Search Results (336)

Physical exercise is a potent non-pharmacological strategy for the prevention and management of Metabolic dysfunction—associated steatotic liver disease (MASLD), a multifactorial disorder characterized by hepatic lipid accumulation, insulin resistance, oxidative stress, and chronic inflammation. Emerging evidence demonstrates that the benefits of exercise extend beyond caloric expenditure and are largely mediated by coordinated molecular and cellular adaptations within the liver and peripheral tissues. This review synthesizes current knowledge on the mechanisms through which exercise modulates MASLD pathophysiology, emphasizing intracellular signaling pathways, mitochondrial remodeling, antioxidant defenses, and myokine-driven muscle–liver crosstalk. Exercise induces acute and chronic activation of pathways such as AMPK, PGC-1α, Nrf2, and Akt, resulting in enhanced mitochondrial biogenesis, improved fatty acid oxidation, restored insulin signaling, and reduced inflammatory and oxidative stress. Repeated skeletal muscle contraction stimulates the release of myokines—including irisin, IL-6, and FGF21—that act through endocrine and paracrine routes to regulate hepatic lipid metabolism, promote systemic metabolic flexibility, and attenuate disease progression. Epigenetic modifications and exercise-responsive microRNAs further contribute to long-term hepatic metabolic reprogramming. Collectively, these molecular adaptations position exercise as a systemic, disease-modifying stimulus capable of restoring hepatic homeostasis, slowing the transition from steatosis to NASH and fibrosis, and improving long-term metabolic health. Understanding these mechanisms provides a foundation for developing targeted, personalized exercise-based interventions in the clinical management of MASLD. Full article

Background/Objectives: Current musculoskeletal health assessment expanded beyond bone mineral density (BMD) at central DXA to include, for instance, trabecular bone score (TBS) and emergent biomarkers, such as adipokines and myokines (e.g., irisin) assays. A current gap in their application is reflected in limited research regarding adrenal tumors, especially non-functional adrenal tumors/mild autonomous cortisol secretion (NFATs/MACS). To assess this current gap, we aimed to explore beyond BMD, specifically, TBS and circulating irisin, in relation to the adrenal status in NFATs/MACS. Methods: This is a prospective, cross-sectional, single-center, exploratory study, conducted between October 2024 and December 2025. Results: A total of 81 menopausal women were included (mean age of 63.26 ± 8.82 years, 15.86 ± 9.5 years since menopause, average BMI of 30.69 ± 5.76 kg/sqcm. Out of them, 33.33% had NFATs/MCAS (group AI) and 66.67% were controls (group C), with similar age, years since menopause, and BMI. The prevalence of type 2 diabetes was 66.67% versus 68.52% (p = 0.865). TBS correlated with lumbar BMD/T-score (N = 33), while age and lumbar BMD were independent TBS predictors (N = 81), but not type 2 diabetes nor NFAs/MCAS. TBS correlated with the five-year age groups (r = −0.273, p = 0.003). Irisin correlated with osteocalcin (r = −0.252, p = 0.007), P1NP (r = −0.187, p = 0.049) and CrossLaps (r = −0.209, p = 0.026) in tumor-free controls. In the AI group, a higher irisin was associated with a higher second-day cortisol after 1 mg DST (r = 0.11, p = 0.584) and a lower ACTH (r = −0.716, p < 0.001). The rate of low TBS (based on 1.350 cutoffs) was 48.15% versus 38.89% in group AI versus C. In the AI group, patients with low TBS had lower osteocalcin, P1NP, and CrossLaps than those with normal TBS, with a similar rate of type 2 diabetes (which might reduce the bone turnover markers) and MACS-positive prevalence (between 25 and 28%). Conclusions: The median glycated hemoglobin A1c (5.78% versus 5.93%, p = 0.94) and median HOMA-IR (1.53 versus 1.42, p = 0.948) suggest a certain level of glucose control, which might not be reflected in severely damaged bone microarchitecture, as shown by TBS. Irisin may be one of the additional factors in these tumors reflecting the hormonal burden. Irisin was statistically significantly elevated with the increase in BMI groups. To our best awareness, this is the first synchronous analysis of TBS and irisin levels in this type of tumor to address the bone status in relation to the glucose profile and adrenal panel. Noting this is an exploratory, hypothesis-generating study, further research will highlight the true value of TBS and irisin for practitioners in the adrenal field, including multi-layered models of bone status prediction. Full article

