGF1 binding to αvβ3 leads to IGF1R activation is unclear. Previous studies showed that Gα13, a guanine nucleotide-binding protein of the G12 class of Gα proteins, binds to the integrin β3 tail through the EEE motif upon fibrinogen binding to integrin αIIbβ3 and induces RhoA activation. We discovered that the EEE/AAA mutation of the β3 tail inhibited IGF1-induced cell survival, suggesting that Gα13 binding to the β3 tail is required for IGF1 signaling. Since RhoA activation may not be directly involved in IGF1R activation, we studied if Gα13 binds to molecules other than RhoA. Since Gα13 binds to several cytoplasmic tyrosine kinases, we studied if Gα13 binds to the IGF1R kinase by a docking simulation. The simulation predicted that Gα13 binds to the IGF1R kinase through a new binding site. Mutating the predicted Gα13 binding site in the IGF1R kinase (residues 1020-1022) or the predicted IGF1R kinase binding site in Gα13 (residues 260-279) inhibited Gα13 binding to the IGF1R kinase, which is consistent with the docking model. Notably, the Gα13(260-279A) mutant inhibited IGF1-induced cell survival. We propose that IGF1 binding to αvβ3 induces Gα13 binding to the β3 tail and subsequent Gα13 binding to the IGF1R kinase, leading to IGF1R activation. Interestingly, Gα13(260-279A) mutation inhibited cell survival due to a constitutively active Gα13(Q226L) mutant. We propose that Gα13(Q226L) induces its effect by binding to the IGF1R kinase. We propose that the Gα13 binding site of the IGF1R kinase or the IGF1R binding site in Gα13 may be a novel therapeutic target. Full article

¹⁸F-fluorodeoxyglucose (FDG) PET/CT is widely used for the evaluation of pulmonary lesions but lacks specificity, as increased FDG uptake is frequently observed in inflammatory and reparative processes. This limitation may lead to false-positive interpretations and unnecessary surgical resections. This study aimed to evaluate the immunohistochemical expression of integrin α_vβ₆ in 18 surgically resected pulmonary lesions that were falsely classified as malignant on FDG PET/CT, in order to find out if ⁶⁸Ga-Trivehexin PET/CT could have superior preoperative diagnostic specificity. Histopathological examination classified all lesions as non-neoplastic inflammatory processes of varying etiologies. Integrin α_vβ₆ expression was detected in all immunohistochemically examined tissue specimens (18/18 cases (100%)), with moderate membranous overexpression in 2/18 cases (11.11%) and strong membranous overexpression in 16/18 cases (88.89%) observed in the alveolar and bronchial epithelium of inflammatory lung lesions. Our findings indicate that integrin α_vβ₆ is upregulated not only in neoplastic lung tissue but also in inflammatory lesions, suggesting that integrin α_vβ₆ may have limited specificity for distinguishing primary neoplastic from inflammatory pulmonary lesions when used alone. Its interpretation requires integration with other clinical imaging modalities and histopathological data. Full article

Galectin-3 (Gal3) is one of the most pro-inflammatory proteins and a biomarker of inflammatory diseases and cancer. Previous studies showed that Gal3 binds to αv and β1 integrins, but it is unclear how Gal3 binds to integrins. Here, we show that Gal3 bound to soluble αvβ3 and αIIbβ3 integrins in 1 mM Mn²⁺ in cell-free conditions in a glycan-independent manner. Docking simulation predicts that Gal3 binds to the classical RGD-binding site (site 1) of αvβ3, but the predicted Gal3-binding site does not include galactose-binding site. RGDfV or eptifibatide inhibited Gal3 binding to αvβ3 and αIIbβ3, respectively, but lactose, a pan-galectin inhibitor, did not inhibit Gal3 binding to integrins. Point mutations of the predicted site 1 binding interface of Gal3 effectively inhibited Gal3 binding to site 1. Site 2 is involved in pro-inflammatory signaling (e.g., TNF and IL-6 secretion), and we previously showed that pro-inflammatory cytokines (e.g., CCL5 and TNF) bind to site 2 and allosteric integrin activation. Docking simulation predicted that Gal3 binds to site 2 of αvβ3 and α5β1. We found that Gal3 induced allosteric activation of soluble integrins αvβ3, αIIbβ3, and α5β1 in 1 mM Ca²⁺ in cell-free conditions. Point mutations in the predicted site 2 binding interface inhibited Gal3-induced integrin activation, suggesting that Gal3 binding to site 2 is required for Gal3-induced integrin activation. Known anti-inflammatory agents, Ivermectin, NRG1, and FGF1, inhibited integrin activation induced by Gal3 in αvβ3 and αIIbβ3. These findings suggest that Gal3 binding to site 2 may be a potential mechanism of pro-inflammatory and pro-thrombotic action of Gal3. Full article

