Bioorganic Chemistry最新文献

{"title":"Supramolecular engineering of J-aggregated BODIPY derivatives with assembly-enhanced ROS generation for mitochondrial Cancer therapy","authors":"Chun-Lin Yu ,&nbsp;Xue-Liang Liu ,&nbsp;Guo-Jiang Mao ,&nbsp;Ming Xu","doi":"10.1016/j.bioorg.2025.109062","DOIUrl":"10.1016/j.bioorg.2025.109062","url":null,"abstract":"<div><div>We engineered a mitochondria-targeting nanophotosensitizer (<strong>1a</strong>) through supramolecular J-aggregation of dual-pyridinium-functionalized twisted BODIPY derivatives. <strong>1a</strong> overcomes aggregation-caused quenching (ACQ), while achieving assembly-enhanced ROS generation, demonstrating a 12.5× increase in singlet oxygen (¹O₂) quantum yield versus its monomeric form. The cationic pyridinium moieties confer dual functionality: targeting mitochondria and enhancing aqueous dispersion. This design synergistically resolves key challenges in conventional PDT: precise spatiotemporal ROS generation and limited ROS yield in aggregated states, achieving 91 % tumor inhibition in murine tumor model.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 109062"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145216857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure-guided olaparib PET probe enables enhanced PARP-1 precision imaging","authors":"Wei Xu ,&nbsp;Junjie Yan ,&nbsp;Donghui Pan ,&nbsp;Chongyang Chen ,&nbsp;Xinyu Wang ,&nbsp;Yuping Xu ,&nbsp;Lizhen Wang ,&nbsp;Min Yang","doi":"10.1016/j.bioorg.2025.109037","DOIUrl":"10.1016/j.bioorg.2025.109037","url":null,"abstract":"<div><div>Poly (ADP-ribose) polymerase 1 (PARP-1) imaging shows great promise in clinical oncology, offering a non-invasive way to quantify tumor PARP-1 expression, select patients for PARP inhibitor therapy, and monitor treatment response in real-time. However, current PARP-1-targeted radiotracers are highly lipophilic, leading to low tumor uptake, high off-target accumulation, and poor imaging contrast, which restrict their diagnostic utility and accuracy. To overcome these limitations, we developed a series of [¹⁸F]AlF-labeled dimeric positron emission tomography (PET) probes based on the olaparib pharmacophore, leveraging a multivalency strategy with PEGylation. Among the candidates, [¹⁸F]AlF-NOTA-L3 (log <em>P</em> = −2.33 ± 0.50, <em>K</em>_D = 75.2 nM) emerged as the most promising, exhibiting high tumor uptake values of 5.77 ± 0.48, 4.21 ± 0.33, and 3.12 ± 0.19 %ID/g at 10, 30, and 60 min post-injection, respectively, with corresponding tumor-to-muscle ratios of 2.75 ± 0.26, 10.75 ± 2.16, and 10.84 ± 3.24, which were markedly superior to the monomeric probe [¹⁸F]AlF-NOTA-L0. Taken together, [¹⁸F]AlF-NOTA-L3 exhibits reduced lipophilicity, enhanced binding affinity, and superior tumor-to-background contrast, demonstrating significant potential to advance the accuracy for PARP-1 PET imaging for clinical translation.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 109037"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145216858","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lujiao Formula attenuates cardiac hypertrophy by modulating AMPK-SIRT1 and PI3K-Akt signaling pathways","authors":"Jianwei Zhang ,&nbsp;Jie Shen ,&nbsp;Wei Liu ,&nbsp;Jiekai Hua ,&nbsp;Fangyuan Wang ,&nbsp;Xiaoli Shi ,&nbsp;Guanglin Xu ,&nbsp;Rongcai Yue ,&nbsp;Xiaolong Wang ,&nbsp;Li Liu","doi":"10.1016/j.bioorg.2025.109001","DOIUrl":"10.1016/j.bioorg.2025.109001","url":null,"abstract":"<div><div>Cardiac hypertrophy (CH) represents a fundamental morphological adaptation that precedes and drives the transition to heart failure (HF). The traditional formulation Lujiao Formula (LJF) has been widely prescribed in clinical practice for more than two decades to alleviate HF, largely through suppressing CH and ventricular remodeling. Yet, the molecular mechanisms that mediate its cardioprotective benefits remain incompletely understood. In this study, we sought to elucidate both the therapeutic efficacy and mechanistic basis of LJF against CH by integrating metabolomic and proteomic profiling with targeted experimental validation. A murine