Long COVID is a complex condition characterized by persistent symptoms following SARS-CoV-2 infection. Understanding its biochemical mechanisms is essential for effective management and treatment strategies. Objective: This study investigated biochemical alterations associated with long COVID in unvaccinated individuals presenting symptoms persisting for more than six months, highlighting the prolonged nature of the condition and its systemic and neurological manifestations. A cross-sectional study was conducted with 60 unvaccinated patients at least six months post-COVID-19 infection. Serum biomarkers, including C-reactive protein (CRP), interleukin-6 (IL-6), N-terminal pro-brain natriuretic peptide (NT-proBNP), and irisin, were analyzed. Correlations between these biomarkers and persistent symptoms were assessed using statistical regression models. Elevated CRP levels were significantly associated with persistent respiratory and musculoskeletal symptoms, suggesting ongoing inflammation. Increased IL-6 levels correlated with fatigue and musculoskeletal complaints. NT-proBNP elevations were linked to cardiovascular manifestations, including dyspnea and chest pain. A positive correlation between irisin and persistent sensory impairments, such as anosmia and dysgeusia, indicates potential neuroinflammatory mechanisms. This study highlights that persistent inflammation plays a critical role in long-term (>6 months) post-COVID manifestations. Monitoring biomarkers such as CRP, IL-6, NT-proBNP, and irisin may enhance understanding and management of prolonged post-COVID conditions. Full article

Background/Objectives: This study evaluated exercise-induced changes in body composition and metabolic biomarkers in women across distinct BMI categories and individuals with Type 2 diabetes. Methods: In this quasi-experimental study, 40 sedentary women were stratified into five groups (n = 8): underweight, normal weight, overweight, obese, and T2DM. The rigorous eight-week supervised program utilized submaximal exercise at 70–85% heart rate reserve, calculated via the Karvonen method and monitored by telemetry. Assessments included anthropometric parameters (BMI, fat mass, visceral fat) and serum biomarkers (irisin, myonectin, HIF-1α, insulin, glucose). Fasting venous samples were collected at baseline and 72 h post-intervention to minimize acute effects, then analyzed using validated ELISA protocols. Statistical data were evaluated using parametric or non-parametric tests with significance set at p < 0.05. Results: Post-intervention, significant reductions in weight, fat mass, and visceral fat occurred in overweight, obese, and T2DM groups (p < 0.05). Muscle mass increased across all cohorts. Fasting insulin and glucose decreased significantly in all except the underweight group, with the most pronounced improvements in T2DM and obese participants. Serum irisin increased significantly across all groups (p < 0.05), indicating a universal exercise-induced myokine response. Conversely, myonectin levels decreased significantly only in the normal-weight group, while HIF-1α increased specifically in the T2DM cohort. These findings suggest that baseline BMI and metabolic status are critical determinants of exercise responsiveness, leading to heterogeneous biomarker patterns despite consistent improvements in body composition and basic glycemic regulation. Conclusions: An eight-week submaximal program effectively improves body composition and glycemic regulation, though specific biomarker responses are highly dependent on baseline BMI and metabolic status. Full article