Alzheimer’s disease (AD) is the leading cause of dementia and imposes a high economic and social burden on healthcare systems. In Brazil, the consistent increase in costs associated with AD hospitalizations, coupled with the absence of curative therapies and population aging, reinforces the need for low-cost, broadly applicable preventive strategies. This study investigated the role of irisin, a myokine induced by physical activity, in the prevention of AD, integrating epidemiological and bioinformatic analyses. Public data on the nutritional status of the Brazilian population in the early 2000s and on AD hospitalizations approximately 20 years later were analyzed, assessing the temporal association using a lagged Spearman correlation. Additionally, genes associated with AD were analyzed through protein–protein interaction networks and functional enrichment. Structural models of irisin and the integrin αV/β5 receptor were employed in molecular docking and molecular dynamics analyses. Historical data indicated a high prevalence of excess weight in the early 2000s (46.7% ± 4.2% of the adult population) and a strong positive correlation with AD hospitalizations two decades later (ρ = 0.88; p = 0.033). Functional analyses revealed enrichment of pathways related to neurodegeneration, neurotrophins, and neuronal plasticity, involving proteins such as BDNF, AKT, ERK1/2, and CREB. Docking and molecular dynamics indicated a stable interaction of irisin with the αV/β5 receptor, suggesting activation of neuroprotective pathways. The findings reinforce physical exercise as a strategic public health tool for the prevention of AD, providing an epidemiological and molecular basis to reduce the future burden of the disease, thereby shifting the focus of public health policy from treatment to prevention. Full article

Autoantibodies targeting α6β4 integrin have been identified in individual patients with mucous membrane pemphigoid (MMP). Reactivity against α6 integrin has been associated with oral lesions, while anti-β4 integrin reactivity has been linked to ocular involvement. However, the pathogenic effects of these antibodies have not been fully elucidated. Here, we investigated the pathogenic potential of anti-α6 and anti-β4 integrin IgG both in vitro and in vivo. Immune complexes of anti-α6 and anti-β4 integrin induced the release of reactive oxygen species from normal human leukocytes and stimulated CXCL2 secretion in cultured murine C5N keratinocytes. In vivo, repeated injections of IgG against a recombinant fragment of β4 integrin into C57BL/6 mice led to palpebral conjunctival swelling and mild oral lesions. The latter was observed following injection of IgG against a recombinant fragment of α6 integrin. Histopathological analysis revealed subepithelial inflammatory infiltrates without evidence of split formation. Direct immunofluorescence microscopy showed linear deposits of IgG at the basement membrane zone in most tissues, whereas C3 deposition was largely absent. This lack of complement activation was corroborated by a complement fixation assay, which confirmed that IgG against α6 and β4 integrin failed to induce C3 deposition in normal murine conjunctivae, buccal mucosa, or skin. Collectively, these findings indicate that IgG autoantibodies against α6 and β4 integrin exhibit pathogenic activity in vitro and induce mild disease in vivo, possibly due in part to relatively inefficient complement activation in this model. Full article

