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peptide science.
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Semaglutide Injection in Indian Patients With Type 2 Diabetes Mellitus: A Randomised, Phase III, Active-Controlled Study.
Diabetes Obes Metab
Unnikrishnan Ambika Gopalakrishnan, Ameya Sudhakar Joshi, Richa Giri +31 more
To evaluate the efficacy, safety and immunogenicity of semaglutide injection (synthetic) (Test group) compared with the Reference semaglutide injection [Ozempic, (Reference group)] in Indian patients with Type 2 diabetes mellitus (T2DM).
The Impact of GLP-1-Based Therapies on Cardiovascular Outcomes in Type 2 Diabetes: A Comprehensive Systematic Review and Network Meta-Analysis.
Diabetes Obes Metab
Shih-Ming Chuang, Sung-Chen Liu, Kuo-Liong Chien +3 more
To provide updated agent-level comparative estimates of GLP-1-based therapies for cardiovascular outcomes in adults with Type 2 diabetes mellitus (T2DM) using a hazard ratio (HR)-based systematic review and network meta-analysis (NMA).
Do GLP-1 Receptor Agonists Sabotage Fat Grafts? : A Scoping Review of GLP-1 Receptor Agonist Effects on Adipocyte Biology and Implications for Autologous Fat Transfer.
Aesthet Surg J
Xavier Chalhoub, Zhi Yang Ng
The rapid adoption of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for weight management has created an unprecedented overlap with aesthetic surgery. Millions of patients experiencing GLP-1-mediated weight loss now present with facial volume depletion, soft tissue deflation, and contour irregularities; conditions for which autologous fat grafting remains the gold-standard solution. However, the fundamental biology of GLP-1 receptor agonism may be inherently antagonistic to the mechanisms upon which fat graft survival depends. This scoping review, conducted in accordance with the PRISMA extension for Scoping Reviews (PRISMA-ScR), synthesizes current preclinical and clinical evidence on the effects of semaglutide, liraglutide, tirzepatide, and the emerging triple agonist retatrutide on adipocyte metabolism, adipose-derived stem cell (ASC) function, and tissue revascularization, and maps these effects onto established models of fat graft take. We identify multiple potential interference points, including GLP-1-mediated adipocyte browning and thermogenic activation with upregulation of UCP1 and mitochondrial uncoupling, enhanced lipolysis through ATGL and HSL upregulation, suppression of white adipogenic differentiation in ASCs with preferential commitment toward thermogenic beige lineages, and modulation of inflammatory and angiogenic signaling during the critical revascularization window. The growing off-label use of retatrutide in bodybuilding communities introduces additional concerns through glucagon receptor-mediated lipolysis and thermogenesis. Despite the strong mechanistic rationale, no clinical or preclinical studies have directly examined fat graft outcomes in patients receiving incretin-based therapies. We propose a framework for future investigation and offer preliminary, mechanism-based clinical considerations regarding perioperative GLP-1 RA management in fat transfer patients. These recommendations should be understood as hypothesis-generating rather than evidence-based guidelines.
[Pulmonary Arterial Hypertension Impairs Duodenal Barrier Integrity in Rats].
Yakugaku Zasshi
Shouei Ishimaru, Satoshi Mizuno, Tomoya Tanada +4 more
Pulmonary arterial hypertension (PAH) is a progressive pulmonary vascular disease that leads to right heart failure and systemic venous congestion. Such congestion can impair multiple organs, including the gastrointestinal tract. Recent clinical studies have reported elevated circulating endotoxin levels in patients with PAH, suggesting a potential disruption of intestinal barrier function. However, whether PAH affects duodenal permeability remains unclear. This study aimed to elucidate the impact of PAH on duodenal barrier integrity. PAH was induced in rats through two subcutaneous injections of monocrotaline (20 mg/kg). Histological analysis was performed, and the mRNA expression levels of duodenal tight junction proteins were quantified using real-time PCR. Duodenal permeability was assessed by performing in situ and ex vivo experiments with paracellular probes. PAH rats exhibited characteristic signs of right heart failure, including reduced weight gain, elevated brain natriuretic peptide levels, and thickening of the right ventricular wall. Histological examination revealed duodenal villous atrophy and thickened muscularis mucosa. Claudin-1 mRNA expression in the duodenum of PAH rats was 70% lower than that in control rats. In situ permeability assays revealed 2.0- and 1.5-fold increases in the portal vein concentrations of polyethylene glycol 400 and 600, respectively. In addition, ex vivo experiments showed a 1.9-fold increase in the cumulative lactulose permeation from the luminal to the vascular side over 120 min. To the best of our knowledge, this is the first report to describe decreased duodenal barrier integrity caused by monocrotaline-induced PAH in rats.