Diabetic retinopathy (DR) stands as a classic microvascular complication of diabetes mellitus. DR is characterized by multidimensional pathological changes in retinal neurons, microvasculature and supportive cells, leading to an intricate damage network. It is predominantly marked by neuropathy, encompassing retinal neuronal dysfunction, aberrant activation of glial cells, and degeneration of synaptic structures. In severe instances, it can result in visual impairment and, in the worst-case scenario, blindness. As diabetes progresses, retinal nerve tissue frequently sustains damage owing to oxidative stress, inflammatory responses, and compromised mitochondrial function. Although the precise neuroprotective mechanisms remain elusive, exercise has the ability to bolster mitochondrial function in retinal cells, diminish oxidative stress, and curb inflammatory reactions, thereby safeguarding the neurophysiological function of the retina. Irisin is a myokine primarily secreted by skeletal muscles in response to exercise stimulation. Moreover, being produced in trace amounts across a variety of tissues, it has the capacity to regulate the physiological processes of multiple organs. Recent studies have indicated that irisin can exert powerful neuroprotective effects by enhancing cellular glucose uptake, improving mitochondrial function, inhibiting the expression of pro-inflammatory factors, and resisting ferroptosis. In this review, we systematically collated and synthesized existing evidence on irisin-related signaling pathways and comprehensively assessed its regulatory potential in alleviating neuroinflammation and promoting neural repair in diabetic retinopathy and offer insights into future research directions in this field. Full article

Aging disrupts the neurovascular unit (NVU) and blood–brain barrier (BBB), elevates glial inflammatory tone, and compromises hippocampal memory. Environmental enrichment (EE)—a multimodal, lifestyle-based intervention—improves cognition, but its association with BBB/NVU and FNDC5/irisin-related signaling in aging remains incompletely understood. Aged male C57BL/6J mice (21 months old) were housed under EE or standard conditions for 11 weeks. Hippocampal-dependent spatial working memory was assessed using the radial eight-arm maze, and neuronal (NeuN), glial (Iba1, GFAP), and BBB/NVU markers (AQP4 endfoot polarity, occludin, ZO-1, PECAM-1, microvessel length/density) were quantified. FNDC5/irisin-related signaling was evaluated by measuring PGC-1α, FNDC5/irisin, IGF-1, BDNF, pAKT, and serum irisin. EE improved spatial working memory in aged mice, reducing working-memory errors, increasing correct choices before the first error, and enhancing path efficiency. EE attenuated the age-related decline of NeuN(+) neurons in the hippocampal CA1 and CA3 regions and suppressed microglial and astrocytic activation. EE strengthened BBB/NVU integrity by restoring AQP4 endfoot polarity, increasing occludin, ZO-1, and PECAM-1, and increasing cortical microvessel length and density. At the molecular level, EE upregulated the PGC-1α–FNDC5/irisin–IGF-1 axis and was accompanied by increased cortical BDNF and pAKT levels, as well as elevated circulating irisin, changes that occurred in parallel with NVU stabilization and reduced glial activation. EE mitigates age-related cognitive decline in association with coordinated neuronal, glial, vascular, and FNDC5/irisin-related signaling changes, supporting BBB/NVU preservation and cognitive resilience during aging. Full article

Monitoring adolescent team-sport athletes may benefit from combining performance and molecular markers, but empirical evidence supporting this approach in youth team sports remains limited. Objective: Our study investigated molecular and physiological adaptations to seasonal training in elite U18 ice hockey players, focusing on aerobic capacity, salivary cortisol, serum irisin, and cell-free DNA (cfDNA) dynamics. Methods: National-level U18 players were enrolled in our study (n = 23 for cross-sectional analysis, n = 12 longitudinal) during the pre- and early-competition season. Aerobic performance was assessed via graded treadmill VO₂max testing, and the biochemical markers quantified using ELISA-based assays. Results: From pre- to early-season (paired n = 12), VO₂max increased by 10.6% (g = +1.00, p = 0.003) and irisin by 14.7% (g = +0.83, p = 0.010). cfDNA decreased by 60.8% (g = −0.54, p = 0.070; moderate effect, not statistically clear), while cortisol remained stable (+11.3%; p = 0.667). Inter-individual variability increased for VO₂max and irisin and decreased by 82% for cfDNA. Exploratory cross-sectional positional analysis indicated higher irisin levels in forwards and elevated cfDNA in defensemen, although differences did not reach statistical significance. Conclusions: These preliminary findings provide cohort-size limited longitudinal evidence of chronic irisin elevation in ice hockey players and highlight the possibility of combining VO₂max + irisin + cfDNA to assist individualized load/recovery in elite youth ice hockey. Full article