model of CH was established using transverse aortic constriction (TAC), while complementary cellular models were induced via angiotensin II (Ang II) stimulation. The anti-hypertrophic activity of LJF was evaluated through echocardiography, heart weight index measurements, and histopathological assessment. Expression of canonical hypertrophic markers, including ANP, BNP, and <em>β</em>-MHC, as well as key regulatory proteins, was quantified by qRT-PCR and Western blotting analysis. LJF treatment markedly reduced left ventricular end-diastolic volume (LVEDV), end-systolic volume (LVESV), and systolic internal diameter (LVIDs), while significantly enhancing ejection fraction (EF) and fractional shortening (FS), thereby mitigating maladaptive myocardial remodeling in vivo. Integrative metabolomic and proteomic analyses highlighted AMPK and PI3K–Akt signaling as principal pathways mediating LJF's cardioprotective effects. Mechanistic investigations confirmed that LJF downregulated ANP, BNP, and <em>β</em>-MHC expression, suppressed PI3K and Akt phosphorylation and concurrently upregulated p-AMPK<em>α</em>1/<em>α</em>2 and SIRT1 protein levels both in vivo and in vitro. Importantly, these beneficial effects were partially abrogated by co-treatment with Compound C (CC, an AMPK inhibitor) or LY294002 (a PI3K inhibitor) in vitro. Collectively, our findings demonstrated that LJF exerted significant anti-hypertrophic effects through coordinated modulation of the AMPK–SIRT1 and PI3K–Akt cascades, offering a strong mechanistic basis for its clinical utility in managing CH.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 109001"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145216860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Olaparib-Cediranib Hybrid as Dual PARP-VEGFR3 Inhibitor Elicits Antitumor Efficacy: Rational Design, Synthesis, Biological Evaluation and Construction of a Charge Convertible pH Responsive Nanoformulation","authors":"Mandeep Rana ,&nbsp;N. VijayKamasewara Rao ,&nbsp;Zih-Yao Yu ,&nbsp;Ram Sharma ,&nbsp;Jacob Mathew ,&nbsp;Yu-Wen Chen ,&nbsp;Sung-Bau Lee ,&nbsp;Ankush Bansode ,&nbsp;Tai-Ju Hsu ,&nbsp;Ajmer Singh Grewal ,&nbsp;Chun Hsu Pan ,&nbsp;Santosh Guru ,&nbsp;Kunal Nepali","doi":"10.1016/j.bioorg.2025.109035","DOIUrl":"10.1016/j.bioorg.2025.109035","url":null,"abstract":"<div><div>Tempted by the clinical outcomes attained with the combination of poly(ADP-ribose) polymerase (PARP) and vascular endothelial growth factor receptor (VEGFR) inhibitors, a compendium of dual PARP-VEGFR inhibitory assemblages based on structural commonalities of Olaparib (PARP inhibitor) and Cediranib (VEGFR inhibitor) was furnished. The aforementioned efforts culminated into a strikingly potent antitumor agent <strong>18</strong> exerting remarkable cell growth inhibitory effects [IC₅₀ = 0.37 μM (HL60); 0.56 μM (A549); 0.80 μM (MDA-MB-231)] through a balanced inhibition of PARP and VEGFR. Specifically, 18 displayed magnificent PARP1, PARP2, and VEGFR3 inhibitory profiles with an IC₅₀ value of 0.0763 nM, 0.0366 nM, and 4.25 nM, respectively. Further, a charge-convertible polymer-based nanoformulation (18-PEG-PLL/DMMA nanoparticles) for targeted drug delivery of <strong>18</strong> was developed. Encouragingly, the nanoformulation demonstrated a cytotoxicity-devoid profile towards normal cells owing to its pH-sensitive behavior and manifested selective cell growth inhibition against solid tumor cells, possibly due to the EPR effect.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 109035"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145243375","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantum chemical-guided design of a near-infrared probe for simultaneous monitoring of SO₂ derivatives and viscosity for mitochondrial in apoptotic cells","authors":"Qiye Liu ,&nbsp;Boxin Li ,&nbsp;Hanwei Wang ,&nbsp;Caidong Shuang ,&nbsp;Weiran Tu ,&nbsp;Shijun Chen ,&nbsp;Wei Shu ,&nbsp;Chaoyuan Zeng ,&nbsp;Weijie Chi","doi":"10.1016/j.bioorg.2025.109034","DOIUrl":"10.1016/j.bioorg.2025.109034","url":null,"abstract":"<div><div>The cellular sulfur dioxide levels