Melanocortin-4 Receptor Agonist Treatment of Hypothalamic Obesity in ROHHAD Syndrome.
Pediatrics
Anna Grünewald, Emma Steidel, Carsten Müntjes +4 more
ROHHAD (rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation) syndrome is a rare and complex pediatric condition marked by severe, early-onset hyperphagia and life-threatening obesity. For the past 2 years, we have been treating a boy, now aged 12 years, with ROHHAD syndrome. In light of the patient's progressive weight gain, intractable appetite, ventilator dependence, metabolic dysfunction-associated steatotic liver disease and behavioral dysregulation, including aggressive outbursts posing significant risk to self and others, we initiated off-label treatment with setmelanotide, a melanocortin-4 receptor (MC4R) agonist. Setmelanotide induced meaningful improvements, including substantial weight loss (28%, from 97 to 70 kg), measurable regression of hepatic steatosis as quantified by ultrasonography-based attenuation imaging, reduced ventilatory support, and a marked improvement in behavioral disorders that permitted the tapering of antipsychotic medication. After 18 months of therapy, insurance coverage for the off-label use was refused, and treatment was discontinued, which resulted in significant weight gain within 3 months (10%, from 70 to 77 kg). This treatment of hyperphagia-associated obesity in ROHHAD syndrome with setmelanotide suggests a potential pathophysiological origin in the MC4R pathway.
Liver Aging Index: A Noninvasive Score for Liver Biological Aging and Liver-Related Outcomes in Multicohorts.
Aging Cell
Zhiyu Wu, Shanshan Wu, Shuyao Song +35 more
Biological aging is a key determinant of liver disease and mortality, but there is little evidence on noninvasive index for assessment of liver biological aging. We developed the Liver Aging Index (LAI) in the China Kadoorie Biobank (CKB, N = 21,629) using Cox-Gompertz proportional hazards model. The LAI incorporated three clinical factors (body mass index, systolic and diastolic blood pressure), eight plasma biomarkers (glucose, total cholesterol, triglycerides, high- and low-density lipoprotein cholesterol, alanine aminotransferase, aspartate aminotransferase, and γ-glutamyl transpeptidase), and two imaging biomarkers (fat attenuation parameter and liver stiffness measurement). External validation was conducted in the National Health and Nutrition Examination Survey (NHANES; N = 3412) and the VCTE-Prognosis cohort (N = 12,170, 16 global centers). Across all cohorts, the LAI demonstrated strong discrimination for all-cause mortality (AUROC: 0.764 in NHANES; 0.759 in VCTE-Prognosis), outperforming chronological age (p < 0.05). Liver aging acceleration (LAA), defined as the difference between LAI and chronological age, was associated with substantially elevated risks: each 1-SD increase in LAA conferred a 22%-85% higher risk of all-cause mortality and a 34%-170% higher risk of liver-related event or mortality. Using genetic instruments identified in CKB, we found genetic predisposition to accelerated liver aging was associated with higher risks of cirrhosis and liver cancer (HR = 3.94 [3.20-4.86] and 7.82 [2.05-29.80]), further validated in Biobank Japan. Integrating genetics and proteomics revealed novel pathophysiological involvement of amyloid-beta clearance pathway and amyloid precursor protein in liver aging. These findings demonstrate the feasibility of a noninvasive, liver-specific biological aging index and provide new insights into mechanisms underlying liver aging.
Acute liver injury associated with tirzepatide: An unexpected adverse event warranting clinical attention.
