Search Results (3,036)

Accurate protein function prediction (PFP) is essential for understanding biological systems. However, structure-based graph neural networks often rely on fixed-distance contact maps, which may inadequately capture continuous, multi-scale spatial topologies, while the long-tail distribution of Gene Ontology (GO) labels may bias prediction toward frequent functions. We propose DHST, a deep hybrid structure–topology framework that integrates sequence semantics from a pretrained protein language model with local structural information learned by a residual graph convolutional network. DHST further introduces site-specific persistent homology to encode multi-scale topological invariants and a topology-guided residue-wise gated fusion module to modulate structure–semantics representations using local topological embeddings. The fused residue features are aggregated through dual-path pooling, and a weighted binary cross-entropy loss is used to mitigate the adverse effects of label imbalance. On the PDB dataset, DHST achieved area under the precision–recall curve (AUPR) scores of 0.779, 0.481, and 0.557 for molecular function (MF), biological process (BP), and cellular component (CC), respectively; on the AF2 dataset, the corresponding scores were 0.729, 0.390, and 0.459. The model also demonstrated robust generalization to low-homology proteins and maintained strong predictive performance across GO terms with different levels of functional specificity. Ablation results supported the contributions of the main components. Full article

The aryl hydrocarbon receptor (AhR) is highly expressed in keratinocytes and functions as an environmental sensor regulating xenobiotic metabolism, epidermal differentiation, and inflammatory responses. Particulate matter (PM), a major environmental pollutant containing reactive oxygen species (ROS), transition metals, and polycyclic aromatic hydrocarbons (PAHs), induces oxidative stress and inflammation, leading to skin barrier dysfunction. Transition metals generate ROS via Fenton-type reactions, whereas PAHs undergo AhR-mediated metabolism that further amplifies oxidative stress. Excessive ROS promotes inflammatory cytokine expression and disrupts barrier-related protein expression. In response, activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway induces antioxidant enzymes, including heme oxygenase-1 (HO-1), to counteract oxidative damage. However, sustained PM exposure may overwhelm these defense mechanisms, resulting in impaired cellular homeostasis. Although the roles of AhR and Nrf2 have been extensively investigated individually, their coordinated regulation in PM-induced skin injury remains underexplored. This review summarizes current evidence on the functional interplay between AhR and Nrf2 and discusses how coordinated activation of these pathways integrates xenobiotic metabolism, antioxidant defense, and barrier-associated functions. Overall, the available evidence supports a dual-pathway framework for maintaining epidermal homeostasis under PM-induced environmental stress. Full article

Glucagon-like peptide-1 (GLP-1) receptor agonists and dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonists have transformed obesity management by producing substantial, sustained weight loss and improving metabolic health. Alongside these benefits, their effects on appetite, food intake, and gastrointestinal function have raised increasing interest in the nutritional consequences of pharmacologically induced weight loss. Although reductions in energy intake contribute to therapeutic efficacy, they may also influence protein intake, dietary quality, micronutrient adequacy, and skeletal muscle health, particularly in individuals with pre-existing nutritional vulnerability. This narrative review summarizes current evidence regarding nutritional considerations during GLP-1-based therapy, including changes in dietary intake, protein and micronutrient adequacy, body composition, muscle health, and nutritional assessment. Particular attention is given to populations at increased nutritional risk, practical approaches to nutritional monitoring, and strategies to support adequate nutrition during treatment. Current evidence suggests that nutritional responses to GLP-1-based therapy are heterogeneous and cannot be adequately evaluated using body weight alone. Assessment of dietary intake, body composition, muscle function, physical performance, and individual clinical characteristics provides a more comprehensive understanding of nutritional status than anthropometric measures alone. While routine supplementation or intensive monitoring is not supported for all patients, a risk-based and individualized approach appears appropriate, particularly for older adults and individuals with sarcopenic obesity, previous bariatric surgery, chronic gastrointestinal disease, or persistent treatment-related gastrointestinal symptoms. Future research should establish clinically meaningful nutritional outcomes and determine which nutritional interventions improve patient-centered outcomes during long-term obesity management. Full article