Background: Irisin, a recently discovered muscle-originating hormone, has been found to act as a biomarker of several ailments, while no guideline clearly indicates its testing so far in any particular population category or pathological condition. Objective: We analyzed blood (circulating) irisin in relation to the potential correlations with the evaluation of glucose and bone profile. Methods: This was a prospective, pilot, exploratory study (between December 2024 and August 2025). The enrolled patients were menopausal women aged ≥50. Exclusion criteria: Endocrine tumors, thyroid dysfunction, malignancies, or chronic kidney disease. Baseline (fasting) testing was followed by 75 g oral glucose tolerance test (OGTT). Enzyme-linked immunosorbent assay (ELISA)-based irisin assay (MyBioSource) was performed. The subjects underwent central Dual-Energy X-Ray Absorptiometry (DXA), which provided lumbar, femoral neck and total hip bone mineral density (BMD)/T-score (GE Lunar Prodigy), and lumbar DXA-based trabecular bone score (TBS iNsight). Results: We enrolled 89 females [mean age of 62.84 ± 9.33 years, average years since menopause (YSM) of 15.94 ± 9.23]. Irisin (102.69 ± 98.14 ng/mL) did not correlate with age, YSM, but with body mass index (r = 0.36, p < 0.001). Bone formation marker osteocalcin (r = −0.25, p = 0.018) was negatively associated with irisin, amidst multiple other mineral metabolism assays (including PTH and 25-hydroxyvitamin D). Irisin positively correlated with insulin (r = 0.385, p = 0.0008), HbA1c (r = 0.243, p = 0.022), and HOMA-IR (r = 0.313, p = 0.007). Additional endocrine assays pointed a statistically significant association between irisin and TSH, respectively, ACTH (r = 0.267, p = 0.01, and r = 0.309, p = 0.041, respectively). No correlation irisin-BMD/T-score/TBS was confirmed. Conclusions: Irisin correlates with markers of glucose status (insulin, HOMA-IR, and HbA1c), as well as body mass index and, to a lesser extent, bone metabolism markers. Interestingly, TSH and ACTH correlations open a new (hypothesis-generating) perspective in the endocrine frame of approaching this exerkine. To the best of our knowledge, no distinct study has so far addressed the TBS–irisin relationship or pinpointed the glucose effects on TBS, particularly in menopausal women. Full article

The global aging population has led to a rising prevalence of cognitive impairment, posing a significant public health challenge. Resistance training (RT) is a non-pharmacological intervention that has been increasingly investigated for its potential to support cognitive function in older adults. Clinical evidence suggests that RT may be associated with benefits in certain cognitive domains, including memory, executive function, processing speed, and visuospatial ability. However, findings across studies remain heterogeneous, with several trials reporting neutral outcomes. Most intervention studies involve structured RT programs conducted at moderate to high intensity and performed multiple times per week. However, optimal training parameters have not yet been clearly established due to variability in study design and the absence of formal dose–response analyses. Emerging evidence suggests that the cognitive effects of RT may be mediated, at least in part, through muscle–brain axis signaling involving exercise-induced myokines. Factors such as irisin, brain-derived neurotrophic factor, interleukin-6, interleukin-15, and insulin-like growth factor-1 have been implicated in processes related to neuroplasticity, neuroinflammatory regulation, and neurovascular function, primarily based on preclinical and translational research. This review synthesizes current evidence on RT-related molecular mechanisms and clinical findings to provide an integrative perspective on the potential role of resistance training in mitigating age-related cognitive decline. Full article