Ann Endocrinol (Paris)
Bayan Alqarni, Shaher Aldadi, Awatef Alotaibi
Tirzepatide is a novel dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist approved for the treatment of type-2 diabetes and for weight management. While generally well-tolerated, common adverse effects include gastrointestinal symptoms such as nausea and vomiting. Hepatotoxicity is not a widely recognized complication of tirzepatide, and reported cases of liver injury are exceedingly rare. As its use expands beyond diabetic populations, emerging safety concerns are increasingly relevant to clinical practice. We report a case of a young, previously healthy female who developed acute hepatocellular liver injury several months after initiating tirzepatide therapy for weight loss. Following dose escalation, she experienced recurrent episodes of abdominal pain radiating to the back. Workup revealed a hepatocellular pattern of injury, with exclusion of viral, autoimmune, biliary or structural causes. Symptoms resolved and liver enzymes normalized within 3weeks of presentation. This case adds to the limited but growing body of literature on tirzepatide-associated hepatotoxicity and emphasizes the importance of considering drug-induced liver injury even with newer agents believed to have favorable safety profiles.
IgG Fc-Binding Motif-Conjugated Exendin-4: A Long-Acting Hypoglycemic Agent via Broad-Spectrum Antibody Engagement for Type 2 Diabetes Therapy.
Bioconjug Chem
Baojing Mi, Shengjie Ding, Ziyu Tian +6 more
Type 2 diabetes mellitus requires therapies that optimize both efficacy and durability. Although incretin mimetics such as exendin-4 (Ex4) enhance glycemic control, their short half-life restricts their clinical utility. Current extension strategies (e.g., Fc fusion) encounter challenges including immunogenicity and manufacturing complexity. Here, we engineered a series of site-specific IgG Fc-binding motif-modified Ex4 analogues using two orthogonal conjugation methods, leveraging Fc-III-4C-mediated IgG binding (human IgG: KD = 20.1 nM) to achieve a significantly extended plasma half-life. Structure-activity relationship studies revealed that the lead candidate, conjugate 7, retained robust GLP-1R activation and acute glucose-lowering efficacy. In human IgG-preconditioned db/db mice, conjugate 7 achieved a hypoglycemic duration comparable to that of semaglutide. Chronic once-daily dosing of the lead conjugate rivaled semaglutide in reducing HbA1c and protecting pancreatic islets, without toxicity. This strategy leverages >80% of endogenous circulating IgG as a biological reservoir to overcome peptide therapy limitations, offering a translatable platform for long-acting antidiabetic agents.
Real-World Effectiveness of Tirzepatide in Japanese Patients with Type 2 Diabetes: A Multicenter Retrospective Observational Study.
Diabetes Ther
Noriyuki Takahashi, Makoto Ohara, Hiroki Yokoyama +14 more
Tirzepatide, a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (GLP-1) receptor agonist, significantly affects glucose and body weight-lowering effects in randomized controlled trials. However, real-world clinical evidence in Japan remains limited. This study aimed to evaluate the real-world effectiveness of tirzepatide on glycemic and metabolic factors in Japanese patients with type 2 diabetes mellitus (T2DM).
An Edible Biohybrid Platform Accomplishes In Situ Fenton-Mediated Enteral Nanoplastics Aging and Excretion.
Adv Sci (Weinh)
Su Zhou, Anran Yan, Haowei Guo +2 more
Ingested nanoplastics (NPs) readily translocate across the intestinal barrier due to their small size, posing a pervasive threat to human health. Current mitigation approaches, constrained to environmental water purification or postexposure injury alleviation, entail unavoidable NPs ingestion or organism damage. Effective strategies to impede NPs internalization at the lumen stage and promote safe elimination remain limited. Here, an edible biohybrid platform, composed of a natural polyphenol reductant, redox-active ferric ions, and H2O2-generating Enterococcus faecalis, is developed to trap NPs within the intestine. The platform enables persistent in situ generation of hydroxyl radicals in the intestine through Fenton reactions, accelerating the oxidative aging and subsequent NP agglomeration into micrometer-scale clusters that exceed the physiological pore-size limit of intestinal barrier. In an in vitro intestinal barrier model, the platform achieved a 96.02% NPs clearance efficiency within 24 h. Daily oral co‑administration effectively blocked NP penetration into lamina propria, alleviated intestinal inflammation, tight‑junction disruption, and mucosal damage in mice, as well as a protective effect further corroborated by the diminished NP fluorescence in C. elegans. Validated with both polystyrene and polypropylene NPs, this strategy of directed regulation of intestinal NP behaviors offers a green and generalizable approach to combat the NP exposure hazards.
