Biomolecules最新文献

{"title":"RT206 Couples Partial PPARα/γ Agonism with Ligand-Dependent Allosteric Potentiation of FXR Signaling in Liver Cells.","authors":"Manuela Leo, Carmen Cerchia, Antonio Laghezza, Francesca Rinaldi, Enrica Calleri, Vittorio Colantuoni, Fulvio Loiodice, Lina Sabatino, Antonio Lavecchia","doi":"10.3390/biom16091316","DOIUrl":"10.3390/biom16091316","url":null,"abstract":"<p><p>Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic disorder characterized by dysregulated lipid handling and bile acid signaling, processes controlled by PPARs and FXR. We report that RT206, a 2-aryloxy-3-phenyl-propanoic acid derivative, combines partial PPARα/γ agonism with positive allosteric modulation of FXR. Transactivation assays and endogenous gene-expression profiling confirmed activation of PPARα/γ-responsive genes. RT206 showed no intrinsic FXR agonism, yet it robustly potentiated FXR-dependent gene transcription in HepG2 cells in the presence of structurally distinct orthosteric agonists. Grating-coupled interferometry revealed weak interaction with apo-FXR that was enhanced by orthosteric ligands, consistent with cooperative ternary complex formation. Docking and molecular dynamics supported a model in which RT206 engages the non-orthosteric FXR S2 site, while orthosteric agonists occupy the S1 primary pocket. Comparison with guggulsterone revealed distinct predicted S2 interaction patterns associated with divergent transcriptional outcomes in vitro. In fatty acid-loaded HepG2 cells, RT206 combined with FXR agonists modulated FXR- and PPAR-regulated metabolic genes and modestly reduced neutral-lipid accumulation. These findings identify RT206 as a proof-of-principle scaffold that integrates partial PPARα/γ agonism with ligand-dependent potentiation of FXR activity and support its further evaluation in more advanced liver models.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"16 9","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13604256/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149058327","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insight into TPS-d Subfamily: The Evolutionary and Functional Diversity in Gymnosperms.","authors":"Sha Wang, Jinzhu Jiang, Sha Chen, Yan Liu, Cong Guo, Qingxia Xu, Jun Zhang, Siyuan Li, An Liu, Xianju Liu","doi":"10.3390/biom16091318","DOIUrl":"10.3390/biom16091318","url":null,"abstract":"<p><p>Gymnosperms represent an ancient lineage with diverse chemical profiles. Their terpenoids constitute a major class notable for substantial structural diversity. Terpene synthases (TPSs) are the driving force of terpene diversity. TPS-d is a gymnosperm-specific TPS subfamily, yet the evolution and functional diversity of TPS-d are still understudied. In this review, we analyze 134 functionally characterized gymnosperm TPSs to elucidate the evolutionary history and functional diversity of the predominant TPS-d subfamily. Phylogenetic analysis revealed substantial lineage-specific expansion and divergence within the TPS-d subfamily post-speciation. Crucially, we highlight the shifts in domain architecture during TPS-d evolution, providing structural evidence for the progressive attrition and eventual loss of the ancestral <i>γ</i> domain in TPS-d2 and TPS-d1 clades. Furthermore, we summarize the functional diversity of TPS-d enzymes in specialized metabolites, emphasizing their ecological roles in plant defense. Overall, this review provides a comprehensive overview of the evolutionary and functional landscape of the gymnosperm-specific TPS-d subfamily, serving as a valuable reference for future studies on TPSs in gymnosperms.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"16 9","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13604524/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149058100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proteomic Analysis of Retinas from Two Different Type-1 Diabetic Models.","authors":"Gieth Alahdab, Sonali Sharma, Nandini Koneru, Mohamed Moustafa, Muhammad N Haque, Kaitlin Lowran, Xiao Zhang, Shether Ahmed, Khaled Elmasry, Mohamed Al-Shabrawey","doi":"10.3390/biom16091314","DOIUrl":"10.3390/biom16091314","url":null,"abstract":"<p><p>This study investigated retinal proteomic alterations associated with type-1 diabetes mellitus (T1DM) using two mouse models of diabetic retinopathy (DR): the genetic Ins2^akita/+ (Akita) model and streptozotocin (STZ)-induced diabetes. Retinas were collected from Akita (n = 4) and STZ-induced diabetic mice (n = 6) 15-16 weeks after the onset of diabetes and compared with age-matched controls. Quantitative mass spectrometry identified 7933 proteins in Akita