and viscosity significantly affect cellular functions, especially apoptosis, driving the need for real-time monitoring via fluorescence imaging. However, near-infrared fluorescence probes capable of simultaneously tracking these dynamic changes during apoptosis are rare. In this study, we introduce AXC-C, a versatile near-infrared fluorescent probe designed using density functional theory (DFT) approaches to monitor sulfur dioxide derivatives and viscosity in the mitochondria of apoptotic cells. We showed that AXC-C distinguishes between sulfur dioxide and viscosity through distinct emission channels, exhibiting high selectivity and sensitivity. Excited-state calculations confirmed that the twisted intramolecular charge transfer (TICT) process governs its viscosity response. At the same time, observations of electrostatic potential and local electron affinity energy identified the sulfur dioxide interaction site. AXC-C demonstrated versatility by effectively visualizing mitochondrial viscosity changes and sulfur dioxide generation during apoptosis, establishing it as a multifunctional detection platform. Additionally, smartphone-based colorimetric analysis enabled rapid, precise, and cost-effective sulfur dioxide detection in real food samples, offering practical solutions for environmental and food safety applications. This study highlights how quantum chemical strategies can revolutionize fluorescent probe design, offering new avenues for real-time cellular imaging and practical detection platforms.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 109034"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145197491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, synthesis and biological activity of novel sulfonatocalix[4]arene-based organophosphorus toxicant scavengers","authors":"Han Zhang ,&nbsp;Litian Jia ,&nbsp;Zhenhai Hu ,&nbsp;Genping Xue ,&nbsp;Sidan Sun ,&nbsp;Jixin Ma ,&nbsp;Yang Liu ,&nbsp;Qingbin Meng","doi":"10.1016/j.bioorg.2025.109067","DOIUrl":"10.1016/j.bioorg.2025.109067","url":null,"abstract":"<div><div>Chemical scavengers based on macrocyclic compounds have made remarkable progress in combating organophosphate toxicants. However, their structural diversity, structure-activity relationships and <em>in vivo</em> therapeutic effects still need further clarification. Here, 9 sulfonatocalix[4]arene derivatives were designed, synthesized and biologically evaluated using <em>in vitro</em> enzymatic assays. Through systematic structure-activity relationships optimization, compounds <strong>1b</strong>, <strong>1f</strong> and <strong>1</strong><strong>g</strong> exhibited particularly remarkable scavenging activities against organophosphate toxicants, with detoxification half-lives of 2.9 min, 4.6 min and 4.1 min, respectively. <em>In vitro</em> studies revealed their cytoprotective effects <em>via</em> reducing intracellular reactive oxygen species, alleviating lipid peroxidation and inhibiting proinflammatory cytokine release. In organophosphate-intoxicated mouse models, these compounds improved survival rates, mitigated seizure severity and reduced multi-organ injury. Notably, compound <strong>1f</strong> stood out with the most outstanding performance, emerging as a promising lead compound for the development of novel therapies against organophosphate poisoning.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 109067"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145217473","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure–activity optimization of Deferasirox–derived aroyl hydrazones: Synthesis, DFT characterization, and mechanistic insights into selective anticancer activity against colon and breast cancer","authors":"Ömer Dilek ,&nbsp;Muzaffer Dükel ,&nbsp;Fatema Zarzour ,&nbsp;Çiğdem Karabacak Atay ,&nbsp;Tahir Tilki","doi":"10.1016/j.bioorg.2025.109061","DOIUrl":"10.1016/j.bioorg.2025.109061","url":null,"abstract":"<div><div>Dysregulated iron metabolism is increasingly recognized as a hallmark of tumor progression in solid malignancies, including colon and breast cancers. Deferasirox (DFX), an oral Fe(III) chelator, exhibits