Background: Irisin, a muscle-derived hormone, enhances the energy metabolism by activating the brown adipose tissue and acts as a bone-forming agent across the entire life span. No consistent clinical data in humans have been published so far to highlight if blood irisin as glucose/bone biomarker should be refined based on the vitamin D status (deficient or sufficient). Therefore, we aimed to objectively assess the level of irisin in female adults with abnormal and normal vitamin D status, as reflected by the level of 25-hydroxyvitamin (25OHD) in relationship with glucose and bone metabolic parameters. Methods: This pilot, prospective, exploratory study included eighty-nine menopausal women aged over 50. We excluded subjects with malignancies, bone and metabolic disorders, insulin treatment, and active endocrine disorders. Fasting profile included glycaemia, insulin, and glycated haemoglobin A1c (HbA1c). Then, 75 g oral glucose tolerance test (OGTT) included glycaemia and insulin assay after 60 and 120 min. Bone status involved bone turnover markers and central dual-energy X-ray absorptiometry providing bone mineral density (BMD) and trabecular bone score. Results: Eighty-nine subjects were included in the following two groups depending on 25OHD: vitamin D-deficient (VDD) group (N = 48; 25OHD < 30 ng/mL) and vitamin D-sufficient (VDS) group (N = 41; 25OHD ≥ 30 ng/mL). The two groups had similar age and menopausal period (62.29 ± 10.19 vs. 63.56 ± 8.16 years, respectively; 15.82 ± 9.55 vs. 16.11 ± 9.00 years, p > 0.5 for each). A statistically significant higher body mass index (BMI) was found in VDD vs. VDS group (32.25 ± 5.9 vs. 28.93 ± 4.97 kg/m², p = 0.006). Circulating irisin was similar between the groups as follows: median (IQR) of 91.85 (44.76–121.76) vs. 71.17 (38.76–97.43) ng/mL, p = 0.506. Fasting profile and OGTT assays showed no between-group difference. Median HOMA-IR in VDD group pointed out insulin resistance of 2.67 (1.31–3.29). Lowest mean/median T-scores at DXA for both groups were consistent with osteopenia category, but they were confirmed at different central sites as follows: femoral neck in both groups [VDD versus VDS group: −1.1 (−1.20–−0.90) vs. −1.1 (−1.49–−0.91), p = 0.526, respectively], only at lumbar spine for VDS group (T-score of −1.18 ± 1.13). The correlations between irisin and the mentioned parameters displayed a different profile when the analysis was performed in the groups with different 25OHD levels. In VDD group, irisin levels statistically significantly correlated with serum phosphorus (r = −0.32, p = 0.022), osteocalcin (r = −0.293, p = 0.038), P1NP (r = −0.297, p = 0.04), HbA1c (r = 0.342, p = 0.014), and BMI (r = 0.408, p = 0.003). Conclusions: This pilot study brings awareness in the analysis of irisin in relationship with glucose and bone-related biomarkers correlates, showing a distinct type of association depending on 25OHD level, which might represent an important crossroad in the multitude of irisin-activated signal transduction pathways. Full article