retinas and 7399 proteins in STZ retinas. Differentially expressed proteins were identified using adjusted <i>p</i>-values and log₂ fold-change, ranked by Manhattan distance, and visualized with volcano plots and heatmaps. The top 20 dysregulated proteins in each model were subjected to canonical pathway analysis. Both models demonstrated upregulation of inflammatory and angiogenesis-associated proteins, including LRRC58, coronin-2A, S100-A4, and COL4A2, supporting a pro-inflammatory and vascular remodeling microenvironment. However, several protein changes differed between the two models. For example, Crystallins were downregulated in the STZ model but upregulated in the Akita model, which were validated by western blot analysis. Canonical pathway analysis revealed activation of platelet-related signaling pathways, enrichment of lipid metabolic networks, and significant alterations in extracellular matrix organization. These findings indicate coordinated inflammatory, metabolic, and structural remodeling in DR and identify candidate molecular pathways for further investigation and therapeutic targeting.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"16 9","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13604719/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149058253","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Perspectives of Natural Products and Sialic Acid Mimetics as Modulators of Human Sialidases NEU1-3 in Atherosclerosis.","authors":"Tatyana I Kovyanova, Vasily P Karagodin, Daria D Borodko, Ulyana V Rozhkova, Stanislav A Antonov, Aleksandra S Utkina, Anastasia N Vaganova","doi":"10.3390/biom16091319","DOIUrl":"10.3390/biom16091319","url":null,"abstract":"<p><p>This narrative review summarizes current data on the role of desialylation of low-density lipoproteins (LDL) as a key initiating mechanism of atherogenesis that precedes oxidative modification. The structural and functional significance of sialic acid in apolipoprotein B-100 is considered, and the enzymes of the sialidase (neuraminidase) family responsible for its cleavage are characterized. The pathogenic role of increased sialidase activity in atherosclerosis, type 2 diabetes mellitus, and other diseases is discussed. The advantages of using dietary supplements based on natural sialidase inhibitors for long-term prevention compared with synthetic drugs are shown. Examples of already existing dietary supplements with antiatherosclerotic effects are described. A separate section is devoted to computer methods (molecular docking) for searching for new sialidase inhibitors among flavonoids; according to virtual screening data, gallated catechins were identified as the most promising candidates. The feasibility of further experimental and clinical studies to create effective and safe nutraceuticals that affect the early stages of atherogenesis is substantiated.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"16 9","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13604521/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149058187","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparative Analysis of Reported Gene Targets and Binding Regions of Glu-CTC tRNA Fragments Across Human Diseases.","authors":"Nikita Gulati, Andrey Grigoriev","doi":"10.3390/biom16091313","DOIUrl":"10.3390/biom16091313","url":null,"abstract":"<p><p>Recurrent detection of overlapping tRNA-derived fragments (tRFs) across diverse disease conditions supports the emerging view that tRFs may act as regulatory molecules rather than random degradation products. While cases of identical tRFs have been described, their comparative analyses are lacking. tRF-Glu-CTC is one such fragment, repeatedly detected in various pathological conditions. We performed a comparative analysis of tRF-Glu-CTC isoforms, their targets and binding regions reported in 18 disease-associated studies. An 18-nucleotide sequence, TCCCTGGTGGTCTAGTGG, was identified in most (14 out of 18) of these studies despite differences in tRF naming, length and disease context. Several reported tRF targets showed consistent binding regions, with reverse complementarity to the tRF sequence. Comparison with databases of tRF targets, tatDB and tRFTar, identified matching target entries and sequence overlaps, often involving common regions rather than full-length matches. Exploratory analysis of target homologs further illustrated that related genes might share candidate target sites. Our findings indicate that tRF-Glu-CTC represents a recurrent candidate regulatory fragment potentially relevant in a broad range of human diseases. Its structural stability, extracellular vesicle association, detection in multiple species and a core sequence shared between related isoforms support further investigation of its biological and translational relevance. Our work illustrates how tRF target databases can be leveraged to advance smaller-scale tRF studies.