Dual-protein systems combining whey protein isolate (WPI) and soy protein isolate (SPI) offer complementary nutritional benefits but are limited by the presence of major allergens. Lactic acid bacteria (LAB) fermentation provides a promising strategy to mitigate this limitation. In this study, Lacticaseibacillus paracasei JM053, selected from 13 LAB strains based on phenotypic screening, significantly reduced the in vitro allergenicity of the dual-protein system, increasing the IgE-binding inhibition rate to 48.75%. Whole-genome sequencing and characterization of JM053 revealed a comprehensive proteolytic system, including the proline-specific peptidase genes pepX and pepQ, which may contribute to the degradation of allergenic peptide sequences. Combined with in silico bioinformatic analysis, potential cleavage sites within the linear epitopes of the dual-protein system were predicted based on the substrate specificity of the identified proteases, offering a testable hypothesis for the strain’s mechanism of action. In addition, in vitro safety assessment and genomic analysis supported the safety potential, stress tolerance, and probiotic characteristics of JM053. Collectively, this study provides a valuable candidate strain for the development of hypoallergenic dual-protein products and offers preliminary genomic insights into LAB-mediated allergenicity reduction. Full article

Background/Objectives: Obesity is a chronic, progressive, and relapsing disease that requires long-term, multidisciplinary management rather than episodic weight-loss treatment. Although novel incretin-based anti-obesity pharmacotherapies, including GLP-1 receptor agonists and dual GIP/GLP-1 receptor agonists, have markedly improved the clinical management of obesity, weight reduction alone does not fully capture treatment success. Body composition, lean mass preservation, physical function, nutritional adequacy, psychological well-being, adherence, and long-term weight-loss maintenance are increasingly recognized as essential therapeutic outcomes. This narrative review critically examines the role of lifestyle medicine as a co-therapeutic strategy during modern anti-obesity pharmacotherapy, with particular attention to physical activity, nutrition, behavioral support, and individualized monitoring. Methods: A narrative literature search was conducted in PubMed up to June 2026. The review included studies addressing adults with overweight or obesity and evidence related to anti-obesity pharmacotherapy, physical activity, nutrition, body composition, functional outcomes, eating behavior, quality of life, treatment tolerability, adherence, weight regain, and long-term maintenance. Results: Current evidence indicates that incretin-based therapies produce substantial and clinically meaningful weight loss, but pharmacological efficacy may be limited by reductions in lean mass, gastrointestinal adverse events, inadequate nutritional intake, treatment discontinuation, and weight regain after drug withdrawal. Physical activity should be considered a therapeutic component rather than only a tool for increasing energy expenditure, as aerobic exercise supports cardiometabolic health and cardiorespiratory fitness, while resistance training helps preserve muscle strength, bone health, and functional capacity. Nutritional strategies are equally important, particularly during appetite suppression, to maintain adequate protein, fiber, fluids, micronutrients, and diet quality. Behavioral factors, including sleep, stress, mood, stigma, self-regulation, and the food environment, may influence adherence and long-term outcomes. Conclusions: Novel anti-obesity drugs should not be viewed as replacements for lifestyle medicine but as powerful tools within an integrated chronic-care model. The goal of treatment should move beyond maximal body-weight reduction to durable improvements in body composition, metabolic health, physical function, nutritional status, quality of life, and weight-loss maintenance. Full article