Circulating irisin, a myokine implicated in energy expenditure and adipose tissue regulation, has been increasingly studied as a potential biomarker of metabolic dysfunction. This study evaluated the relationship between serum irisin and metabolic indices, including the atherogenic index of plasma (AIP), the lipid accumulation product (LAP), and hypertriglyceridemic-waist (HTGW) phenotype in individuals with prediabetes (PreDM) and newly diagnosed type 2 diabetes mellitus (T2DM). A total of 138 participants (48 PreDM, 90 T2DM) were assessed for anthropometric, glycemic, and lipid parameters. Serum irisin levels were measured by enzyme-linked immunosorbent assay (ELISA) and correlated with insulin resistance indices (Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), Quantitative Insulin Sensitivity Check Index (QUICKI)), glycemic control (glycosylated hemoglobin A1c (HbA1c)), and composite lipid markers (total triglycerides-to-high-density lipoprotein cholesterol (TG/HDL-C)). Group differences were evaluated using non-parametric tests; two-way ANOVA assessed interactions between phenotypes and markers; multiple linear regression (MLR) and logistic regression models explored independent associations with metabolic indices and HTGW; receiver operating characteristic (ROC) analyses compared global and stratified model performance. Serum irisin was significantly lower in T2DM than in PreDM (median 140.4 vs. 230.7 ng/mL, p < 0.0001). Irisin levels remained comparable between males and females in both groups. Post hoc analysis shows that lipid indices and irisin primarily distinguish HTGW phenotypes, especially in T2DM. In both groups, irisin correlated inversely with HOMA-IR, AIP, and TG/HDL-C, and positively with QUICKI, indicating a possible compensatory role in early insulin resistance. MLR analyses revealed no independent relationship between irisin and either AIP or LAP in PreDM, while in T2DM, waist circumference remained the strongest negative predictor of irisin. Logistic regression identified age, male sex, and HbA1c as independent predictors of the HTGW phenotype, while irisin contributed modestly to overall model discrimination. ROC curves demonstrated good discriminative performance (AUC = 0.806 for global; 0.794 for PreDM; 0.813 for T2DM), suggesting comparable predictive accuracy across glycemic stages. In conclusion, irisin levels decline from prediabetes to overt diabetes and are inversely linked to lipid accumulation and insulin resistance but do not independently predict the HTGW phenotype. These findings support irisin’s role as an integrative indicator of metabolic stress rather than a stand-alone biomarker. Incorporating irisin into multi-parameter metabolic panels may enhance early detection of cardiometabolic risk in dysglycemic populations. Full article

Exercise-induced myokines have emerged as crucial mediators of the beneficial effects of physical activity on neurodegenerative diseases through complex molecular mechanisms involving oxidative stress reduction, neuroinflammation suppression, and synaptic plasticity enhancement. Among these myokines, irisin, encoded by the FNDC5 gene, has gained significant attention as a potential therapeutic target in neurodegenerative conditions due to its ability to cross the blood–brain barrier and exert pleiotropic neuroprotective effects. This review synthesizes current evidence from both preclinical and clinical studies examining the role of exercise-induced irisin in neurodegeneration, with particular emphasis on translational potential and therapeutic applications. A comprehensive search was conducted across PubMed, Web of Science, Scopus, and EMBASE databases (spanning January 2015 to December 2024) to identify peer-reviewed articles investigating irisin’s neuroprotective mechanisms in neurodegenerative diseases. Ten studies met the inclusion criteria (five rodent/primate model studies and five human clinical investigations), which were analyzed for methodological rigor, intervention protocols, biomarker quantification methods, and reported outcomes. Reviewed studies consistently demonstrated that exercise-induced endogenous irisin elevation correlates with improved cognitive function, reduced neuroinflammatory markers, enhanced synaptic plasticity, and modulation of neurodegenerative pathways, with exogenous irisin administration reproducing several neuroprotective benefits observed with exercise training in animal models. However, substantial heterogeneity exists regarding exercise prescription parameters (intensity, duration, frequency, modality), training-induced irisin quantification methodologies (ELISA versus mass spectrometry), and study designs (ranging from uncontrolled human observations to randomized controlled trials in animal models). Critical appraisal reveals that human studies lack adequate control for confounding variables including baseline physical fitness, comorbidities, concurrent medications, and potential sources of bias, while biochemical studies indicate distinct pharmacokinetics between endogenous training-induced irisin and exogenous bolus dosing, necessitating careful interpretation of therapeutic applicability. The translational potential of irisin as a therapeutic agent or drug target depends on resolving methodological standardization in biomarker measurement, conducting well-designed clinical trials with rigorous control for confounders, and integrating findings from molecular/biochemical studies to elucidate mechanisms linking irisin to disease modification. Future research should prioritize establishing clinical trial frameworks that harmonize exercise prescriptions, employ robust biomarker quantification (mass spectrometry), and stratify participants based on disease stage, comorbidities, and genetic predisposition to clarify irisin’s role as a potential therapeutic intervention in neurodegenerative disease management. Full article

