IGF-1 LR3

The insulin receptor inhibitor BMS-754807 alleviates neuroinflammation and Alzheimer's disease pathologies across human cellular and mouse models.

Hyun-Ju Lee, Jaewoo Seok, Sora Kang +5 more

BMS-754807 is a dual inhibitor of insulin-like growth factor 1 receptor (IGF-1R) and insulin receptor (IR) that is in phase II clinical trials for the treatment of HR-positive and HER2-negative breast cancer. Because IGF-1R signaling regulates inflammatory responses, pharmacological modulation of IGF-1R may have therapeutic potential for Alzheimer's disease (AD); however, the effects of BMS-754807 on neuroinflammatory responses/AD pathology and cognitive function have not been fully investigated.

Innovations in Obesity Treatment: Beyond Adipose Tissue Dysfunction.

Jesica Martínez-Godfrey, Irene Pomares-Bri, Paula de Juan-Maciá +5 more

Obesity, a chronic disease characterized by excessive adipose tissue accumulation, represents a critical global health challenge with profound metabolic, inflammatory, and oncogenic implications. To provide a multidisciplinary perspective, this narrative review integrates current literature examining metabolic, immunological, and oncological evidence to outline obesity as a multisystem disorder. Chronic inflammation is examined as a central mediator linking excessive adiposity to insulin resistance, type 2 diabetes, and cancer development, specifically detailing how adipose tissue dysfunction, altered adipokine profiles, and immune cell infiltration drive systemic pathogenesis. Emerging insights into the molecular mechanisms of tumor progression in a metabolically altered environment are highlighted, emphasizing the roles of hyperinsulinemia and dysregulated adipokines like leptin and adiponectin. In addition, the review explores innovative therapeutic strategies for obesity-related cancer, including the use of metformin and therapies targeting insulin-like growth factor 1 receptor and colony-stimulating factor 1 receptor pathways. It also discusses the therapeutic promise of white adipose tissue browning through inductors such as menthol and capsinoids to enhance metabolic homeostasis. Furthermore, hormonal and neural dysregulation of appetite control are addressed. Novel pharmacological treatments targeting appetite, such as glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide receptor agonists, as well as neuromodulation techniques are discussed as promising avenues for personalized and effective interventions. This comprehensive understanding of obesity's complex nature is crucial for developing novel, integrated approaches to complement traditional diet and exercise strategies.

Roles of insulin-like growth factor 1 receptor in growth regulation in 15q26 deletion and duplication syndrome.

Kexin Yu, Xin Xu, Bo Liu +12 more

The 15q26 deletion and duplication syndromes are rare chromosome diseases with growth deviation and structural anomalies such as facial abnormality, cardiac malformation and hand/foot/skeleton malformations. Insulin-like growth factor 1 receptor (IGF1R), located on chromosome 15q26, is key for pre- and postnatal growth. The present study aimed to determine whether IGF1R serves as a key factor in growth regulation in 15q26 deletion and duplication syndromes. Patients with 15q26 deletions and duplications enrolled in the China Neonatal Genomes Project (CNGP) were recruited. A systematic review of 15q26 deletion and duplication cases was performed, followed by meta-analysis to evaluate the roles of IGF1R and three other genes [myocyte enhancer factor 2A (MEF2A), leucine-rich repeat kinase 1 (LRRK1) and nuclear receptor subfamily 2 group F member 2] involved in growth regulation. A total of 10 eligible patients from the CNGP, including seven with deletions and three with duplications, were identified. The literature search and screening yielded 78 patients with 15q26 deletions and 10 with 15q26 duplications. Clinical features observed in >70% of the patients in the deletion group were facial abnormalities, developmental delay, short stature and hand/foot/skeleton malformations, whereas the duplication group exhibited facial abnormality, hand/foot/skeleton malformation and speech development delay. In 15q26 deletion, three candidate genes were associated with an increased risk of short stature: IGF1R [odds ratio (OR): 8.43; 95% confidence interval (CI): 2.22-32.00], LRRK1 (OR: 100.00; 95% CI: 11.86-843.23) and MEF2A (OR: 32.21; 95% CI: 3.81-272.47). In 15q26 duplication, none of the candidate genes significantly affected tall stature. Using meta-analysis, the present study revealed that IGF1R is not the only key gene responsible for growth abnormalities in 15q26 deletion and duplication syndromes.

IGF1 Binding to Integrin αvβ3 Induces Direct Gα13 Binding to IGF1R Kinase.

Yoko K Takada, Chun-Yi Wu, Yoshikazu Takada

IGF1 plays a critical role in cell proliferation and survival. Previous studies show that IGF1 binds to integrin αvβ3 and induces αvβ3-IGF1-IGF1R ternary complex formation. However, how IGF1 binding to αvβ3 leads to IGF1R activation is unclear. Previous studies showed that Gα13, a guanine nucleotide-binding protein of the G12 class of Gα proteins, binds to the integrin β3 tail through the EEE motif upon fibrinogen binding to integrin αIIbβ3 and induces RhoA activation. We discovered that the EEE/AAA mutation of the β3 tail inhibited IGF1-induced cell survival, suggesting that Gα13 binding to the β3 tail is required for IGF1 signaling. Since RhoA activation may not be directly involved in IGF1R activation, we studied if Gα13 binds to molecules other than RhoA. Since Gα13 binds to several cytoplasmic tyrosine kinases, we studied if Gα13 binds to the IGF1R kinase by a docking simulation. The simulation predicted that Gα13 binds to the IGF1R kinase through a new binding site. Mutating the predicted Gα13 binding site in the IGF1R kinase (residues 1020-1022) or the predicted IGF1R kinase binding site in Gα13 (residues 260-279) inhibited Gα13 binding to the IGF1R kinase, which is consistent with the docking model. Notably, the Gα13(260-279A) mutant inhibited IGF1-induced cell survival. We propose that IGF1 binding to αvβ3 induces Gα13 binding to the β3 tail and subsequent Gα13 binding to the IGF1R kinase, leading to IGF1R activation. Interestingly, Gα13(260-279A) mutation inhibited cell survival due to a constitutively active Gα13(Q226L) mutant. We propose that Gα13(Q226L) induces its effect by binding to the IGF1R kinase. We propose that the Gα13 binding site of the IGF1R kinase or the IGF1R binding site in Gα13 may be a novel therapeutic target.

Aspirin (Acetylsalicylic Acid) Exerts Antineoplastic Effects on Bile Duct Carcinoma Cells Through Modulation of COX-2/ EGFR, AMPK, and IGF-1R Signaling Pathways.

Yoonchan Lee, Jin Lee, Eun Mi Hong +3 more

Bile duct carcinoma (BDC) is a highly aggressive malignancy. While epidemiological evidence suggests that acetylsalicylic acid (ASA [aspirin]) reduces BDC risk, the underlying molecular mechanisms have not been fully elucidated. This investigation explored the antineoplastic mechanisms of ASA in BDC cells.

Dual inhibition of intercellular adhesion molecule-1 and nucleolin reduces RSV infection efficiency in human respiratory organoids.