Cardiac amyloidosis (CA) is an infiltrative cardiomyopathy caused by extracellular deposition of misfolded proteins, most commonly immunoglobulin light chains (AL) or transthyretin (ATTR). Once considered a rare disease, CA is increasingly recognised due to improved diagnostic strategies and the availability of disease-modifying therapies. Early diagnosis is crucial, as treatment efficacy and clinical outcomes are strongly influenced by the stage of cardiac involvement. Multimodality cardiac imaging plays a central role in the diagnostic pathway, risk stratification, and evaluation of therapeutic response in CA. Echocardiography represents the first-line imaging modality and is essential for raising clinical suspicion through the identification of characteristic structural and functional abnormalities, including ventricular wall thickening, diastolic dysfunction, and distinctive strain patterns. Bone scintigraphy has revolutionised the non-invasive diagnosis of ATTR-CA, allowing accurate identification of transthyretin-related disease in the absence of monoclonal gammopathy, which needs to be excluded via serum and urinary immunofixation. Cardiovascular magnetic resonance provides advanced tissue characterisation through late gadolinium enhancement and quantitative mapping techniques, enabling detection of early myocardial involvement and robust prognostic stratification. Emerging imaging modalities, including dual-energy (spectral) computed tomography and positron emission tomography tracers, show promise in myocardial amyloid quantification and subtype differentiation, although their role is still evolving. Integration of imaging findings with clinical and laboratory parameters allows comprehensive disease assessment, facilitating early diagnosis, guiding therapeutic decisions, and improving risk stratification. This review summarises the current role of multimodality imaging in CA, highlighting its contribution from early detection to prognostic evaluation and monitoring of treatment efficacy, with particular emphasis on the emerging role of quantitative imaging in monitoring treatment response. Full article

Background: As a member of the T-box transcription factor family, TBX18 was found to be involved in ESCC progression, while its role in regulating radiotherapy resistance in ESCC remains unclear. This study was designed to investigate the molecular mechanisms underlying the regulation of radioresistance in ESCC by TBX18. Methods: Sphere formation assay, Transwell invasion assay, and wound healing assay were conducted to show the influence of TBX18 on tumor stemness and epithelial–mesenchymal transition (EMT). Western blot, immunofluorescence, chromatin immunoprecipitation-qPCR (ChIP-qPCR) and dual-luciferase reporter assay were preformed to identify regulatory networks. A nude mouse xenograft tumor model was established to assess the regulatory effect of TBX18 and SIX1 on radioresistance of ESCC in vivo. Results: TBX18 expression was positively associated with stemness markers, including CD44, CD271, and SOX2. TBX18 promoted stemness-associated phenotypes, EMT, migration, invasion, and radioresistance in ESCC cells. Mechanistically, TBX18 directly bound to the SIX1 promoter and transcriptionally activated SIX1 expression. In turn, SIX1 enhanced TBX18 protein stability by suppressing ubiquitin–proteasome-mediated degradation, thereby forming a positive feedback loop. Functional rescue experiments demonstrated that the TBX18/SIX1 axis coordinately maintained stemness and EMT phenotypes and attenuated radiotherapy-induced apoptosis. In vivo studies further confirmed that TBX18 knockdown enhanced radiosensitivity, whereas SIX1 overexpression partially reversed this effect. In addition, immunohistochemical analysis revealed that TBX18 and SIX1 were significantly upregulated in ESCC tissues and positively correlated with each other. Full article