anticancer activity; however, its structural optimization may enhance potency and selectivity. Here, six novel DFX-based aroyl hydrazone derivatives were synthesized, structurally characterized, and evaluated in vitro. Quantum chemical calculations and two-dimensional NMR confirmed their configurations, while molecular dynamics simulations demonstrated stable protein–ligand interactions. Compound 5e exhibited potent and selective cytotoxicity against triple-negative breast cancer (MDA-MB-231) and metastatic colon cancer (SW620) cells. Mechanistic studies revealed that 5e induces apoptosis and cell cycle arrest in a dose-dependent manner, with reactive oxygen species (ROS) generation playing a central role. Increased oxidative stress triggered autophagy, as evidenced by upregulation of Beclin-1, ATG5, and LC3 conversion. Co-treatment with the ROS scavenger <em>N</em>-acetylcysteine significantly reversed these effects, confirming the ROS-mediated mechanism. These findings highlight compound 5e as a multi-targeted anticancer agent warranting further in vivo and combination therapy investigations.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 109061"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145217474","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization and bioevaluation of radioiodinated oseltamivir phosphate for inflammation imaging as a new perspective","authors":"Safaa B. Challan ,&nbsp;Mamoun S.M. Abd El-Kareem ,&nbsp;A.M. Rashad ,&nbsp;S.I. Khater","doi":"10.1016/j.bioorg.2025.109050","DOIUrl":"10.1016/j.bioorg.2025.109050","url":null,"abstract":"<div><div>This study explores the dual antibacterial and imaging capabilities of radioiodinated Oseltamivir phosphate [¹³¹I]IodoTam for distinguishing infection from sterile inflammation. Oseltamivir phosphate (Tamiflu) was successfully labeled with iodine-131 via electrophilic substitution, achieving a high radiochemical yield (96.5 ± 1.2 %) under optimal conditions: 100 μg Tam, 100 μg chloramine-T, pH 4, 30-min incubation at room temperature, 25 °C. Quality control confirmed tracer purity through TLC and HPLC techniques. The in vitro antibacterial activity of Tamiflu was evaluated using a standard agar disk diffusion test against <em>Staphylococcus aureus</em>. A clear dose-dependent inhibition was observed, with zones measuring 10–24 mm in diameter at increasing Tamiflu doses (5–50 μg), exceeding the positive control (vancomycin 50 μg, 16 mm zone). Additionally, bacterial binding tests showed substantial uptake of [¹³¹I]IodoTam by <em>S. aureus</em> (56 ± 0.32 %), highlighting its potential targeting ability. In vivo, bioevaluation revealed that the [¹³¹I]IodoTam tracer accumulated more in infected tissue (T/NT = 6.6 at 2 h post-injection) compared to sterile inflamed tissue (T/NT = 2.71 at 2 h post-injection). It was also significantly higher than the ratio of commercially available ^99mTc-ciprofloxacin (T/NT = 3.18 at 1 h post-injection). These findings suggest that [¹³¹I]IodoTam could be a valuable tool for differentiating bacterial infections from sterile inflammation, demonstrating its potential as a dual-action antiviral and antibacterial agent for imaging and therapy in infectious diseases.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 109050"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205022","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular and biological characterization of VEGF-mimetic peptidomimetic containing a morpholine β-amino acid","authors":"Raffaella Bucci ,&nbsp;Lucia De Rosa ,&nbsp;Gianmarco Bertoni ,&nbsp;Rossella Di Stasi ,&nbsp;Maria della Valle ,&nbsp;Donatella Diana ,&nbsp;Silvia Peppicelli ,&nbsp;Kaliroi Peqini ,&nbsp;Maria Luisa Gelmi ,&nbsp;Francesca Bianchini ,&nbsp;Luca Domenico D'Andrea","doi":"10.1016/j.bioorg.2025.109039","DOIUrl":"10.1016/j.bioorg.2025.109039","url":null,"abstract":"<div><div>The QK peptide is a 15-residue VEGF-mimetic compound known for its proangiogenic activity. Its helical conformation plays a crucial role in binding to VEGF receptors, activating intracellular signaling pathways in endothelial cells, promoting