Background/Objectives: Rosacea increasingly appears to involve systemic immune and metabolic disturbances rather than isolated cutaneous inflammation. To evaluate inflammatory, platelet, and oxidative–metabolic biomarkers in rosacea and explore their interrelations. Methods: 90 patients with rosacea and 90 healthy controls were evaluated for hematologic inflammatory indices—neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune–inflammation index (SII), pan-immune–inflammation value (PIV), mean platelet volume (MPV), and C-reactive protein (CRP)—along with oxidative–metabolic regulators including sirtuin 1 (SIRT1), sirtuin 3 (SIRT3), visfatin, and irisin. Logistic regression and receiver operating characteristic (ROC) analyses were used to identify independent predictors of rosacea, while inter-marker associations were evaluated using Spearman’s rank correlation. Results: Rosacea patients showed higher NLR, PLR, SII, PIV, MPV, CRP, and LDL cholesterol (p < 0.05) and lower SIRT1, SIRT3, visfatin, and irisin (p < 0.01). MPV independently predicted rosacea (OR = 7.24; AUC = 0.827), whereas SIRT1 inversely correlated with disease risk. SIRT1, SIRT3, and visfatin showed inverse correlations with HbA1c and waist-to-height ratio, while fasting glucose and HOMA-IR remained within normal ranges. Conclusions: Rosacea exhibits dual systemic activation, an inflammatory–platelet and an oxidative–metabolic axis bridging immune dysregulation, mitochondrial stress, and vascular dysfunction. Recognition of these pathways highlights the potential of redox-targeted and metabolic interventions beyond symptomatic treatment. 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

Background: The myokine response to various types of exercise may differ and influence the adaptations to various physiological systems in response to training. This study aimed to compare systemic myokines’ (apelin, interleukin-6 [IL-6], interleu-kin-15 [IL-15], fibroblast-growth factor-21 [FGF-21], and irisin) responses to acute moderate-intensity cardiovascular exercise (MICE), high-intensity interval exercise (HIIE), or resistance exercise (RE). Methods: Six healthy, recreationally active adults (n = 4 males, n = 2 females) completed this crossover pilot study. After baseline testing, in a balanced randomized order, participants completed all three exercise sessions with one week between each of the exercise sessions. Blood samples were obtained at rest, immediately post-exercise, and 1 and 3 h post-exercise. Myokine response was analyzed using a 3 (exercise condition: MICE, HIIE, RE) × 4 (time: baseline, post-exercise, 1 and 3 h post-exercise) repeated-measures ANOVA. Results: Our results showed no significant interaction of time × exercise type in any of the analyzed myokines (all p > 0.05). A significant main effect of time was found for FGF-21, where concentrations at baseline (188.96 ± 127.34 pg/mL; p = 0.038) and immediately post-exercise (206.27 ± 135.95 pg/mL; p = 0.006) were higher than 3 h post-exercise (111.08 ± 127.65 pg/mL). No other main effects for time or exercise type were identified (all p > 0.05). Conclusions: The three exercise types, when analyzed together in this study, demonstrated a reduction in FGF-21 3 h post-exercise, suggesting this myokine was removed from the systemic circulation following exercise. The negative results of this study are inconclusive given the lower statistical power observed in this research. These preliminary results indicate the need for a larger trial to evaluate the effects of different types of exercise on the specificity of myokine responses and how acute exercise responses may translate into long-term exercise training adaptations. Full article