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"16 9","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13604853/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149058128","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microbial Proteases as Product-Directed Catalysts for Industrial Proteolysis.","authors":"Sang-Woo Han","doi":"10.3390/biom16091317","DOIUrl":"10.3390/biom16091317","url":null,"abstract":"<p><p>Microbial proteases are widely used for industrial proteolysis in detergents, food processing, hydrolysate production, product stabilization, and side-stream valorization. Their industrial value is not determined by general activity or degree of hydrolysis alone, but by the ability of a defined catalyst to operate reliably under process conditions and generate the intended product endpoint. This review frames microbial proteases as product-directed biocatalysts whose performance depends on the alignment of catalyst identity, process compatibility, substrate access, and product outcome. Production, maturation, and immobilization are considered determinants of the deployed enzyme form, while biocatalyst identity, process translation, product outcome, and endpoint refinement provide a framework for evaluation. Across protease classes, industrial utility is shaped by acid-window matching, operating-window engineering, catalyst definition, metal-state compatibility, and peptide-pool refinement. Data-guided workflows integrating protease discovery and engineering, cleavage prediction, peptidomic mapping, real-substrate validation, and enzyme-system optimization offer a path toward more predictable product-oriented industrial proteolysis.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"16 9","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13604415/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149058215","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interleukin-11 Signaling in Liver Disease: Mechanisms, Cellular Crosstalk, and Therapeutic Potential.","authors":"Zhiyuan Chen, Fan Yu, Yanhua Qiu, Jun Lin, Meilian Yu, Jinwei Yan, Xianzhi Liu","doi":"10.3390/biom16091309","DOIUrl":"10.3390/biom16091309","url":null,"abstract":"<p><p>The liver has a remarkable regenerative capacity, but persistent injury caused by drugs, metabolic dysfunction, alcohol, and chronic inflammation can overwhelm this process and promote fibrosis and hepatocellular carcinoma. Interleukin-11 (IL-11), a cytokine that signals through glycoprotein 130 (gp130), was historically considered hepatoprotective; however, accumulating experimental evidence predominantly identifies endogenous IL-11 as an amplifier of liver injury and maladaptive repair. In hepatocytes, IL-11 promotes oxidative stress, mitochondrial dysfunction, and cell death while limiting effective regeneration. In hepatic stellate cells, it sustains myofibroblastic activation and extracellular matrix production, while crosstalk with hepatocytes, macrophages, and the matrix reinforces a fibroinflammatory niche. In hepatocellular carcinoma, experimental and associative clinical evidence implicates IL-11 in tumor growth, invasion, metastatic colonization, postoperative recurrence, stromal remodeling, and immune suppression. These findings have supported the development of therapeutic strategies targeting the IL-11/IL-11RA axis, with the potential to provide broad therapeutic benefits across a wide spectrum of liver diseases. This review summarizes IL-11 regulation and signaling in liver disease; discusses its roles in liver injury, fibrosis, and hepatocellular carcinoma; and evaluates the opportunities and challenges of IL-11-targeted therapy.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"16 9","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13604896/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149058069","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stage-Specific Mucin Reprogramming Across the Gastric Cancer Cascade: Unveiling Molecular Mechanisms and Novel Therapeutic Vulnerabilities.","authors":"Xiao Dong, Xiaoyang Wu, Zeyu You, Kexin Lu, Huan Cai, Bo Zhang, Yuehua Gong, Qinchuan Wang, Yuan Yuan, Huakang Tu","doi":"10.3390/biom16091307","DOIUrl":"10.3390/biom16091307","url":null,"abstract":"<p><p>Mucins are a class of highly glycosylated macromolecules that constitute a cornerstone of the gastrointestinal mucosal barrier and play multiple essential roles in maintaining tissue homeostasis. During the progression from normal gastric mucosa through precancerous lesions to gastric cancer and metastasis, the expression profiles, glycosylation patterns, and spatial distribution of mucins undergo systematic and programmatic alterations, a process referred to as \"mucin reprogramming.