Background: Vedolizumab (VDZ) is an α4β7 anti-integrin monoclonal antibody effective in Crohn’s disease (CD). While its short- and mid-term efficacy is well established, real-world data on long-term outcomes beyond 3 years are scarce. Recent studies suggest a progressive decline in persistence rates after 2 to 3 years, with very limited data beyond this period. The primary objective of this study was to evaluate the 5-year persistence of VDZ. Secondary objectives were to describe clinical, biological, and endoscopic responses at 2 years among patients remaining on treatment, and to identify predictors of long-term persistence, including the baseline Clinical Decision Support Tool (CDST) score. Methods: We conducted a retrospective observational study which included 60 adult patients with CD treated with VDZ before April 2025. Collected baseline variables included age, sex, BMI, smoking status, disease duration and location, prior biologic exposure, and CDST score. Treatment persistence was evaluated at 5 years. Clinical, biological, and endoscopic responses were assessed at 2 years. A global response was then defined as the achievement of a clinically significant improvement, normalization or marked reduction in inflammatory biomarkers, and endoscopic improvement. Predictors of persistence were also analyzed. Results: The mean age of this cohort was 45.4 ± 15.2 years, mean disease duration was 12.7 ± 10.1 years, and mean CDST score was calculated at 20.6 ± 2.7. At 5 years, 23/41 patients (56.1%) remained on VDZ therapy. Persistence was significantly associated with male sex (65.2% vs. 27.8%), longer disease duration (215 vs. 106 months), absence of rheumatologic manifestations (13.0% vs. 44.4%), and clinico-biological response at 12 months (65.2% vs. 30.8%). At 24 months, a global response was observed in all patients persisting at 5 years compared to 22.2% of those who discontinued (p < 0.001). At 2 years, 39/51 patients (76.5%) remained on VDZ. Persistence was associated with longer disease duration (189 vs. 75 months), male sex (61.5% vs. 25.0%), and absence of isolated colonic disease (0% vs. 16.7%). A global response at 2 years was achieved by 89.7% of persistent patients compared with none of the non-persistent group (p < 0.001). The CDST, uniformly elevated in this cohort, did not discriminate between persistent and non-persistent patients, but reflected appropriate initial patient selection. Conclusions: This real-world study documents 5-year outcome data on VDZ persistence in Crohn’s disease, a duration infrequently studied, with 56% of patients maintaining treatment. Early response at 12 and 24 months emerged as a key determinant of long-term persistence, highlighting the value of assessing 2-year outcomes to identify durable responders. Although not discriminatory in this homogeneous cohort, the CDST score emphasizes the potential role of predictive tools in guiding personalized therapeutic strategies. These results contribute to defining the long-term role of VDZ in the management of CD. Full article

Beyond their canonical role in promoting G1/S progression, the complexes formed by cyclin D and cyclin-dependent kinase (CDK) 4/6 have emerged as contributors to enhanced cell migration. However, a direct link between this complex and cytoskeletal remodeling during cell motility has remained poorly understood. Here, we show that CDK4/6 inhibition in HeLa cells disrupts lamellipodia formation and subsequent focal adhesion assembly, leading to a reduction in cell migration and invasion. Notably, CDK4, but not CDK6, in complex with cyclin D1/D2, localizes to membrane ruffles to facilitate cytoskeletal reorganization. Mechanistically, proteomic and phosphoproteomic analyses revealed that CDK4 inhibition attenuates the transforming growth factor β (TGFβ) pathway via reduced Smad3 phosphorylation at Thr8, downregulating integrin subunits (α5, α6, and β1). Furthermore, CDK4 inhibition significantly decreased focal adhesion kinase (FAK) phosphorylation at Tyr397 and Rac1-GTP levels. Importantly, the resulting migration defect was largely restored by activation of either Rac1 or FAK. Thus, our data support a model in which cyclin D1/D2–CDK4 promotes phosphorylation of Smad3, leading to upregulation of integrin subunits, activation of FAK and Rac1, and consequent lamellipodia formation and cell migration. These findings provide direct evidence that CDK4 regulates actin cytoskeletal reorganization during cell migration and suggest that CDK4/6 inhibitors may dampen cytoskeleton-dependent tumor invasion, in addition to their antiproliferative effects. Full article