Abeer Keshta, Rina Hashimoto, Yuki Kitai +5 more

Respiratory syncytial virus (RSV) is one of the major causes of lower respiratory tract infections, particularly in infants and older adults. However, the host factors mediating infection remain poorly defined. It has been suggested that four host surface proteins, namely intercellular adhesion molecule-1 (ICAM-1), epidermal growth factor receptor (EGFR), nucleolin (NCL), and insulin-like growth factor 1 receptor (IGF1R), may interact with the RSV fusion (F) protein. To investigate these roles under physiologically relevant conditions, we employed human induced pluripotent stem cell (iPSC)-derived respiratory organoids as a model for RSV infection. In this model, ICAM-1 and EGFR were genetically depleted using the CRISPR-Cas9 genome editing technique, while NCL and IGF1R were inhibited with neutralizing antibodies. Suppression of ICAM-1 or NCL significantly reduced RSV nucleoprotein gene expression, whereas inhibition of EGFR or IGF1R had no observable effect on viral gene expression. Notably, simultaneous suppression of ICAM-1 and NCL resulted in a more substantial reduction in infectious viral titers and RSV F protein expression than inhibition of either protein alone. Our results suggest that both ICAM-1 and NCL may play important roles during RSV infection in human iPSC-derived respiratory organoids.

Comparative network pharmacology analysis of ketamine and xanomeline in major depressive disorder: Shared and distinct molecular mechanisms.

Xin Ding, Kenji Hashimoto, Jian-Jun Yang

Major depressive disorder (MDD) is a leading cause of disability worldwide, and currently available antidepressants remain limited by delayed onset of action, incomplete response, and adverse effects. Ketamine is a rapid-acting antidepressant, whereas xanomeline, an M1/M4 muscarinic receptor agonist, may represent a mechanistically distinct non-monoaminergic strategy. However, the molecular basis by which xanomeline may influence depression-related pathways, and its relationship to ketamine, remain unclear. We used network pharmacology and molecular docking to compare the shared and distinct molecular mechanisms of xanomeline and ketamine in MDD. Potential drug targets were collected from public databases and intersected with MDD-related targets. Protein-protein interaction analysis was performed to identify hub genes, followed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. Drug-pathway-target-disease networks were constructed, and shared core targets were further evaluated by molecular docking. We identified 368 overlapping targets for xanomeline-MDD and 714 for ketamine-MDD. Three KEGG pathways were shared between the two networks: EGFR tyrosine kinase inhibitor resistance, Ras signaling, and Rap1 signaling. EGFR, insulin-like growth factor 1 receptor (IGF1R), and SRC proto-oncogene, non-receptor tyrosine kinase, emerged as common core targets. Xanomeline was more strongly associated with receptor tyrosine kinase and PI3K/AKT-related signaling, whereas ketamine was more strongly linked to synaptic transmission, NMDA receptor-related functions, and glutamatergic signaling. Molecular docking supported structurally plausible binding of both drugs to EGFR, IGF1R, and SRC. These findings suggest partial convergence on downstream plasticity-related signaling nodes despite distinct upstream mechanisms and warrant further experimental investigation. However, the results should be interpreted as hypothesis-generating rather than as evidence of shared functional target engagement.

Tumor-specific lncRNA IGF1R-AS1 trans-regulates chromatin interactions associated with oncogenic MYC signaling.

Yongyong Yang, Ting-You Wang, Joshua Fry +24 more

LncRNAs have emerged as pivotal regulators in the development and progression of various human cancers. However, understanding the precise mechanisms by which lncRNAs influence cancer progression remains a substantial challenge, largely due to their cell type- and tissue-specific expression patterns and the lack of well-defined functional domains or motifs. In this study, we investigate the complex interplay between super-enhancers and lncRNAs through a comprehensive analysis of lncRNA expression in a cohort of metastatic castration-resistant prostate cancer patients. Our analysis identifies 1344 lncRNAs, among which an antisense lncRNA in the IGF1R locus named IGF1R-AS1 displayed the strongest super-enhancer association. Through pan-cancer transcriptome analysis, we find that IGF1R-AS1 is specifically transcribed in tumor specimens and is overexpressed in prostate and lung cancers. Notably, we reveal a non-canonical trans-acting role for IGF1R-AS1 whereby it interacts with chromatin remodeling complexes and architectural proteins to facilitate long-range chromatin looping between distal MYC enhancers and its promoter, leading to MYC overexpression and enhanced tumorigenicity. Collectively, our findings elucidate a mechanism by which a tumor-specific trans-acting lncRNA modulates oncogenic MYC expression through long-range chromatin interactions, suggesting IGF1R-AS1 may play an important role in the pathogenesis of MYC-driven malignancies.

[The physiological roles of primary ciliary resorption and its potential as therapeutic targets].

Masaki Saito, Gen-Ichi Atsumi

Primary cilia are cellular antennae protruding from the surface of nearly all cell types during the G0 phase. They control the organization and maturation of systemic tissues and organs by receiving selective signals. Ciliopathies are heritable disorders that cause dysplasia of various tissues and organs, as well as the progression of obesity. In contrast, recent studies using cultured cells have revealed that cilia were resorbed upon receiving selective proliferative stimuli, thereby reentering the cell cycle into the G1/S phase. However, the physiological significance and molecular mechanisms of ciliary resorption were unclear, as no diseases caused by abnormal ciliary resorption had been identified in humans or experimental animals. To address this problem, we focused on the role of the cytoplasmic dynein light chain Tctex-1. We found that activating the insulin-like growth factor-1 receptor at cilia results in the phosphorylation of threonine 94 in Tctex-1 and subsequent endocytosis of the ciliary pocket membrane surrounding the ciliary basal region. This mechanism is responsible for ciliary resorption and reentry into the G1/S phases of the cell cycle. Additionally, we found that phospho-(T94)Tctex-1 localizes to the ciliary transition zone of neural progenitor cells in the fetal cerebral cortex, where it regulates cell cycle reentry and neurogenesis. Recent reports indicate that mice with abnormal ciliary resorption develop microcephaly-like symptoms. Our study and these reports shed light on the physiological significance of ciliary resorption. Finally, this review discusses new directions in ciliary resorption research and its potential therapeutic applications.

Severe Short Stature and rhGH Resistance in a Child Born SGA: The Role of a Novel IGF1R Mutation, Case Report and Narrative Review.

Giovanni Luppino, Eleonora Ini', Letteria Anna Morabito +5 more

Background: Genetic causes of growth failure should be suspected in patients born small for gestational age (SGA) who fail to show postnatal catch-up growth, present with severe short stature (SS), and exhibit a poor or absent response to growth hormone (rhGH) therapy. Mutations in the insulin-like growth factor 1 receptor (IGF1R) gene are associated with impaired growth, intrauterine growth restriction (IUGR), low birth weight and/or length, and postnatal SS. Case Description: A 9-year-old boy, born SGA for birth length, was evaluated for severe SS. Common causes of SS were excluded. At 9 years and 7 months of age, his height was 112.6 cm (-3.99 SDS), weight 18 kg (-3.79 SDS), and BMI 14.2 kg/m2 (-1.8 SDS); pubertal development was Tanner stage 1. The target height was 158 cm (-2.62 SDS). Bone age was delayed by approximately one year compared with chronological age. Serum IGF-1 levels were within the upper-normal range for age. GH therapy (0.035 mg/kg/day) was initiated due to the lack of catch-up growth in an SGA subject. After three years of treatment, the height gain was only 0.5 SDS. IGF-1 levels showed a transient treatment-related increase, followed by persistent normalization during ongoing therapy. Next-generation sequencing (NGS) analysis identified novel heterozygous paternal nonsense variant in the IGF1R gene: c.3498C>G (p.Tyr1166Ter). At 12 years of age, impaired fasting glucose and reduced glucose tolerance were detected; consequently, it was decided to discontinue rhGH therapy, also in light of the IGF1R mutation and the lack of height recovery. Conclusions: This case underlines the critical role of genetic testing in the evaluation of patients born SGA. The coexistence of SGA status and an IGF1R gene mutation may provide a clear explanation for both the poor response to rhGH therapy and the increased risk of alterations in glucose metabolism. An extensive narrative review of the literature on growth outcomes and glucose metabolism abnormalities during GH treatment in SGA patients carrying IGF1R variants was also performed.