Background/Objectives: While currently termed premature ovarian insufficiency (POI), premature ovarian failure (POF) remains a prominent driver of female infertility with a molecular pathogenesis that is still lacking comprehensive clarification. In in vitro studies, the pathology of POI is commonly simulated through a well-characterized model involving VCD (4-vinylcyclohexene diepoxide)-mediated cytotoxicity within KGN-derived human granulosa cells. However, the key regulatory molecular networks involved in this process are still poorly characterized. Although microRNAs (miRNAs) have emerged as critical regulators in ovarian function decline, the specific role and underlying mechanism of miR-27b-3p in POI remain elusive. Methods: A VCD-induced KGN cell injury model was established by treating cells with 1.0 mM VCD for 24 h. Cell viability, apoptosis rate, and miR-27b-3p expression were assessed by CCK-8 assay, flow cytometry, and RT-qPCR, respectively. Overexpression and targeted suppression of miR-27b-3p were achieved by introducing its specific mimics and inhibitors, respectively. Target identification was conducted via bioinformatic prediction, EdU incorporation, Western blot, and dual-luciferase reporter assays. Functional rescue experiments were carried out by co-transfection with a PAPPA-overexpressing plasmid (oe-PAPPA). IGF-1 secretion was quantified by ELISA, and phosphorylation of IGF1R and AKT was analyzed by Western blot to determine whether miR-27b-3p modulates cellular phenotypes via the PAPPA–IGF-1–PI3K/AKT axis. Exogenous IGF-1 supplementation was further applied to confirm pathway dependence. Results: VCD treatment dose-dependently restrained cellular growth and stimulated apoptotic pathways in KGN cells; paralleling these phenotypic changes, miR-27b-3p abundance was remarkably increased. Ectopic expression of miR-27b-3p exacerbated VCD-induced growth inhibition and apoptosis, whereas its inhibition conferred cytoprotective effects. Through the integration of computational predictions and dual-luciferase reporter systems, PAPPA was definitively established as a direct downstream target of miR-27b-3p. miR-27b-3p negatively regulated both PAPPA mRNA and protein levels, thereby impairing PAPPA-mediated cleavage of IGF-binding proteins (e.g., IGFBP4) and subsequent release of free IGF-1. This led to reduced IGF-1 secretion and significantly diminished phosphorylation of IGF1R and AKT. Remarkably, PAPPA overexpression effectively reversed the detrimental effects of miR-27b-3p, and exogenous IGF-1 supplementation similarly attenuated miR-27b-3p–mediated proliferation arrest and pro-apoptotic phenotypes. Conclusions: This study uncovers a novel pathogenic mechanism whereby miR-27b-3p exacerbates VCD-induced granulosa cell injury by directly targeting PAPPA, suppressing IGF-1 release, and consequently inhibiting the PI3K/AKT pro-survival signaling pathway. A novel perspective on the fundamental basis of POI is established by this research, which further posits therapeutic manipulation of the miR-27b-3p/PAPPA/IGF-1 module as a prospective treatment for disrupted ovarian function. Full article

The high mortality associated with largemouth bass ranavirus (LMBRaV) disease requires rapid and sensitive diagnosis methods to prevent virus spread and subsequent outbreak. The recombinase polymerase amplification combined with the CRISPR/Cas12a system (RPA-CRISPR/Cas12a) assay and RPA-CRISPR/Cas12a, coupled with lateral flow dipstick (RPA-CRISPR/Cas12a-LFD) assay for LMBRaV, were established in this study for low viral load surveillance. The major capsid protein (mcp) gene is highly conserved and is widely used as the target sequence in LMBRaV detection. First, based on the mcp gene sequence of LMBRaV, three candidate crRNAs were designed. Among them, the crRNA-2, which exhibited the highest cleavage activity, was selected through dual evaluation of fluorescence signal intensity and LFD color development. Then, the key reaction conditions for both assays were optimized as follows: LbCas12a protein concentration of 150 nM, crRNA-2 concentration of 200 nM, and ssDNA reporters’ concentration of 200 nM. Moreover, specificity evaluation showed that both combined assays specifically recognized LMBRaV, with no cross-reactivity detected against other aquatic pathogens, such as CyHV-2, GSIV, ISKNV, WSSV, GCRV II or CrERV. The detection limit was 1 copy/μL of DNA sample for both RPA-CRISPR/Cas12a and RPA-CRISPR/Cas12a-LFD assays. Finally, validation using 24 clinical samples (16 positive, eight negative) showed that both LMBRaV RPA-CRISPR/Cas12a assays achieved 100% detection rate, whereas conventional PCR detected 13 positive samples (detection rate 81.26%). ddPCR served as the reference method for clinical validation. Therefore, the LMBRaV RPA-CRISPR/Cas12a assay and the RPA-CRISPR/Cas12a-LFD assay provide sensitive, specific, and easy-to-operate methods for the rapid detection of LMBRaV. Full article