cell migration, proliferation, and survival. However, peptides composed exclusively by natural amino acids often suffer from poor stability in biological fluids, limiting their therapeutic potential. In this study, we modified the QK sequence shortening the peptide chain by incorporating a non-natural β-amino acid with a morpholine core, that promotes helical secondary structures in model peptides. Structural analysis using CD, FT-IR and NMR revealed that in water, MQK adopts a mixed conformation with partial helical content. Biological characterization on endothelial cells demonstrated that MQK peptidomimetic promotes cell proliferation, survival, migration and invasion providing strong evidence for its pro-angiogenic activity, and a reasonable protease resistance. In definitive, insertion of the morpholine β-amino acid partially destabilizes the helical structure and increases peptide flexibility relative to QK, without impairing biological function. This suggests that the enhanced conformational adaptability of MQK may favor adoption of the bioactive conformation and the interaction with the biological target.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 109039"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145211117","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advances in targeting glycogen synthase kinase 3β for diabetes therapy","authors":"Fuyu Wang ,&nbsp;Yating Li ,&nbsp;Lan Bai ,&nbsp;Wenjing Xiao ,&nbsp;Ling Zhong ,&nbsp;Jianyou Shi","doi":"10.1016/j.bioorg.2025.109051","DOIUrl":"10.1016/j.bioorg.2025.109051","url":null,"abstract":"<div><div>Diabetes mellitus is a chronic metabolic disease characterized by hyperglycemia, which is caused by absolute or relative insulin deficiency in secretion and impaired insulin utilization. The newly added content is as follows: Diabetes mellitus is typically classified into two main types: type 1 diabetes (T1DM) and type 2 diabetes (T2DM). Type 1 diabetes primarily arises from the erroneous attack on pancreatic β-cells by the autoimmune system, resulting in β-cell damage and an absolute deficiency in insulin secretion. Genetic factors play a crucial role in its pathogenesis. In contrast, the pathogenesis of type 2 diabetes is more complex, mainly involving insulin resistance and relative insulin deficiency. Its onset is closely linked to both genetic factors and lifestyle, with high-calorie diets, insufficient physical activity, and obesity being significant risk factors.Despite the differences in their pathogenic mechanisms, insulin plays an extremely important role in both types of diabetes. Glycogen synthase kinase 3 (GSK3) is a highly conserved kinase that can activate glycogen synthase. As a key molecule in the glucose metabolic pathway, GSK3β is involved in various cellular activities and plays a crucial role in multiple diseases. Therefore, pharmacological inhibition of the activity and expression of GSK3β represents a promising approach for the treatment of diabetes. In recent years, GSK3 has been implicated in skeletal muscle insulin resistance in obese animal models and obese individuals with type 2 diabetes mellitus (T2DM). It leads to increased glucose production and decreased insulin sensitivity by inhibiting glycogen synthase. These findings indicate that studies utilizing specific and sensitive GSK3 inhibitors have provided new insights into the role of GSK3 in regulating the effect of insulin on glucose transport in muscles. However, diabetes therapeutic drugs targeting GSK3β directly have not yet been approved for marketing worldwide. Herein, we describe the role of GSK3β in diabetes, clarify the central role of GSK3β in cellular signaling pathways, and summarize GSK3β inhibitors for the treatment of diabetes. Finally, we hope that these latest research advances will facilitate the discovery of safe and effective GSK3β inhibitors for the treatment of diabetes.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"166 ","pages":"Article 109051"},"PeriodicalIF":4.7,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145265750","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}