Two contrasting cases of adrenal insufficiency in adults: a case report.
J Med Case Rep
Yingqi Guo
Adrenal insufficiency (AI) is a clinical syndrome characterized by insufficient secretion of glucocorticoids and/or mineralocorticoids. The incidence of AI is low, and its clinical manifestations are non-specific, including fatigue, generalized weakness, nausea, and weight loss. Consequently, the condition can easily be misdiagnosed or overlooked. If not treated promptly, it may progress to a life-threatening adrenal crisis. This paper reports one case of primary and one case of secondary adrenal insufficiency, aiming to enhance clinical vigilance regarding this disease through a comparative case analysis.
The clinical efficacy of Astragalus-containing Chinese patent medicines in the effective treatment of heart failure: A systematic review and network meta-analysis.
Medicine (Baltimore)
Fangfang Rui, Yunfeng Di, Chun Li +2 more
The incidence of cardiovascular diseases, particularly heart failure, has been rising year by year. Traditional Chinese medicines containing Astragalus have been widely used in clinical research. However, there is no definitive research on the efficacy of proprietary Chinese medicines containing Astragalus. A network meta-analysis was conducted to investigate the efficacy and safety of oral traditional Chinese medicines containing Astragalus for the treatment of heart failure.
Precision Management of Autoimmune Ocular Complications: Th17 Mechanisms and Therapeutic Innovations.
Exp Eye Res
Hongyu Li, Ting Wang, Chuyao Wang +3 more
Precision management of ocular complications in systemic autoimmune diseases, such as Sjögren's syndrome (SS), systemic lupus erythematosus (SLE), Behçet's disease, and thyroid-associated ophthalmopathy (TAO), requires integration of immune mechanisms with clinical translation. These disorders manifest as dry eye, uveitis, retinal vasculitis, optic neuritis, and orbital fibroinflammatory disease, posing a substantial risk of irreversible visual loss. Recent studies highlight the T-helper 17 (Th17)/interleukin-17 (IL-17) axis, tumor necrosis factor-alpha (TNF-α), complement component 5a (C5a), and TAO-related immunostromal remodeling as pivotal inflammatory drivers. Specifically, TAO is increasingly recognized as an immunostromal disorder in which fibroblast-immune crosstalk connects thyrotropin receptor antibody/insulin-like growth factor-1 receptor signaling with orbital edema, adipogenesis, and fibrosis. Disease-specific pathways, including anti-Sjögren's-syndrome-related antigen A (anti-SSA)-mediated lacrimal damage and the human leukocyte antigen B27 (HLA-B27) gut-eye axis, further enrich etiological insights. Diagnostically, aqueous IL-17, C-X-C motif chemokine ligand 10 (CXCL10), tear biomarkers, and optical coherence tomography angiography (OCTA) enable more precise phenotyping, whereas invasive ocular-fluid testing requires careful risk-benefit evaluation. Therapeutically, anti-TNF-α monoclonal antibodies, teprotumumab, and avacopan target critical pathways and improve refractory cases, while Janus kinase inhibitors, B-cell-directed combinations, and engineered regulatory T-cell therapies show promise but require rigorous safety and translational validation. This review discusses major advances in immunopathogenesis, diagnostics, and therapeutics, comparing disease commonalities and distinctions to propose a framework for precision management. It envisions multi-omics phenotyping, artificial intelligence-assisted diagnostics, and pathway-directed immunomodulation to reduce blindness and enhance quality of life, bridging rheumatology and ophthalmology.
Hypericin Alleviates High Glucose-Induced Ferroptosis in Cultured Rat Satellite Glial Cells via Targeting P2X7R to Activate the Akt/GSK3β/Nrf2 Axis.