Background/Objectives: To evaluate the association between the modified hemoglobin–albumin–lymphocyte–platelet (mHALP) score and disease complexity in patients hospitalized with deep neck infections (DNIs) and to compare performance with HALP and individual laboratory markers. Methods: This dual-center retrospective study included 367 adults hospitalized with DNIs between December 2021 and September 2025. Patients were classified as having complicated or non-complicated disease. The mHALP score was calculated from admission laboratory values and incorporated C-reactive protein. ROC curve and multivariable logistic regression analyses were performed. The primary model evaluated natural-log-transformed, standardized mHALP after adjustment for age, maximum abscess diameter, and study center. Results: Fifty-nine patients (16.1%) had complicated DNIs. Median mHALP was lower in the complicated group than in the non-complicated group (0.0137 vs. 0.0486; p < 0.001). mHALP showed moderate discrimination (AUC = 0.756, 95% CI 0.677–0.834) and performed better than CRP alone (AUC difference = 0.077; p < 0.001), but not better than HALP, albumin, or lymphocyte count. An exploratory cut-off of ≤0.0302 yielded 74.6% sensitivity and 71.8% specificity. In the primary multivariable model, each one-standard-deviation increase in log-transformed mHALP was associated with lower odds of complicated disease (adjusted OR = 0.592, 95% CI 0.397–0.884; p = 0.010). Adding mHALP to the clinical model increased the AUC from 0.858 to 0.864, whereas adding HALP increased it to 0.894. Conclusions: Lower mHALP was independently associated with complicated DNIs, but its incremental value beyond clinical variables was modest, and it did not outperform HALP. mHALP may be considered an adjunctive, rather than stand-alone, marker, pending external validation. Full article

Major depressive disorder (MDD) is a heterogeneous psychiatric disorder characterized by impaired mood, neuroplasticity, neuroinflammation, and dysregulated stress response systems. Chronic stress can induce epigenetic changes leading to depression. Evidence suggests that histone acetylation and deacetylation are epigenetic processes involved in changes in gene expression. Histone deacetylases (HDACs) modulate chromatin structure and transcription, and their dysregulation is associated with stress susceptibility, decreased brain-derived neurotrophic factor (BDNF) signaling, impaired synaptic plasticity, and inflammatory activation. HDAC isoforms HDAC3 and HDAC6 have emerged as epigenetic regulators in stress-induced depression. HDAC3 is a transcriptional regulator involved in neuroplasticity-related gene expression, inflammatory signaling, and glucocorticoid receptor-mediated stress responses. In contrast, HDAC6 is cytoplasmic and regulates non-histone substrates involved in microtubule dynamics, synaptic function, protein trafficking, and the regulation of the hypothalamic–pituitary–adrenal axis (HPA axis). Preclinical studies show that HDAC3 or HDAC6 inhibition can exert antidepressant-like effects by promoting neuroplasticity, reducing neuroinflammation, and restoring stress-related signaling. Dual targeting is an interesting therapeutic approach because both regulate complementary mechanisms. However, clinical translation is limited by poor blood–brain barrier penetration, systemic toxicity, insufficient isoform selectivity, and a lack of clinical evidence. This review summarizes the roles and mechanisms of HDAC3 and HDAC6, the rationale for dual targeting, translational limitations, and future therapeutic perspectives. Full article