Neudesin modulates IGF1 and insulin signaling pathways by regulating the surface expression of IGF1R through a conserved WPE motif.

Yoshiaki Nakayama, Motohiro Nonaka, Yuki Masuda +13 more

Neudesin, a secreted protein implicated in diverse physiological processes, such as metabolism and immunity, lacks an identified receptor, which has prevented a detailed understanding of its molecular mechanisms. In this study, we aimed to elucidate the function of neudesin by identifying its cognate receptor and investigating its effects on cellular signaling. Using a combination of phage display, bioinformatics, and biochemical analysis, we identified insulin-like growth factor 1 receptor (IGF1R) as a high-affinity receptor for neudesin, with a binding affinity of 1.78 ± 1.87 nm. This interaction was mediated by a conserved tryptophan-proline-glutamic acid (WPE) motif in the IGF1R extracellular domain. Our cellular assays revealed that, while neudesin binding to IGF1R induces basal phosphorylation of the downstream signaling molecules extracellular signal-regulated kinase (ERK) and AKT (also known as Protein Kinase B, or PKB) in a cell-line-specific manner, it consistently acts as a negative modulator, attenuating both IGF1- and insulin-induced signaling. Mechanistically, neudesin promoted the downregulation of cell surface IGF1R, thereby reducing the receptor pool available for ligand stimulation. Furthermore, neudesin inhibited insulin signaling, likely through the co-internalization of IGF1R/insulin receptor (INSR) hybrid complexes. The physiological significance of this role was underscored in 3 T3-L1 adipocytes, where neudesin knockdown enhanced insulin-induced signaling and accelerated triglyceride accumulation. These results establish a novel molecular link between neudesin and the IGF1/insulin signaling axis, suggesting that neudesin may serve as an endogenous modulator of IGF1R/insulin activity, with potential implications for metabolic and growth-related diseases.

Early GH therapy and neurodevelopmental outcome in a child with compound heterozygous IGF1R variants.

Mariana Sá Pinto, Mariana Oliveira, Tomás Ferrão +3 more

Causal variants in the IGF 1 receptor (IGF1R) gene are associated with variable degrees of growth and neurodevelopmental impairment. While heterozygous variants often manifest as less severe phenotypes, homozygous loss-of-function mutations are widely regarded as incompatible with life. Biallelic hypomorphic variants are exceptionally rare and their clinical spectrum remains poorly defined. We report the case of a girl born at term after severe symmetric fetal growth restriction (FGR), identified prenatally through trio whole-exome sequencing as carrying compound heterozygous IGF1R variants-c.155G>C (p.Cys52Ser) and c.3476A>G (p.Asp1159Gly). Postnatally, she exhibited microcephaly, dysmorphic features, and marked growth failure. Growth hormone therapy was initiated at 13 months of age, leading to gradual and sustained improvement in head circumference, linear growth, and psychomotor development. We report a rare case of a prenatal diagnosis of compound heterozygous IGF1R variants with early GH treatment. The case broadens current knowledge on IGF1R-related disorders, shows that survival is possible in compound heterozygous states, and suggests a potential benefit of early GH therapy.

Fetal gastric maturation in a rat model: gestational changes in glucose transporter-1, glucose transporter-4, and insulin-like growth factor-1 receptor expression.

Pelin Coştur Filiz, Emin Türkay Korgun

To investigate the relationship between histological maturation of the fetal rat stomach and gestational stage-dependent expression patterns of glucose transporter (GLUT)-1, GLUT-4, and IGF-1 receptor (IGF-1R).

Therapeutic targets for fibro-inflammation in Graves' orbitopathy.

Young Jae Kang, Jin Sook Yoon

Graves' orbitopathy (GO), a complex autoimmune disorder, remains the most common extrathyroidal manifestation of Graves' disease. Its pathogenesis is characterized by a progressive transition from inflammation to fibrosis, leading to debilitating ocular complications. While high-dose intravenous glucocorticoids have been the standard treatment for active moderate-to-severe GO, their lack of specificity to GO pathogenesis and limited efficacy in the fibrotic phase underscore the need for targeted therapies. This review explores emerging therapeutic targets in GO, focusing on pathways implicated in both inflammatory and fibrotic mechanisms. Teprotumumab, an insulin-like growth factor 1 receptor (IGF-1R) inhibitor, has revolutionized GO treatment, demonstrating clinical efficacy in reducing proptosis and inflammation. Interleukin-6 (IL-6) inhibitors including satralizumab are undergoing clinical trials. New studies on molecular pathways have been conducted regarding inflammation and fibrosis of GO, including platelet-derived growth factor/fibroblast growth factor signaling, yes-associated protein 1/transcriptional coactivator with PDZ-binding motif mechanotransduction, sphingosine-1-phosphate (S1P)/S1P receptor axis, bone morphogenic protein 7, IL-11, IL-17 and microRNAs as well as, IGF-1R/thyroid-stimulating hormone receptor crosstalk, and IL-6 trans-signaling. Most studies focus on exploring the potential of therapeutic agents through preclinical investigations but represent promising therapeutic avenues. Therapies targeting these pathways may offer a promising potential efficacy across the entire disease spectrum, from inflammation to fibrosis, thus overcome the limitations of conventional glucocorticoid therapy and expand therapeutic options in GO. Advances in in vivo GO models may bring forward a new era of GO treatment.

miR-449b-5p from adipose-derived mesenchymal stem cell-derived exosomes targets IGF1R to alleviate airway inflammation and improve airway smooth muscle cell dysfunction in children with asthma.

ShuXiang Sui, LiJuan Yang, DongMei Ji +1 more

This study investigated the protective effect of miR-449b-5p from adipose-derived mesenchymal stem cell-derived exosomes (ADSC-Exos) targeting type 1 insulin-like growth factor receptor (IGF1R) on airway smooth muscle cells (ASMCs) and further investigated its mechanism of action. ADSC-Exos were isolated and characterized. Cellular uptake of ADSC-Exos by ASMCs was observed. Differences in serum miR-449b-5p expression levels between healthy children and asthmatic children were detected by RT-qPCR. The possible binding sites of miR-449b-5p and IGF1R were identified and then verified. The proliferation of ASMCs was determined by MTT assay and EdU assay. Cell cycle of ASMCs was measured by flow cytometry. Cell contraction of ASMCs was evaluated by inverted microscopy. IL-4, IL-5, and IFN-γ were measured by ELISA to evaluate the inflammatory response of ASMCs. ADSC-Exos exerted therapeutic effects on ASMCs by effectively inhibiting proliferation, cell contraction, and inflammatory response. miR-449b-5p upregulation in ASMCs effectively inhibited the promoting effect of PDGF-BB on cellular proliferation and contraction, while IGF1R upregulation showed the opposite effect. miR-449b-5p in ADSC-Exos targeted IGF1R to alleviate airway inflammation in asthma and improve ASMC dysfunction. ADSC-Exos carrying miR-449b-5p improve ASMC dysfunction, excessive proliferation, and inflammatory responses by downregulating IGF1R.