Neuropharmacology
Qixing Hu, Congfa Zhou, Hongmin Guo +6 more
Hyperglycemia is a major risk factor for diabetic cardiovascular autonomic neuropathy (DCAN), but the underlying cellular mechanisms remain incompletely understood. To address this gap, this in vitro study aimed to determine whether high glucose induces ferroptosis in primary satellite glial cells (SGCs) isolated from rat stellate ganglia (SG) and to evaluate the protective mechanism of hypericin. Our results showed that high glucose markedly upregulates P2X7 receptor (P2X7R) expression in SGCs, leading to reduced cell viability and characteristic ferroptotic events, including increased levels of reactive oxygen species (ROS), abnormal iron accumulation, enhanced lipid peroxidation, and a marked decline in both glutathione (GSH) content and the activity of glutathione peroxidase 4 (GPX4). Hypericin at 0.1 μmol/L exhibited strong protective effects against high glucose-induced injury. Mechanistically, hypericin directly binds to the K110 site of P2X7R, inhibiting its function and subsequently activating the Akt/GSK3β pathway. This activation stabilizes Nrf2 by suppressing its ubiquitin-mediated degradation, promotes Nrf2 nuclear translocation, and upregulates the GPX4/SLC7A11 antioxidant axis. Genetic knockdown of P2X7R or Nrf2 confirmed their essential roles in this pathway. These findings reveal a previously unrecognized mechanism by which hypericin alleviates SGCs ferroptosis under high glucose conditions through the P2X7R/Akt/GSK3β/Nrf2 axis, highlighting its potential relevance to DCAN.
GLP-1 receptor agonists for weight management and potential thromboembolic risk reduction in high risk population with cancer, diabetes, cardiovascular disease: A systematic review.
Dis Mon
Rushin S Parekh, Pugazhendi Inban, Andy Thai +3 more
Thromboembolic risk is increased in obesity and cardiometabolic disorders. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) also facilitate weight loss and cardiovascular benefits, yet their effects on thromboembolic events risk reduction in high-risk populations are not completely understood.
Physiological brain clearance architecture revealed by neuronal protein tracing.
Cell
Yuichi Chayama, Nalini R Rao, Daniela Perla +17 more
The brain must efficiently clear protein waste to maintain homeostasis, yet physiological drainage pathways remain poorly defined. Standard tracer injection approaches may not reflect endogenous efflux. Here, we develop a non-invasive genetic system to trace neuron-derived protein clearance from the brain to cerebrospinal fluid (CSF) and border tissues. We identify distinct drainage routes and border hotspots missed by tracer injection, confirmed by bioorthogonal labeling of endogenous neuronal proteins. Pulse-chase kinetics reveal slow skull outflow versus rapid dural and nasal clearance. Transcriptomic analyses uncover border cells sampling neuronal antigens, including tolerogenic skull-resident B cells. Region-restricted reporter expression demonstrates compartmentalized clearance following a "nearest exit" principle, where anatomical origin dictates drainage pathway. Disease disrupts clearance through distinct mechanisms: inflammation drives vascular leakage into blood, while amyloid pathology causes parenchymal retention and border exit obstruction. These findings define brain clearance as a compartmentalized system of organized pathways and immune niches whose dysfunction may underlie regional vulnerability in neurological disease.
Aging in orbit: the twelve hallmarks as a bidirectional bridge between spaceflight-induced senescence and terrestrial geroscience.
Ageing Res Rev
Piercarlo Minoretti, Simone Lista, Susana López-Ortiz +4 more
Human spaceflight exposes crew members to a combination of environmental stressors - including microgravity, galactic cosmic radiation, circadian disruption, and prolonged confinement - that together induce multisystem physiological changes resembling terrestrial aging. In this narrative review, we examine how short- and medium-term spaceflight affects all twelve recognized hallmarks of aging. Integrated multi-omics analyses in astronauts and rodent models identified mitochondrial dysfunction as a central node of spaceflight biology, with oxidative damage propagating genomic instability, cellular senescence, and chronic inflammation. At the chromosomal level, telomere dynamics were characterized by a paradoxical elongation-shortening cycle that may compress years of terrestrial attrition into months. In parallel, epigenetic clock analyses showed a ~1.9-year biological age acceleration in astronauts after a 9-day orbital mission, with hierarchical post-flight recovery (reversible transcriptomic and epigenomic shifts versus persistent chromosomal inversions and clonal hematopoiesis mutations). This partial reversibility distinguishes the spaceflight paradigm from the largely unidirectional trajectory of chronological aging. We conclude that the relationship between spaceflight biology and terrestrial geroscience is bidirectional. Aging research on Earth provides the interpretive framework that renders astronaut molecular data biologically meaningful, and spaceflight offers geroscience a compressed, partially reversible aging-like phenotype in healthy young subjects that has no direct terrestrial counterpart. The observation that space radiation induces qualitatively distinct senescent phenotypes amenable to senolytic clearance supports a translational framework in which geroprotective strategies may simultaneously serve astronaut health and promote healthy longevity in the broader aging population.