The characteristic red walnut germplasm ‘RW-1′ (Juglans regia L.) exhibits a stable red seed coat phenotype due to the abundant accumulation of anthocyanins and proanthocyanidins (PAs). The regulatory mechanisms underlying PA biosynthesis in red walnut remain poorly studied, which hinders the improvement of walnut color quality. Leucoanthocyanidin reductase (LAR) is a key enzyme in the PA metabolic pathway, while its function in red walnut remains unclear. Here, the leucoanthocyanidin reductase gene JrLAR1, whose expression pattern is consistent with the accumulation trend of PAs, was cloned from the seed coats of red walnut ‘RW-1′, and its function in PA biosynthesis was verified via heterologous overexpression in Arabidopsis thaliana, a well-recognized cross-species LAR functional validation system free of endogenous LAR interference due to absent native homologs. The results showed that the full-length coding sequence (CDS) of JrLAR1 gene is 1104 bp, encoding a 367-amino-acid protein belonging to the NADB_Rossmann superfamily, and the protein shares an extremely high sequence similarity with grape VvLAR2. Heterologous overexpression of JrLAR1 significantly increased total PA content in the leaves and seeds of A. thaliana. Integrated transcriptomic and metabolomic analyses further revealed that JrLAR1 overexpression markedly upregulated the core genes involved in PA metabolism and the transcription factor GL3 in A. thaliana, specifically induced (+)-catechin synthesis, and ultimately promoted the significant accumulation of procyanidin B3. In addition, a set of antioxidant enzyme-encoding genes were substantially upregulated in JrLAR1-overexpressing A. thaliana lines. Yeast one-hybrid and dual-luciferase reporter assays demonstrated that JrEGL1b, a homolog of A. thaliana GL3, can bind to the promoter region of JrLAR1 gene and significantly enhance its transcriptional activity. Transient overexpression of JrLAR1 or JrEGL1b in red walnut leaves significantly promoted PA accumulation, and JrEGL1b overexpression notably upregulated JrLAR1 expression. In conclusion, JrLAR1 plays a crucial role in PA biosynthesis in red walnut and is positively regulated by the transcription factor JrEGL1b. These findings improve the molecular regulatory network of pigment metabolism in red walnut and provide valuable molecular targets for the quality improvement and directional breeding of walnuts. Full article

In modern societies, the renewed concept of food as medicine coexists with unprecedented consumption of highly processed foods, food additives, environmental xenobiotics, and pharmacological agents, contributing to the increasing prevalence of metabolic and degenerative diseases and accelerated aging. Although modern pharmacotherapies have transformed disease management, long-term drug exposure introduces additional metabolic burdens, off-target effects, and cumulative toxicities that are profoundly influenced by nutritional status. Collectively, dietary constituents, environmental chemicals, endogenous metabolic by-products, and therapeutic agents constitute a complex exposome that requires continuous recognition, utilization, detoxification, and clearance. Within this context, the liver sinusoidal clearance system (LSCS) emerges as a central regulator of systemic homeostasis. We propose a conceptual framework in which circulating molecules are classified as self (S), modified self (M), and foreign (F) molecules according to their physiological handling by the LSCS. Through coordinated hepatic utilization of S molecules and selective clearance of M and F molecules, fenestrated liver sinusoidal endothelial cells (LSECs) maintain metabolic homeostasis, immune tolerance, and physiological pharmacokinetics. Conversely, chronic dietary overload, poor dietary quality, food processing, and sustained exposure to pro-inflammatory and oxidative dietary and environmental molecules initiate chronic low-grade inflammation, which promotes LSEC capillarization, impairs hepatic clearance, increases the modification of S molecules into M molecules and establishes a feed-forward cycle that further amplifies chronic inflammation and metabolic dysfunction. Finally, we discuss recent advances in the programmable modulation of the LSCS, including its transient suppression to prolong therapeutic exposure and its activation to enhance the clearance of metabolically harmful M and F molecules through coordinated upregulation of the endoglin–stabilin-2–FcγRIIb axis and the LSEC markers Oit3 and Dnase1L3. We highlight dual-function supramolecular nanofiber platforms that enable bidirectional regulation of the LSCS through nanofiber complexes with therapeutic proteins, thereby expanding their therapeutic potential and enhancing efficacy in the treatment of metabolic, inflammatory, and age-related diseases. Full article