Apoptosis induction and migration suppression through regulation of IGF-1R/FoxO signaling pathways in Panc1 pancreatic cancer cells by hAMSCs secretome: An in vitro cell-based therapy.

Fatemeh Safari, Mohammad Rasouli, Mana Alavi

Pancreatic cancer often referred to as the "king of cancers," is a disease with no symptoms and lacks effective therapy. Current treatment options for pancreatic cancer have not been successful, highlighting the need for new therapeutic avenues with minimal side effects and improved effectiveness. In recent years, new cell-based therapies using stem cells or their derivatives have shown promise in treating various diseases, including cancer. Here, we aimed to explore the impact of the secretome of human amniotic mesenchymal stem cells (hAMSCs) on Panc1 pancreatic cancer cells, focusing on the insulin-like growth factor 1 receptor (IGF-1R)/FoxO signaling pathways. To achieve this, we developed a co-culture system utilizing 6-well plates transwell. After 72 h, cell death and cell invasion in hAMSCs-treated Panc1 cells were assessed using Western blot, Scratch assay, and DAPI staining. Our results showed an increase in the expression levels of AKT, AMPK, FasL, and cleaved caspases 3/9, while there was a decrease in FoxO, IGF-1R, PI3K, 14-3-3, p-FoxO, MMP3, Integrin α3, and Integrin β6 expression. These findings suggest that hAMSCs' secretome promotes cell death and inhibits cell invasion in Panc1 cells, indicating its potential as a novel targeted therapy approach for pancreatic cancer.

Nuclear Translocation of IGF1R Induces Cell Cycle Re-entry via Cyclin D1 Regulation in an Aβ-Driven Alzheimer's Disease Model.

Priyanka Sengupta, Debashis Mukhopadhyay

Alzheimer's disease (AD) involves progressive neurodegeneration, with abnormal receptor signaling and disrupted cell-cycle activity leading to neuronal loss. Here, we identify a previously unknown mechanism linking β-amyloid (Aβ) exposure to the nuclear translocation of the Insulin-like Growth Factor 1 Receptor (IGF1R) in differentiated SH-SY5Y neuronal cells. The differentiated cholinergic model induced by retinoic acid and BDNF expresses acetylcholinesterase (AChE) and indicates that under amyloidogenic stress, IGF1R may transition from homeostatic membrane and vesicular signaling to a nuclear-centric function. We show that prolonged Aβ treatment causes phosphorylation-dependent nuclear import of IGF1R, confirmed by confocal imaging and biochemical fractionation. IGF1R is conventionally located in the membrane and vesicular membranes; however, under amyloidogenic stress, we show here that it is imported to the nucleus and exerts transcriptional control. The buildup of nuclear IGF1R coincided with increased Cyclin D1 levels and redistribution of neurons into S and G₂ phases, indicating abnormal cell-cycle re-entry. Chromatin immunoprecipitation demonstrated increased IGF1R binding at the CCND1 and JUN promoters after Aβ exposure, suggesting a direct role in gene transcription. Pharmacological blockade of IGF1R phosphorylation by PPP or SUMOylation by Ginkgolic acid significantly reduced Cyclin D1 elevation, implying that both post-translational modifications are involved in receptor nuclear trafficking. Co-immunoprecipitation and confocal imaging identified Nucleophosmin (NPM1) as a putative IGF1R interacting partner, potentially contributing to its nuclear transport and stabilizing receptor-chromatin complexes. These results establish IGF1R as a signaling-transcription connector linking extracellular amyloid stress to nuclear gene regulation, providing a mechanistic explanation for faulty neuronal cell-cycle re-entry in AD. We suggest that abnormal IGF1R-NPM1 interactions contribute to receptor mislocalization and cell-cycle failure, highlighting new targets for therapeutic intervention aimed at receptor trafficking and neuroprotection in Alzheimer's disease.

Molecular and Cellular Effects of Therapies for Thyroid Eye Disease on Ocular Surface and Adnexal Homeostasis.

Monika Sarnat-Kucharczyk, Wojciech Luboń, Dorota Wyględowska-Promieńska +1 more

Thyroid eye disease (TED) is an autoimmune inflammatory disorder primarily affecting orbital tissues, but ocular surface and adnexal involvement represent a frequent and clinically significant component of disease burden. Beyond mechanical exposure resulting from eyelid retraction and proptosis, TED-associated ocular surface disease arises from complex interactions between immune activation, epithelial stress, glandular dysfunction, and altered neuro-epithelial signaling. Increasing use of systemic immunomodulatory therapies, biologics, and orbital radiotherapy has improved control of orbital inflammation; however, their molecular and cellular effects on ocular surface homeostasis remain incompletely defined. This review summarizes current evidence on the cellular and molecular mechanisms underlying ocular surface dysfunction in TED and examines how disease-modifying therapies influence epithelial integrity, tear film stability, meibomian and lacrimal gland function, and local immune signaling. Key pathways discussed include cytokine-mediated inflammation, thyroid-stimulating hormone receptor and insulin-like growth factor-1 receptor crosstalk, pro-fibrotic signaling, neuro-inflammatory mechanisms, and epithelial stress responses involving mitogen-activated protein kinase and nuclear factor kappa B pathways. We further highlight the challenge of disentangling therapy-induced molecular effects from persistent exposure-related mechanical stress. Understanding how TED therapies modulate ocular surface and adnexal homeostasis is essential for optimizing integrated management strategies that address both orbital inflammation and long-term ocular surface stability.

High Expression of PAPP-A Predicts Poor Outcomes in Oestrogen Receptor-Positive Breast Cancer Patients.

Zeanap Mabruk, Esme Bullock, Xue Xiao +10 more

Insulin-like growth factor 1 (IGF-1)/IGF-1 receptor (IGF-1R) signalling is activated in breast cancer and associated with disease progression. Pregnancy-associated plasma protein-A (PAPP-A) is a metalloproteinase that can cleave IGF binding proteins leading to the release of bioactive IGF-1 and the subsequent activation of IGF-1 signalling. Here, we aimed to assess the prognostic significance of PAPP-A in breast cancer.

IGF1/IGF-1R promotes hepatocellular carcinoma progression by activating the Akt/GSK-3β pathway.

Jiaojiao Liang, Xueyi Song, Yang Liu +3 more

The incidence of hepatocellular carcinoma (HCC) is increasing each year, with challenges such as increasing drug resistance and a high post-treatment recurrence rate. Therefore, investigating the novel pathogenic mechanisms is warranted. In this study, we investigated novel molecular mechanisms that affect HCC progression. Immunofluorescence analysis, immunohistochemical staining, and immunoblotting were performed to assess elevated IGF-1R expression in HCC cells. The EdU incorporation and colony formation assays revealed that IGF-1R promotes HCC cell proliferation. Furthermore, wound healing and Transwell migration assays revealed that IGF-1R phosphorylation enhances the migration of HCC cells. In addition, JC-1 apoptosis assays revealed that IGF-1R inhibits HCC cell apoptosis. Immunoblotting was performed to assess the protein phosphorylation level of Akt/GSK-3β downstream of IGF1/IGF-1R to explore the molecular mechanism. IGF-1R expression was significantly increased in HCC cells, and ligand-induced phosphorylation promoted HCC cell proliferation and migration and inhibited apoptosis. Additional studies revealed that the activation of IGF-1R phosphorylation promotes epithelial-mesenchymal transition in HCC cells by increasing the phosphorylation levels of Akt and GSK-3β. Collectively, our study findings suggest that IGF-1/IGF-1R promotes HCC progression by activating the Akt/GSK-3β pathway.