Periostin is a matricellular protein induced by type 2 cytokines. It has been shown to play important roles in airway inflammation and tissue remodeling. Although periostin has been studied in asthma and chronic rhinosinusitis, its role in allergic rhinitis (AR) and nasal hyperresponsiveness (NHR) is unclear. This study aimed to determine whether periostin is involved in the development of NHR in AR. A murine AR model was established by sensitization and repeated intranasal challenges with Japanese cedar pollen (JCP). In this animal model of AR, an increase in nasal responsiveness to histamine was observed 24 h after the last JCP challenge, indicating the development of NHR. RT-qPCR analysis revealed that the JCP-induced NHR was accompanied by increased periostin gene expression. Immunohistochemical examinations demonstrated the expression of integrin subunits α_V (Itgav), β₃ (Itgb3) and β₅ (Itgb5), which are known as receptors for periostin, in the nasal mucosa, especially in the mucosal epithelium. Notably, repeated intranasal administration of recombinant periostin to healthy I mice reproduced the NHR phenotype, as observed in AR model mice. These findings suggest that periostin upregulation in the nasal mucosa plays a causal role in the development of NHR, a key feature of AR. Full article

Introduction: The proportion of elderly patients with IBD is steadily increasing due to the aging population and improved survival. Patients in this age group present specificities in diagnosis and treatment, particularly regarding the use of biological agents, where immunosenescence, multimorbidity, and polypharmacy affect the precise assessment of benefit and risk. Aim: This systematic review, which was conducted in accordance with the PRISMA 2020 statement, aims to synthesize available data on the epidemiology, clinical characteristics, and therapeutic management of IBD in the elderly, with emphasis on the most recent data and practical guidelines for the use of biological therapies. Methods: A systematic search of PubMed, Scopus, and Embase was conducted. A total of 40 studies were included, comprising 5 randomized controlled trials, 15 prospective cohort studies, and 20 retrospective observational studies. Eligible studies included randomized controlled trials, observational cohort studies, and population-based analyses. Given substantial clinical and methodological heterogeneity, findings were synthesized narratively. Data on demographics, disease phenotype, comorbidities, and treatment outcomes were extracted and analyzed. In addition, a narrative synthesis of major randomized trials of biologic therapies, recent guidelines, and data from prospective studies and patient registries was performed with a focus on safety and real-world outcomes in the elderly. Risk of bias was assessed using the Newcastle–Ottawa Scale (NOS) and the Cochrane Risk of Bias tool. Results: The majority of included studies (85%) were found to have a low to moderate risk of bias, providing a reliable basis for the synthesis. Data show an increasing incidence of IBD in the elderly, often with a milder clinical course and a higher ratio of UC to CD. Multimorbidity and polypharmacy are significant challenges that increase the risk of adverse events. Although classic therapies remain effective, in many cases, a lower threshold is required to initiate advanced therapies, such as biologic agents. Anti-tumor necrosis factor (anti-TNF) agents, as well as biologics with alternative mechanisms of action such as vedolizumab (α4β7 integrin antagonist) and ustekinumab (interleukin-12/23 inhibitor), represent key therapeutic options in elderly patients with IBD. These biologic factors have efficacy comparable to that in younger patients and are considered attractive options due to reduced systemic immunosuppression and favorable safety profiles. JAK inhibitors are a practical option but are associated with an increased thromboembolic risk and require careful patient selection. Older age is associated with higher absolute rates of serious infections, hospitalizations, and, in some series, mortality. Individualized decision-making, including frailty assessment, vaccination coverage, infection control, and dose adjustments based on renal and hepatic function, is essential for optimal care. Conclusions: IBD in the elderly is a distinct clinical entity with unique challenges in diagnosis and management. A multidisciplinary approach and individualized treatment strategies are essential to ensure the balance between disease control and minimizing the risks associated with comorbidity and polypharmacy. Further research, including specifically designed clinical trials, is needed to optimize treatment and outcomes in this unique patient group. Full article