\" Recent studies have revealed that this reprogramming is by no means a passive bystander phenomenon accompanying tumorigenesis; rather, it is a central biological event that actively drives malignant transformation, shapes an immunosuppressive microenvironment, and influences therapeutic response. This article aims to systematically delineate the dynamic landscape of mucin expression changes during gastric cancer progression, to provide an in-depth analysis of the underlying molecular mechanisms, and to focus on its clinical value and translational potential in the early diagnosis, molecular classification, prognostic assessment, and targeted therapy of gastric cancer. In addition, this review also discusses recent applications of artificial intelligence in the precise identification of mucin phenotypic features. By integrating the latest research advances, this review seeks to provide new perspectives and a theoretical basis for a deeper understanding of the mechanisms of mucin reprogramming during gastric cancer progression and for the development of novel diagnostic and therapeutic strategies.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"16 9","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13604348/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149058420","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Circulating Amino Acid Profiles in Adults with Abnormal Body Mass Index: Associations with Triglycerides, HDL Cholesterol, LDL Cholesterol, and Total Cholesterol in an Exploratory Cross-Sectional Metabolomic Pilot Study.","authors":"Marta Jaskulak, Iwona Rybakowska, Magdalena Gregorczyk, Klaudia Antoniak-Pietrynczak, Patrycja Jabłońska, Katarzyna Zorena","doi":"10.3390/biom16091305","DOIUrl":"10.3390/biom16091305","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background/objectives: &lt;/strong&gt;Circulating amino acids are not only markers of nutritional status; in experimental and interventional models they have been linked to hepatic lipogenesis, lipoprotein assembly, mitochondrial fatty acid oxidation, and bile acid conjugation, which makes them plausible candidate correlates of obesity-related lipid dysregulation. Despite this, most metabolomic studies of excess adiposity have focused either on a single lipid parameter-typically triglycerides-or only on branched-chain amino acids (BCAAs). This pilot study was designed to generate hypotheses about these associations across the full standard lipid panel using a targeted 19-amino acid liquid chromatography-tandem mass spectrometry (LC-MS/MS) panel in adults spanning the body mass index (BMI) spectrum, with an analytical framework oriented around lipid phenotype variance rather than body weight classification. The design is cross-sectional and the analysis exploratory; no causal or predictive claim is made.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Targeted LC-MS/MS quantification of 19 plasma amino acids was performed in 50 adults grouped as normal weight (&lt;i&gt;n&lt;/i&gt; = 20; BMI 22 ± 1.5 kg/m&lt;sup&gt;2&lt;/sup&gt;), overweight (&lt;i&gt;n&lt;/i&gt; = 20; BMI 28 ± 1.5 kg/m&lt;sup&gt;2&lt;/sup&gt;), or obese (&lt;i&gt;n&lt;/i&gt; = 10; BMI 34 ± 2.0 kg/m&lt;sup&gt;2&lt;/sup&gt;). The analytical framework included: (i) one-way analysis of variance (ANOVA) with Bonferroni correction; (ii) Pearson correlation analysis; (iii) principal component analysis (PCA) performed on the lipid profile itself with amino acid projection vectors; (iv) K-means clustering based on lipid phenotype (K = 3); (v) Ward-linkage hierarchical clustering of the amino acid-lipid correlation matrix; (vi) Random Forest permutation importance for all four lipid outcomes; and (vii) composite lipid risk indices including atherogenic index (TG/HDL-C) and non-HDL cholesterol.