Teprotumumab-Associated Hyperglycemia: A Large-Scale Multinational Cohort Study.

Natan Lishinsky-Fischer, Rena Pollack, Zvi Gur

Teprotumumab, a monoclonal antibody targeting the insulin-like growth factor-1 receptor, represents the first Food and Drug Administration (FDA)-approved treatment for thyroid eye disease (TED). However, hyperglycemia has emerged as a significant adverse event, with limited real-world data on its incidence and clinical impact. This study aimed to evaluate the risk of glycemic abnormalities associated with teprotumumab treatment using a large, multinational electronic health records database.

Mechanism underlying the regulation of gut microbiota-metabolite axis and growth/immune function in lambs by leaf-derived polysaccharides from Taraxacum kok-saghyz.

Alimu Aersilan, Zulikeyan Manafu, Gulibanu Aosiman +5 more

Taraxacum kok-saghyz polysaccharide (TKP) possesses multiple biological activities and is a potential candidate for regulating lamb health. Using multi-omics analysis, this study investigated the immunomodulatory and growth-regulating effects of TKP produced from leaves (TKP-L) and roots (TKP-R) in lambs.

IGF-1 and insulin receptors in LepRb neurons jointly regulate body growth, bone mass, reproduction, and metabolism.

Mengjie Wang, Piotr J Czernik, Beata Lecka-Czernik +1 more

Leptin receptor (LepRb)-expressing neurons integrate metabolic and reproductive signals, yet the role of insulin-like growth factor 1 receptor (IGF1R) signaling within these neurons remains unclear. Because IGF-1 and insulin can partially activate each other's receptors, we generated mice lacking IGF1R selectively in LepRb neurons (IGF1RLepRb) as well as mice lacking both IGF1R and insulin receptor (IR) in LepRb neurons (IGF1R/IRLepRb). These models were used to assess body growth, skeletal development, reproductive function, energy balance, and metabolic homeostasis. Deletion of IGF1R alone in LepRb neurons delayed pubertal onset, impaired adult fertility, and accelerated reproductive aging, accompanied by transient postnatal growth retardation. IGF1R deficiency also altered trabecular and cortical bone structural parameters in both sexes, supporting a role for IGF1R signaling in coordinating growth, skeletal physiology, and reproductive function. Despite reduced food intake and increased energy expenditure in females after adjusting for lean mass, IGF1R deletion caused only modest metabolic alterations, with transient decreases in body weight and largely unchanged body composition and locomotor activity. In contrast, combined deletion of IGF1R and IR in LepRb neurons resulted in marked metabolic disturbances, including increased adiposity, reduced lean mass, lower energy expenditure, decreased locomotor activity, and impaired insulin sensitivity in males. These findings indicate cooperative roles of IGF1R and IR signaling within LepRb neurons in regulating body composition, energy balance, and glucose homeostasis. Together, our results demonstrate that IGF1R signaling in LepRb neurons primarily regulates reproductive development, skeletal physiology, and growth, whereas combined IGF1R and IR signaling is required for maintaining metabolic homeostasis. These findings identify LepRb neurons as an important neuroendocrine hub integrating IGF and insulin signaling to coordinate growth, reproduction, and metabolism in a sex-dependent manner.

[Expression of Concern] Insulin-like growth factor-1 receptor knockdown enhances radiosensitivity via the HIF-1α pathway and attenuates ATM/H2AX/53BP1 DNA repair activation in human lung squamous carcinoma cells.

Xiaoxing Liu, Haiyan Chen, Xin Xu +8 more

Synergistic effects through targeting the PI3K and IGFR pathways in treating lung cancer carrying activation alterations along the PI3K pathway.

Mohamed Abd El-Salam, Wu Chen, Yan Tang +9 more

Alterations in the PI3K/AKT pathway occur in over 60 % of lung squamous cell carcinoma and approximately 20 % of lung adenocarcinoma, driving tumor progression and therapeutic resistance. While PI3K-targeted therapies suppress proliferation in PIK3CA-mutant non-small cell lung cancer (NSCLC), their clinical impact is limited due to compensatory activation of insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF-1R) signaling. This study aimed to determine whether dual blockade of PI3K and IR/IGF-1R signaling could overcome this adaptive resistance.

SELFormer-guided discovery of xanthohumol and cirsilineol as multi-target natural therapeutics for type 2 diabetes: computational prediction and experimental validation.

Junyu Zhou, Chen Li, Meiling Liu +1 more

Type 2 diabetes mellitus (T2DM) requires multi-target therapeutic approaches addressing both insulin resistance and insulin secretion deficits. Although natural compounds are promising multi-target candidates, systematic identification of their polypharmacological profiles remains challenging. The objective of this study was to establish a computational framework for identifying natural compounds with multi-target therapeutic potential against T2DM through integrated structure-activity analysis and experimental validation. We developed an SELFormer deep learning model to predict natural compound activities against six T2DM-related proteins including glucagon-like peptide-1 receptor (GLP1R), kinesin family member-11 (KIF11) for insulin secretion and insulin receptor (INSR), peroxisome proliferator-activated receptor-gamma (PPARG), fibroblast growth factor receptor-1 (FGFR1) and insulin-like growth factor-1 receptor (IGF1R) for insulin resistance. Uniform Manifold Approximation and Projection (UMAP) for dimension reduction clustering characterized chemical space distributions and molecular docking validated multi-target binding. Selected compounds were experimentally validated using 3T3-L1 adipocytes and mouse insulinoma (MIN6) pancreatic β-cells. The SELFormer model achieved R2 = 0.937 and RMSE = 0.331 on the training dataset and R2 = 0.918 and RMSE = 0.353 on the testing dataset, with minimal overfitting (ΔR2 = 0.019). Among approximately two million screened compounds, 35 natural compounds demonstrated high predicted activity (pIC50 > 7), clustering into eight distinct chemical families. Multi-target network analysis and molecular docking identified curcumin, xanthohumol, hesperetin, (-)-epicatechin, and cirsilineol as lead candidates with favorable binding energies ranging from -7 to -10 kcal mol-1 across the six targets. Food source analysis identified strawberries, grapes, and tea as rich dietary sources of these bioactive compounds. In 3T3-L1 adipocytes, all five compounds significantly enhanced insulin-stimulated glucose uptake at 10 μM, achieving efficacy comparable to that of metformin. In MIN6 cells, xanthohumol and cirsilineol increased glucose-stimulated insulin secretion to levels comparable to exendin-4, while curcumin, hesperetin, and (-)-epicatechin produced modest but significant increases. In conclusion, this integrated computational and experimental framework identified food-derived natural compounds with validated dual-pathway therapeutic activity against T2DM, providing a systematic and reproducible methodology for multi-target drug discovery in complex metabolic disorders.

Human Umbilical Cord Blood Mesenchymal Stem Cells Ameliorate Autism-Like Behaviors in a Valproic Acid-Induced Mouse Model via the IGF-1/Akt Signaling Pathway.