TGM2 drives microglial senescence by inhibiting autophagy via the PI3K/AKT/mTORC1 pathway.
Free Radic Biol Med
Zhiqiang Li, Yuxiang Tang, Dongyuan Zhang +6 more
Microglial senescence is increasingly recognized as a driver of age-related neurodegeneration by impairing autophagic clearance and exacerbating neuroinflammation. However, the molecular mechanisms coupling senescence to autophagy dysfunction remain unclear. Here we identify transglutaminase 2 (TGM2) as a critical regulator linking these processes. We show that TGM2 is selectively upregulated in senescent microglia, where it assembles a previously unrecognized signaling complex with 14-3-3γ (YWHAG) and PI3K (p85α). This complex sustains AKT phosphorylation, constitutively activates mTORC1, and thereby inhibits autophagic flux. Pharmacological inhibition of TGM2 with cystamine dihydrochloride (CD) reduces this complex, restores autophagy, attenuates senescence-associated secretory phenotype (SASP) and reactive oxygen species (ROS) level, and significantly reverses cognitive and motor deficits in aged mice. These findings support a model in which TGM2-related signaling is linked to microglial autophagy dysfunction and senescence, suggesting that targeting TGM2 may offer a novel therapeutic approach for age-related neurodegenerative disorders.
Convergence of neuroinflammation across major neurotropic viral exposomes in AD and ADRD.
J Neuroinflammation
Jamile Harmouch, Ryan Green, Karthick Mayilsamy +3 more
Alzheimer's disease (AD) and Alzheimer's disease-related dementias (ADRD) are multifactorial neurodegenerative disorders driven by complex interactions among genetic susceptibility, aging, and environmental exposures. Growing epidemiological and mechanistic evidence implicates neurotropic viral exposomes, defined as cumulative lifetime viral infections, as significant contributors to AD risk. Viral encephalitis and common viral infections, including herpes simplex virus type 1 (HSV-1), human immunodeficiency virus (HIV), cytomegalovirus (CMV), SARS-CoV-2, and influenza, have been associated with an increased incidence of AD/ADRD; however, the molecular mechanisms underlying these associations remain incompletely understood.
Hormonal, metabolic and metabolomic biomarkers in long COVID.
Adv Clin Chem
Dimitra Petropoulou, Irene Karampela, Gerasimos Socrates Christodoulatos +3 more
Long COVID (LC), a complex syndrome affecting approximately 6-12 % of individuals post infection, is characterized by persistent, fluctuating, or progressive symptoms lasting at least three months. Its pathogenic mechanisms involve viral persistence, chronic inflammation, immune dysregulation, endothelial dysfunction, and endocrine/metabolic abnormalities. Currently, no specific diagnostic tests exist for LC, highlighting the need for reliable biomarkers. This review synthesizes current evidence on hormonal, metabolic, and metabolite biomarkers in LC. While vitamin D deficiency is prevalent in LC, being associated with neurocognitive symptoms, delayed recovery and poor physical performance, particularly in older adults, its lack of specificity reduces diagnostic utility. Insulin resistance markers consistently correlate with fatigue, mood disturbances, and myalgia, suggesting a distinct metabolic LC phenotype. Lower cortisol frequently correlates with fatigue, sensory disturbances, and neurocognitive symptoms. Alterations in cortisol/adrenocorticotropic hormone, growth hormone, prolactin, and gonadotropins suggest a potential hypothalamic-pituitary axis involvement; however, these abnormalities are often transient, dynamic or nonsignificant. While some patients may exhibit low free triiodothyronine associated with fatigue, no significant incidence of thyroid dysfunction and autoimmunity was associated with LC. Despite the absence of a distinct and consistent metabolomic signature, LC is characterized by the activation of the kynurenine pathway, including increased kynurenine and quinolinic acid, being associated with fatigue, neurocognitive and depressive symptoms. Emerging metabolites of mitochondrial dysfunction and lipid metabolism alterations require further validation. Despite promising findings, evidence remains scattered, hindered by small sample sizes and methodological limitations. Future research should prioritize standardization of biomarker assessment, validation in diverse populations, and exploration of targeted therapeutic interventions.