Background/Objectives: Vedolizumab (VDZ), a monoclonal antibody targeting α4β7 integrin, is used in Crohn’s disease (CD) management, yet patients’ responses vary, underscoring the need for pharmacogenomic (PGx) markers. This study aimed to identify PGx pathways associated with suboptimal VDZ response using a rare-variant analytical framework. Methods: DNA from 63 CD patients treated with VDZ as first-line advanced therapy underwent whole-exome sequencing. Clinical response at week 14 classified patients as optimal responders (ORs) or suboptimal responders (SRs). Sequencing data were processed using GATK Best Practices, annotated with variant effect predictors, and filtered for rare damaging variants (damaging missense and high-confidence loss-of-function; minor allele frequency < 0.05). Variants were mapped to genes specific for SRs and ORs, and analyzed for pathway enrichment using the Reactome database. Rare-variant burden and composition differences were assessed with Fisher’s exact test and SKAT-O gene-set association analysis. Results: Suboptimal VDZ response was associated with pathways related to membrane transport (ABC-family proteins, ion channels), L1–ankyrin interactions, and bile acid recycling, while optimal response was associated with pathways involving MET signaling. SKAT-O identified lipid metabolism-related pathways as significantly different—SRs harbored variants in pro-inflammatory lipid signaling and immune cell trafficking genes (e.g., PIK3CG, CYP4F2, PLA2R1), whereas ORs carried variants in fatty acid oxidation and detoxification genes (e.g., ACADM, CYP1A1, ALDH3A2, DECR1, MMUT). Conclusions: This study underscores the potential of exome-based rare-variant analysis to stratify CD patients and guide precision medicine approaches. The identified genes and pathways are potential PGx markers for CD patients treated with VDZ. Full article

Background: Mechanical loading is a fundamental regulator of bone remodelling; however, the mechanotransduction mechanisms governing alveolar bone adaptation under tensile-dominant orthodontic loading remain insufficiently defined. In particular, the molecular pathways associated with tension-driven cortical modelling in the periodontal ligament (PDL)–bone complex have not been systematically interpreted in the context of advanced biomechanical simulations. Methods: A nonlinear finite element model of the alveolar bone–PDL–tooth complex was developed using patient-specific CBCT data. Three loading configurations were analysed: (i) conventional orthodontic loading, (ii) loading combined with corticotomy alone, and (iii) a translation-dominant configuration generated by the Bone Protection System (BPS). Pressure distribution, displacement vectors, and stress polarity within the PDL and cortical plate were quantified across different bone density conditions. The mechanical outputs were subsequently interpreted in relation to established mechanotransductive molecular pathways involved in osteogenesis and angiogenesis. Results: Conventional loading generated compression-dominant stress fields within the marginal PDL, frequently exceeding physiological thresholds and producing moment-driven root displacement. Corticotomy alone reduced local stiffness but did not substantially alter stress polarity. The BPS configuration redirected loads toward a tensile-favourable mechanical environment characterised by reduced peak compressive pressures and parallel (translation-dominant) displacement vectors. The predicted tensile stress distribution is compatible with activation profiles of key mechanosensitive pathways, including integrin–FAK signalling, Wnt/β-catenin–mediated osteogenic differentiation and HIF-1α/VEGF-driven angiogenic coupling, suggesting a microenvironment that may be more conducive to cortical apposition than to resorption. Conclusions: This study presents a computational–molecular framework linking finite element–derived tensile stress patterns with osteogenic and angiogenic signalling pathways relevant to alveolar bone remodelling. The findings suggestthat controlled redirection of orthodontic loading toward tensile domains may shift the mechanical environment of the PDL–bone complex toward conditions associated with osteogenic than resorptive responses providing a mechanistic basis for tension-induced cortical modelling. This mechanobiological paradigm advances the understanding of load-guided alveolar bone adaptation at both the tissue and molecular levels. Full article