Jie Tian, Hujing Deng, Zhoujing Hu +9 more

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that significantly impacts children's physical and mental health, yet effective pharmacological treatments remain limited. The primary objective of this study was to investigate the therapeutic effects of human umbilical cord blood mesenchymal stem cells (hUC-MSCs) on ASD, evaluate the safety profile of hUC-MSCs, and elucidate their underlying mechanisms and functional roles.

Oncocytic adrenocortical carcinomas: A clinicopathological and immunohistochemical review of 14 cases of a rare entity.

Niraj Kumari, Amit Agarwal, Navneet Tripathi +2 more

Oncocytic subtypes of adrenocortical carcinomas are rare tumor entities, with relatively better prognosis than the conventional subtype. Owing to its rarity, oncocytic adrenocortical carcinomas (OACCs) have not been studied extensively. The study aims to analyze the clinicopathological and therapy-relevant immunohistochemical profile of OACC.

Identification of a small-molecule targeting PLAGL2 DNA-binding domain inhibits extracellular matrix formation and enhances lenvatinib sensitivity in hepatocellular carcinoma.

Weiwei Hu, Jiaping Ni, Shufang Zheng +15 more

The increased stiffness of the extracellular matrix (ECM) is known to promote the progression of hepatocellular carcinoma (HCC). Currently, there are no approved therapies for targeting ECM sensors and remodelers. The objective of this study was to identify the molecular mechanisms underlying the role of Pleomorphic adenoma gene-like 2 (PLAGL2) in HCC ECM remodeling and to formulate compounds that effectively inhibit PLAGL2 transcriptional regulation. Our work revealed that PLAGL2 remodeled the ECM produced by HCC cells via an autocrine mechanism and activated HSCs via a paracrine pathway. Mechanistically, PLAGL2 functioned as a transcriptional regulator of insulin-like growth factor 2 (IGF2) and insulin-like growth factor 1 receptor (IGF1R). IGF2 enhanced ECM remodeling by HCC cells and activated HSCs through the IGF1R-PI3K-Akt signaling pathway. Furthermore, using a computer-aided drug design strategy, a novel compound, DC218, derived from the chemical evolution of cytisine, has been developed for the first time to exhibit specificity as an inhibitor of the PLAGL2 DNA binding domain. DC218 significantly degraded ECM, overcame lenvatinib resistance, and synergistically inhibited HCC. These findings provide mechanistic insight into the role of PLAGL2 in HCC ECM remodeling, as well as suggest a novel strategy for inhibiting ECM and treating HCC.

Myrtenol from Lavender Essential Oil Possesses Neuroprotective Effects and Promotes Neurite Outgrowth by Potentially Targeting TrkA and IGF-1R in PC12 Cells.

Ting Jiang, Lan Xiang, Jianhua Qi

Alzheimer's disease (AD) is a prevalent chronic neurodegenerative disorder; the progression of this disease is driven by cellular determinants such as oxidative stress and dysregulated neurotrophic signaling. Lavender essential oil is traditionally used in aromatherapy for neuronal regulation and neuroprotection, suggesting its potential neuroprotective effects for chronic neurodegenerative disorders like AD. However, the key active constituents responsible for its benefits and the specific molecular pharmacological mechanisms remain unclear. In this study, we isolated myrtenol from lavender essential oil under the guidance of activity evaluation. Its neuroprotective effects were evaluated in PC12 cells via neurite outgrowth, anti-Aβ/H2O2 cytotoxicity, and antioxidant assays. Targets and pathways were explored using inhibitor experiments, cell thermal shift assay (CETSA), drug affinity responsive target stability (DARTS), and Western blot. Myrtenol significantly induced neurite outgrowth in PC12 cells and effectively mitigated cytotoxicity and oxidative stress damage induced by Aβ25-35 and H2O2. Mechanistic studies revealed that myrtenol's effects are associated with the modulation of tyrosine kinase receptor A (TrkA) and insulin-like growth factor-1 receptor (IGF-1R), activating phospholipase C (PLC)/protein kinase C (PKC) and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathways to jointly mediate neuroprotection effects against the pathology of AD. This study demonstrates that myrtenol as a highly active component of lavender essential oil possesses NGF-like neuritogenic activity and neuroprotective effects. It provides a foundation for understanding the cellular mechanisms of myrtenol as a small-molecule lead for further investigation in neurodegeneration-related research.

Mechanisms of Rat Gastrocnemius Muscular Atrophy Induced by Hindlimb Unloading.

Lingying Liu, Yaoyuan Cui, Ruipeng Wu +2 more

Muscle atrophy is a critical health challenge during spaceflight. This study investigated the mechanism of muscle atrophy induced by 21-d hindlimb unloading (HLU) and metabolomic changes in rat gastrocnemius muscle (GM) and plasma.

Bovine respiratory syncytial virus utilizes the human insulin-like growth factor 1 receptor in the late stages of infection.

Sodbayasgalan Amarbayasgalan, Tatsuki Takahashi, Yoshiro Sugiura +4 more

Bovine respiratory syncytial virus (BRSV) is a major viral pathogen associated with the bovine respiratory disease complex, which is a leading cause of morbidity, mortality and economic loss in the cattle industry worldwide. Clinical infection is most severe in young calves, where it commonly causes lower respiratory tract inflammation, bronchopneumonia and predisposition to secondary bacterial infections. In experimental research, BRSV is typically maintained in Vero and MDBK cells. Although reverse genetics systems have been established for BRSV, we developed a bacterial artificial chromosome-based reverse genetics system for the virus. We successfully recovered a recombinant BRSV with the ZsGreen reporter gene inserted between the P and M genes. The recombinant virus displayed comparable growth kinetics to the WT strain, demonstrating the utility of the system for generating reporter viruses. Reporter virus infectivity assessments in mammalian MDBK, VeroE6, HEp-2 and HEK293T cells revealed that HEK293T cells are permissive to BRSV. To investigate the potential role of human insulin-like growth factor 1 receptor (hIGF1R), which human RSV uses for entry, we infected insulin-like growth factor 1 receptor (IGF1R)-knockout (KO) 293 T cells with BRSV-ZsGreen. At 24 h post-infection (hpi), ZsGreen levels were similar between WT and hIGF1R-KO cells; however, by 72 hpi, viral spread was markedly reduced in hIGF1R-KO cells and correlated with IGF1R levels. These findings suggest that IGF1R is dispensable for early BRSV infection but contributes to efficient viral propagation in later stages.

Network analysis-guided drug repurposing: IGF1R as a novel melanoma target and therapeutic potential of dapagliflozin.

Fatemeh Hajipour, Melika Alesheikh, Maliheh Safavi +3 more

Skin Cutaneous Melanoma (SKCM) is an aggressive malignancy requiring novel therapeutic targets.

miR-133a-3p promotes T-2 toxin-induced chondrocyte damage via targeting IGF1R.

Kangting Luo, Lingyu Wang, Zhengyan Zhang +13 more

T-2 toxin is one of the important environmental risk factors of Kashin-Beck disease, which seriously damages cartilage. The present study employed miRNAs to investigate the toxic mechanism of T-2 toxin. In this study, miR-133a-3p was highly expressed in cartilage tissue lesions and chondrocyte damage induced by T-2 toxin. Overexpression of miR-133a-3p promoted T-2 toxin-induced extracellular matrix degradation and apoptosis of chondrocytes. However, inhibition of miR-133a-3p had the opposite effect. These results revealed that miR-133a-3p was involved in regulating T-2 toxin-induced chondrocyte damage. Bioinformatics analysis and dual luciferase assay demonstrated that IGF1R was targeted by miR-133a-3p. The small interfering RNA of IGF1R (Si- IGF1R) promoted T-2 toxin-induced chondrocyte damage. The miR-133a-3p mimics/inhibitor and Si-IGF1R were co-transfected into chondrocytes, and the results showed that the miR-133a-3p mimics strengthened the effect of Si-IGF1R, contrary to the effect of miR-133a-3p inhibitor. In conclusion, miR-133a-3p promoted T-2 toxin-induced chondrocyte damage via targeting IGF1R.