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;A distinct amino acid correlation pattern was observed for each of the four lipid fractions. Triglycerides (TG) correlated most strongly with glutamic acid (r = 0.58) and inversely with glutamine (r = -0.58). High-density lipoprotein cholesterol (HDL-C) correlated most strongly with glutamic acid (r = -0.61) and serine (r = 0.49). The strongest correlates of low-density lipoprotein cholesterol (LDL-C) were phenylalanine (r = 0.56) and leucine (r = 0.56), and those of total cholesterol (TC) were leucine (r = 0.63) and, inversely, glycine (r = -0.54). The atherogenic index (TG/HDL-C) increased 2.9-fold from normal to obese and was most strongly correlated with glutamic acid, isoleucine, and glycine. In the multivariable models the amino acid panel accounted for a modest share of the variance in TG (adjusted R&lt;sup&gt;2&lt;/sup&gt; = 0.43; F(19,30) = 2.97, &lt;i&gt;p&lt;/i&gt; = 0.004) and HDL-C (adjusted R&lt;sup&gt;2&lt;/sup&gt; = 0.35; F(19,30) = 2.40, &lt;i&gt;p&lt;/i&gt; = 0.016). For LDL-C and TC the adjusted R&lt;sup&gt;2&lt;/sup&gt; values were close to zero (0.06 for both) and the overall models were n","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"16 9","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13604323/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149058023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chitosan-Orientin Nanoparticles Attenuate Hypoxia-Induced Pulmonary Inflammation in Rats.","authors":"Gülfem Özduygu, İhsan Topaloğlu, Çağrı Atasoy, Eren Erdoğdu, Güntuğ Batıhan, Semih Çiftçi, Volkan Gelen, Kübra Kaya, Adem Kara, Ali Yeşildağ, Elif Erbaş, Deniz Ekinci","doi":"10.3390/biom16091306","DOIUrl":"10.3390/biom16091306","url":null,"abstract":"&lt;p&gt;&lt;p&gt;&lt;b&gt;Background:&lt;/b&gt; Hypoxia triggers pulmonary inflammation and oxidative stress, leading to endothelial dysfunction, apoptosis and lung injury. Although the flavonoid orientin exhibits potent antioxidant and anti-inflammatory properties, its pharmacokinetic behavior remains incompletely characterized. Nanoparticle-based delivery systems may enhance efficacy. This study investigated whether Orientin delivered via chitosan nanoparticles (CNP-orientin) protects against hypoxia-induced pulmonary inflammation, oxidative stress, and tissue injury in rats. &lt;b&gt;Methods:&lt;/b&gt; A total of 48 female Sprague-Dawley rats were randomized into four normoxic and four hypoxic groups (&lt;i&gt;n&lt;/i&gt; = 6 per group). Rats in the hypoxic groups were exposed to intermittent hypoxia (7% O&lt;sub&gt;2&lt;/sub&gt;, 8 h/day for 7 days). Hypoxic rats were allocated to experimental groups, including an untreated hypoxia group and groups receiving orientin alone, chitosan nanoparticles alone or orientin-loaded chitosan nanoparticles (CNP-orientin), while normoxic rats served as controls. Hypoxic exposure was conducted using a controlled glove box system. At the end of the protocol, blood samples were collected for serum inflammatory marker analysis, and lung tissues were harvested to assess oxidative stress parameters, hypoxia- and inflammation-related signaling pathways, apoptosis-related gene expression, and histopathological lung injury and fibrosis. &lt;b&gt;Results:&lt;/b&gt; Intermittent hypoxia significantly increased pulmonary &lt;i&gt;HIF-1α and iNOS&lt;/i&gt; expression, oxidative stress markers (increased malondialdehyde and decreased superoxide dismutase and glutathione), pro-inflammatory cytokines (TNF-α, IL-1β), apoptotic signaling and histopathological lung injury compared with normoxic controls (&lt;i&gt;p&lt;/i&gt; &lt; 0.05). Treatment with orientin or chitosan nanoparticles alone attenuated hypoxia-associated biochemical and molecular alterations compared to untreated hypoxic rats (&lt;i&gt;p&lt;/i&gt; &lt; 0.05). Notably, CNP-orientin treatment significantly attenuated multiple oxidative stress, inflammatory, and apoptosis-related alterations compared with untreated hypoxic rats (&lt;i&gt;p&lt;/i&gt; &lt; 0.05). These protective effects were observed despite the substantially lower orientin-equivalent dose in the CNP-orientin formulation compared with free orientin. NF-κB and TNF-α expression, caspase-3 levels, antioxidant markers, and Bcl-2 expression differed significantly among hypoxic groups (&lt;i&gt;p&lt;/i&gt; &lt; 0.05). Histopathological lung injury and Modified Ashcroft fibrosis scores were significantly lower in the CNP-orientin group than in the untreated hypoxic group (&lt;i&gt;p&lt;/i&gt; &lt; 0.01 and &lt;i&gt;p&lt;/i&gt; &lt; 0.001, respectively). &lt;b&gt;Conclusions:&lt;/b&gt; Orientin-loaded chitosan nanoparticles effectively mitigate hypoxia-induced pulmonary inflammation, oxidative stress, apoptosis and fibrotic injury. These findings identify CNP-orientin as a promising nanotherapeutic strategy for hypoxia-associated lung diseases and support further translational investi","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"16 9","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13604851/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149058027","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}