Background: Naegleria fowleri is a free-living amoeba that inhabits warm freshwater and causes primary amoebic meningoencephalitis (PAM), a rapidly fatal infection with >95% mortality. Due to the lack of early diagnosis and effective therapy, preventive vaccination represents a promising strategy. Methods: This study evaluated short- and long-term immune protection in BALB/c mice (20 mice per group) immunized intranasally with total N. fowleri extract co-administered with cholera toxin (CT). Mice were challenged with a lethal dose of trophozoites either 24 h (short-term) or three months (long-term) after the fourth immunization; the latter group received a booster 24 h before challenge. Serum and nasal washes were analyzed for IgA and IgG antibodies by immunoblot, and lymphocyte subsets from nasal-associated lymphoid tissue (NALT) and nasal passages (NPs) were characterized by flow cytometry. Results: Immunization conferred complete (100%) survival in the 24 h group and 60% protection in the 3-month group, whereas all control mice died. Immunoblotting showed that IgA and IgG antibodies recognized major N. fowleri antigens of 37, 45, 48 and 19, 37, and 100 kDa, respectively. Flow cytometry revealed increased activated and memory B lymphocytes, dendritic cells, and expression of CCR10, integrin α4β1, and FcγRIIB receptors, particularly in the 24 h group. Conclusions: Intranasal immunization with N. fowleri extract plus CT elicited both systemic and mucosal immune responses capable of short- and long-term protection. These findings highlight the potential of this immunization strategy as a foundation for developing effective vaccines against PAM. Full article

Background: Irisin, an exercise-induced myokine, has emerged as a potent neuroprotective factor, though a systematic synthesis of its role across neurological disorders is lacking. This review systematically evaluates clinical and preclinical evidence on irisin’s association with neurological diseases and its underlying mechanisms. Methods: Following PRISMA 2020 guidelines, a systematic search of PubMed/MEDLINE, Scopus, Web of Science, Embase, and Cochrane Library was conducted. The review protocol was prospectively registered in PROSPERO. Twenty-one studies were included, comprising predominantly preclinical evidence (n = 14), alongside clinical observational studies (n = 6), and a single randomized controlled trial (RCT) investigating irisin in cerebrovascular diseases, Parkinson’s disease (PD), Alzheimer’s disease (AD), and other neurological conditions. Eligible studies were original English-language research on irisin or FNDC5 and their neuroprotective effects, excluding reviews and studies without direct neuronal outcomes. Risk of bias was independently assessed using SYRCLE, the Newcastle–Ottawa Scale, and RoB 2, where disagreements between reviewers were resolved through discussion and consensus. Results were synthesized narratively, integrating mechanistic, pre-clinical, and clinical evidence to highlight consistent neuroprotective patterns of irisin across disease categories. Results: Clinical studies consistently demonstrated that reduced circulating irisin levels predict poorer outcomes. Lower serum irisin was associated with worse functional recovery and post-stroke depression after ischemic stroke, while decreased plasma irisin in PD correlated with greater motor severity, higher α-synuclein, and reduced dopamine uptake. In AD, cerebrospinal fluid irisin levels were significantly correlated with global cognitive efficiency and specific domain performance, and correlation analyses within studies suggested a closer association with amyloid-β pathology than with markers of general neurodegeneration. However, diagnostic accuracy metrics (e.g., AUC, sensitivity, specificity) for irisin as a standalone biomarker are not yet established. Preclinical findings revealed that irisin exerts neuroprotection through multiple mechanisms: modulating microglial polarization from pro-inflammatory M1 to anti-inflammatory M2 phenotype, suppressing NLRP3 inflammasome activation, enhancing autophagy, activating integrin αVβ5/AMPK/SIRT1 signaling, improving mitochondrial function, and reducing neuronal apoptosis. Irisin administration improved outcomes across models of stroke, PD, AD, postoperative cognitive dysfunction, and epilepsy. Conclusions: Irisin represents a critical mediator linking exercise to brain health, with consistent neuroprotective effects across diverse neurological conditions. Its dual ability to combat neuroinflammation and directly protect neurons, demonstrated in preclinical models, positions it as a promising therapeutic candidate for future investigation. Future research must prioritize the resolution of fundamental methodological challenges in irisin measurement, alongside investigating pharmacokinetics and sex-specific effects, to advance irisin toward rigorous clinical evaluation. Full article