MUC15 loss promotes perineural invasion in pancreatic cancer by activating the IGF1R/STAT3/NGF pathway.

Simei Zhang, Tao Qin, Shuai Wu +12 more

Perineural invasion (PNI) is a critical yet poorly understood feature that significantly influences the prognosis of pancreatic ductal adenocarcinoma (PDAC), a disease notorious for its dismal survival rates. Although PNI is recognized as a hallmark of pancreatic cancer, the molecular mechanisms underlying this process remain complex and incompletely defined. Recent insights into tumor-nerve interactions have highlighted the role of glycocalyx components, particularly mucin 15 (MUC15), in regulating neural invasion. In this study, we demonstrate that loss of MUC15 promotes PNI by activating the IGF1R/STAT3/NGF signaling axis. Specifically, reduced MUC15 expression weakens its interaction with IGF1R, leading to decreased receptor ubiquitination and increased phosphorylation, which in turn activates STAT3 signaling and drives NGF transcription and secretion. Loss of MUC15 also promotes epithelial-mesenchymal transition (EMT) and alters interactions with the tumor microenvironment, further facilitating neural invasion. Importantly, pharmacologic inhibition of IGF1R reverses these effects, suggesting that restoring MUC15 expression or targeting the IGF1R/STAT3-NGF axis may represent a potential therapeutic strategy to limit PNI in pancreatic cancer. These findings reveal a novel regulatory pathway connecting tumor-intrinsic signaling, EMT, and the neural microenvironment in PDAC progression.

Pyrroloquinoline quinone alleviates age-related osteoarthritis via nuclear factor erythroid 2-related factor 2-mediated stress response and insulin-like growth factor 1 receptor upregulation.

Qi Xue, Yueqiang Gu, Ran Qin +8 more

Age-related knee osteoarthritis (OA) arises from cumulative oxidative damage, chondrocyte senescence and extracellular matrix loss; yet safe and effective disease‑modifying interventions for aging‑associated OA are lacking. Pyrroloquinoline quinone (PQQ; molecular formula C14H6N2O8) is a naturally bioactive compound that has been reported to activate nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor that regulates antioxidant and cytoprotective gene expression. However, its effects on age-related OA and the underlying mechanisms remain unclear.

Insulin-like growth factor 1 receptor (IGF1R)-dependent signaling regulates blastocyst formation during early embryonic development.

Chi-Hun Park, Young-Hee Jeoung, JiTao Wang +1 more

Insulin-like growth factor 1 (IGF1) signaling is a conserved regulator of embryonic growth and survival. However, the specific role of IGF1 signaling mediated by its cognate receptor IGF1R during mammalian preimplantation development remains unclear and unexplored. In this study, we employed both genetic ablation using cytidine deaminase base editors and pharmacological inhibition to assess the role of IGF1R in porcine early embryonic development. Embryos lacking IGF1R advanced through early cleavage divisions and progressed to blastocyst formation; however, they displayed delayed blastocyst development and significantly increased apoptosis. Lineage segregation was largely unperturbed. Exogenous IGF-1 supplementation did not ameliorate developmental impairments in IGF1R-knockout embryos and instead exacerbated apoptotic responses when receptor signaling was compromised. Collectively, these results establish that IGF1R signaling is dispensable for cell fate specification but is crucial for regulating blastocyst growth dynamics and embryonic viability.

Insulin receptor trafficking and interactions in muscle cells.

Haoning Howard Cen, Aurora J Mattison, Alireza Omidi +7 more

Insulin action is critical for energy homeostasis and its dysfunction in muscle cells is associated with type 2 diabetes. Insulin receptor (INSR) internalization and cell-surface dynamics at rest and during insulin exposure are incompletely understood in muscle cells.

Beyond the Eyes: Is Teprotumumab Effective for Thyroid Dermopathy?

Dana Hamadi, Suhail Saad-Omer, David Toro-Tobon +1 more

Pretibial dermopathy (PTD) is a rare, disfiguring manifestation of Graves' disease. The shared pathophysiology with thyroid eye disease (TED), centered on fibroblast activation via a thyroid-stimulating hormone receptor and insulin-like growth factor-1 receptor (IGF-1R) complex, provides a strong rationale for using the IGF-1R inhibitor, teprotumumab.

Redefining evidence for teprotumumab in thyroid eye disease: an updated meta-analysis of efficacy and safety.

Rongjing Song, Wei Zhao, Shasha Li +5 more

Thyroid eye disease (TED) is a sight-threatening autoimmune disorder with limited effective therapies. Teprotumumab, an insulin-like growth factor-1 receptor inhibitor, has emerged as a promising treatment. However, a comprehensive synthesis of its efficacy and safety across randomized trials remains limited.

Peripheral and CSF protein quantification in Parkinson's disease and multiple system atrophy-the nucleic acid-linked immuno-sandwich assay.

Nirosen Vijiaratnam, Christine Girges, Arthur Mitchell +13 more

There are currently no validated peripheral biomarkers for the diagnosis, differentiation or progression of the neurodegenerative synucleinopathies, Parkinson's disease and multiple system atrophy. Diagnostic biomarkers that reflect the disease mechanisms or progression biomarkers that change with disease severity would be extremely valuable for assessing disease-modifying therapies. Our objective was to explore putative protein biomarkers of Parkinson's disease and multiple system atrophy, in relation to clinical disease severity, using the nucleic acid-linked immuno-sandwich assay central nervous system disease panel for biomarker quantification. We used the nucleic acid-linked immuno-sandwich assay CNS disease panel to test plasma from 161 Parkinson's disease patients collected at three time points (0, 48, 96 weeks) and serum from 43 multiple system atrophy patients at three time points (0, 24, 48 weeks) and compared results to paired plasma and serum samples collected from (n = 39) age-matched healthy control individuals at a single time point. We also tested paired CSF samples collected on two occasions, separated by 96 weeks from a subgroup of Parkinson's disease participants (n = 51) and after an interval of 48 weeks in a subgroup of multiple system atrophy participants (n = 23). All samples were taken contemporaneously with objective clinical assessments of disease severity. Biomarker comparisons were made across disease status and in relation to disease severity using linear modelling. Multiple proteins showed significantly different quantitative levels (false discovery rate-corrected P value < 0.05) between peripheral samples from Parkinson's disease and healthy controls and multiple system atrophy and healthy controls. For Parkinson's disease, we identified three key classes of proteins that showed significant differences between Parkinson's disease and controls: (i) amyloidogenic proteins, specifically, oligomeric alpha-synuclein was significantly higher in Parkinson's disease compared to controls. A number of other aggregating proteins also exhibited differences. (ii) Metabolic pathways, including the adipokine (chemokine-like protein TAFA-5), were associated with Parkinson's disease diagnosis, and (iii) inflammatory pathways (interleukin-7) were associated with Parkinson's disease diagnosis. Importantly, some of these same proteins were significantly associated with Parkinson's disease severity including oligomeric and phosphorylated forms of alpha-synuclein and insulin-like growth factor-1 receptor. We also confirmed as expected that neurofilament light levels strongly distinguish multiple system atrophy patients from healthy controls, while also demonstrating that serum inflammatory proteins (interleukin-6) as well as the phosphorylated alpha-synuclein ratio are strongly associated with multiple system atrophy severity. These results from the nucleic acid-linked immuno-sandwich assay multiplex platform provide additional insights into the complex pathogenetic mechanisms associated with alpha-synucleinopathy related neurodegeneration. Individual protein levels or the combination of multiple protein candidates may usefully serve as diagnostic biomarkers, or as biomarkers for disease progression in trials of potential disease-modifying interventions.