Background: Noise-induced hearing loss (NIHL) is a pervasive occupational health challenge, yet the individual susceptibility mechanisms remain unclear. Ferroptosis, an iron-dependent form of programmed cell death, has been implicated in cochlear hair cell damage. This study aims to elucidate the regulatory role of the transcription factor FOXA2 and the deacetylase SIRT1 in ferroptosis and to investigate the association between SIRT1 genetic polymorphisms and NIHL susceptibility in occupational populations. Methods: We employed a multi-level study design combining epidemiological investigation, animal models, and cellular experiments. First, a case–control study was conducted involving 1314 noise-exposed workers (639 cases vs. 675 controls) from a chemical fiber enterprise in Jiangsu Province to analyze the association between SIRT1 single nucleotide polymorphisms (SNPs) and NIHL risk. Second, a C57BL/6J mouse model exposed to 120 dB white noise was established to assess cochlear morphology and protein expression. Third, in HEI-OC1 cochlear hair cells, we performed siRNA-mediated knockdown of Foxa2 and dual-luciferase reporter assays to verify the transcriptional regulation of SIRT1 and its downstream effects on the ferroptosis pathway. Results: Population analysis revealed that the SIRT1 rs12778366 C allele was significantly associated with increased NIHL risk (OR = 1.386, 95% CI: 1.084–1.772, p = 0.009), and this association remained significant after adjustment (p = 0.041). Stratified analysis further revealed a significant gene–environment interaction in workers with >15 years of noise exposure (OR = 2.126, 95% CI: 1.401–3.226, p < 0.001). In vivo, noise exposure led to significant downregulation of Sirt1 and Foxa2 in cochlear tissues, accompanied by elevated ferroptosis markers (Fe²⁺, MDA) and depleted antioxidant defenses (GSH, xCT, and GPX4). Mechanistically, we demonstrate that FOXA2 transcriptionally activates SIRT1 by binding to its promoter. Knockdown of FOXA2 in vitro suppressed SIRT1 expression, suppressed xCT, a key component of the System Xc⁻/GPX4 antioxidant axis, and promoted ferroptosis-related cellular changes. Conclusions: This study identifies a novel protective axis where FOXA2 prevents noise-induced ferroptosis in cochlear hair cells by transcriptionally upregulating SIRT1 and maintaining xCT-mediated antioxidant defense. Furthermore, the SIRT1 rs12778366 polymorphism is identified as a candidate variant warranting further investigation in independent cohorts before clinical translation. Full article

Background: Incretin-based therapies (IBTs), including glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonists (GIP/GLP-1 RAs), have transformed the management of obesity and type 2 diabetes mellitus (T2DM). Although these agents provide substantial metabolic and cardiometabolic benefits, their effects on skeletal muscle, particularly in older adults at increased risk of sarcopenia and functional decline, remain incompletely understood. Methods: This narrative review synthesizes evidence from randomized controlled trials (RCTs) and observational studies evaluating the effects of semaglutide and tirzepatide on skeletal muscle mass (SMM), muscle quality, strength, and physical performance. Current evidence on nutritional and exercise strategies aimed at preserving skeletal muscle during IBT was also reviewed. Results: Both semaglutide and tirzepatide induce substantial weight loss accompanied by reductions in lean body mass (LBM). However, current evidence indicates that LBM loss is generally proportional to the magnitude of weight loss and should not be interpreted as a direct surrogate for skeletal muscle loss or drug-induced myotoxicity. Tirzepatide appears to improve skeletal muscle composition by reducing muscle fat infiltration (MFI), whereas semaglutide shows more heterogeneous effects on muscle strength and physical performance, particularly in older or frail individuals. Emerging evidence highlights the importance of muscle quality, nutritional adequacy, and resistance exercise as key determinants of muscle preservation, although functional outcomes and data in older adults remain limited. Conclusions: The effects of incretin-based therapies (IBTs) on skeletal muscle are multifactorial and influenced by age, baseline muscle reserve, nutritional status, and physical activity. Preserving skeletal muscle health should be considered an integral component of obesity management through individualized nutritional care, adequate protein intake, resistance exercise, and regular functional assessment. Future research should prioritize the standardized evaluation of muscle quality and function and determine whether targeted nutritional interventions can improve the quality of weight loss and support healthy aging during IBT. Full article