A Deep Learning Framework for Predicting Teprotumumab Treatment Response in Thyroid Eye Disease.

Saul Langarica, Nahyoung Grace Lee, Adham M Alkhadrawi +4 more

To develop and evaluate a deep learning-based framework for quantifying thyroid eye disease (TED) severity before and after teprotumumab treatment, an insulin-like growth factor-1 receptor inhibitor, and to create a predictive model for forecasting individual patient responses to therapy.

The therapeutic revolution in thyroid eye disease: from orbital radiotherapy to teprotumumab and AI.

XiaoLi Yuan, Han Li, Feng Wang

Thyroid eye disease (TED) is a vision-threatening and quality-of-life-impairing manifestation of autoimmune thyroid disease, driven by orbital fibroblast activation, inflammation, and tissue remodeling. This review synthesizes current evidence on TED epidemiology and pathogenesis, with a particular focus on the pathogenic synergy between the thyrotropin receptor (TSHR) and the insulin-like growth factor-1 receptor (IGF-1R). We discuss how this receptor complex propagates intracellular signaling that leads to disease hallmarks: fibroblast proliferation, glycosaminoglycan secretion, and adipogenesis. While we outline the established paradigm of management-encompassing glucocorticoids, orbital radiotherapy, and surgery-a key emphasis is placed on the recent therapeutic revolution ushered in by targeted biological agents, most notably IGF-1R inhibition. As well as research on new targets for immunotherapy such as Tregs and other aspects such as IL-6 or TNF-α. Finally, we explore the nascent role of artificial intelligence in refining diagnosis and prognostic assessment. This overview aims to equip clinicians and researchers with a forward-looking perspective on the evolving landscape of TED management.

Beyond the membrane: Internalization and compartmentalization of insulin‑like growth factor 1 receptor signaling in cancer pathogenesis and treatment (Review).

Tiehong Zhang, Ling Li, Chunling Du

The insulin‑like growth factor 1 receptor (IGF‑1R) plays a central role in tumor initiation, progression and response to treatment. IGF‑1R internalization and compartmentalization have profound effects on tumor biology, extending beyond classical signaling associated with receptors at the cell membrane. Following internalization, IGF‑1R alters its intracellular localization and induces new signaling functions. These changes affect the duration and spatial dynamics of signal activation, thereby influencing tumor cell proliferation, migration and the development of drug resistance. However, the exact molecular mechanisms that mediate these processes remain elusive, and the inherent complexity of the downstream signaling network continues to limit the clinical translation of IGF‑1R‑targeted therapies. The present review systematically summarizes the current knowledge on the molecular mechanisms of IGF‑1R internalization and compartmentalization, highlighting their roles in tumor progression and treatment response. The recent advancements and persistent challenges in this field are also critically discussed, aiming to provide a theoretical foundation and new insights for the development of more efficient and effective therapeutic plans that specifically target IGF‑1R.

Styrylquinoline Derivatives as IGF1R Inhibitors.

Patryk Zioła, Katarzyna Malarz, Marcin Pacholczyk +4 more

Styrylquinoline analogues exhibiting antiproliferative activity against glioblastoma multiforme were tested for tyrosine kinase inhibition. A preliminary structure activity relationship analysis based on previous results showed that the styrylquinoline fragment is a promising privileged structure. The addition of appropriate pharmacophores to both the quinoline structure and the benzene ring, which was attached to the 2-position, significantly altered the antiproliferative properties. Namely, OH or NO2 substituents had a positive effect on activity, while F and OAc molecular fragments had a negative impact. Screening conducted on a panel of receptor tyrosine kinases revealed the high potential of the tested compounds for use as insulin-like growth factor 1 receptor inhibitors. Molecular docking performed on the insulin-like growth factor 1 receptor unphosphorylated inactive conformation supports screening results suggesting high binding affinity of the active styrylquinoline derivatives.

Mechanism of Scoparone Against Knee Osteoarthritis: A Study Integrating Network Pharmacology, Animal Experiments, and Molecular Docking.

Linshuai Shi, Lei Zhao, Xinqi Li +2 more

Knee osteoarthritis (KOA) is a degenerative joint disease commonly seen in middle-aged and elderly individuals. With the increasing aging population, the incidence of KOA has been rising annually, yet there remains no definitive cure. Studies have shown that scoparone exhibits potent anti-inflammatory effects in treating inflammatory diseases, but its specific mechanism in KOA remains unclear. Network pharmacology was employed to systematically predict the putative therapeutic targets and signaling pathways of scoparone against KOA. The resulting candidate genes and pathways were subsequently examined by molecular docking and then experimentally verified in a well-established KOA mouse model. ELISA, HE staining, immunohistochemical staining, and western blot were used to detect the expression of related factors. Network pharmacology analysis initially identified 15 intersecting target genes of scoparone in the treatment of KOA. These target genes were primarily enriched in 46 signaling pathways, with the most significant involvement in focal adhesion, Ras-related protein 1 (RAP1) signaling pathway, high-affinity IgE Fc receptor (FcεRI) signaling pathway. Molecular docking results revealed that prostaglandin-endoperoxide synthase 2 (PTGS2), insulin-like growth factor 1 receptor (IGF1R), and cathepsin K (CTSK) exhibited the highest binding affinity with scoparone. Animal experiments demonstrated that scoparone reversed the abnormal expression of PTGS2, IGF1R, and CTSK in the knee cartilage of KOA mice. Additionally, scoparone suppressed inflammation and extracellular matrix degradation in KOA mice by modulating the RAP1 signaling pathway and the FcεRI/spleen tyrosine kinase (Syk) signaling pathway. These findings provide a critical theoretical foundation for further research and development of scoparone in the treatment of KOA.

HOTAIR promotes the progression of B-cell acute lymphoblastic leukemia by regulating the miR-326/IGF-1R axis and activating the PI3K/AKT signaling pathway.

Xue-Mei Zhao, Ya-Qin Jiang, Xin Wen +8 more

B-cell acute lymphoblastic leukemia (B-ALL) is an aggressive hematological malignancy. Long non-coding RNAs (lncRNAs) play important roles in hematological diseases; nevertheless, their mechanistic contributions to B-ALL are still poorly defined.

Systemic Effects of Teprotumumab Treatment on Thyroid Function in Patients With Thyroid Eye Disease: A Retrospective Study.

Rafaella C Penteado, Suzan Sargsyan, Leo L T Meller +5 more

Teprotumumab, a monoclonal antibody targeting the insulin-like growth factor-1 receptor, has demonstrated significant efficacy in treating thyroid eye disease. While its ophthalmic benefits are well established, limited data exist regarding its effects on thyroid hormone regulation.