Exploring IGF1R as a New Therapeutic Target in Myasthenia Gravis

A recent study published in CNS Neuroscience & Therapeutics explores new biological pathways underlying myasthenia gravis (MG)​. Building on previous observations of oxidative stress involvement in neuromuscular disorders, the researchers investigated the potential roles of uric acid (UA) and the type 1 insulin-like growth factor receptor (IGF1R), which is a key regulator of muscle repair and neuronal survival, in MG development and progression.

Through meta-analytic, genetic, clinical, and pharmacological approaches, the study proposes IGF1R as a novel protective factor and therapeutic target.

Study Design: A Multilayered Approach

This study used a multi-layer approach to identify and validate UA’s significance in MG, utilizing:

• Meta-analysis: Six studies pooled; random-effects modeling due to moderate heterogeneity (I² = 69 percent).
• Mendelian Randomization: Used European and Asian GWAS datasets along with an MG dataset for genetic investigation; genetic instruments were validated for lack of pleiotropy.
• Clinical cohort: Serum from 83 MG patients was measured for IGF1R by ELISA. Patients with hyperuricemia were excluded.
• Bioinformatics: TCGA and GEO public datasets were used for an RNA sequencing analysis to investigate the relationship between IGF1R and UA in MG patients.
• Drug Discovery: Virtual screening of the DrugBank library, followed by molecular docking targeting IGF1R.

Uric Acid and Myasthenia Gravis

The study began with a meta-analysis of six clinical studies, totaling 683 MG patients and 908 controls. The findings demonstrated significantly lower serum UA levels among MG patients compared to controls (mean difference of −48.46; p<0.00001).

Given UA’s recognized role as an endogenous antioxidant, these results prompted further investigation into a potential causal relationship.

Using two-sample Mendelian randomization with European and Asian GWAS datasets, the researchers identified a genetic association between decreased UA levels and higher risk for MG (p=0.024 and p=0.036, respectively). These analyses were robust, with no evidence of significant heterogeneity or horizontal pleiotropy.

Identification of IGF1R as a Key Molecular Mediator

Bioinformatics analyses, including pathway enrichment and protein–protein interaction networks, identified IGF1R as a principal gene linking UA levels and MG risk. IGF1R was selected for further validation based on its role in muscle maintenance and antioxidant defense mechanisms.

Evaluation of RNA sequencing data from the TCGA thymoma cohort revealed significantly lower IGF1R expression among MG patients compared to non-MG thymoma cases (p<0.05).

Prognostic analyses indicated that higher IGF1R expression was associated with better clinical outcomes. Single-cell RNA sequencing from two GEO datasets (GSE227835 and GSE222427) reinforced these findings, showing lower IGF1R expression in MG patients and upregulation after crisis treatment (p<0.05).

Clinical Correlations and Potential Implications

Among 83 MG patients enrolled prospectively, higher IGF1R expression correlated with higher UA levels (p<0.05) and milder clinical phenotypes, including a greater proportion of ocular MG cases and lower MGFA scores (p<0.05). No significant differences were observed in age of onset, disease duration, or thymoma presence between high and low IGF1R expression groups.

These findings propose that higher IGF1R expression may mitigate disease severity, potentially by enhancing muscle resilience and counteracting oxidative injury at the neuromuscular junction.

Therapeutic Exploration: Small Molecule Candidates Targeting IGF1R

Through virtual screening and molecular docking of over 10,000 small molecules from the DrugBank database, several candidates were identified with strong binding affinities to IGF1R. Notable molecules included Bizelesin, Phthalocyanine, Murizatoclax, and Midostaurin.

Although further experimental validation is required, these compounds may lead to a potential therapeutic avenue for modulating IGF1R activity to ameliorate MG symptoms.

Conclusion

This study presents new evidence linking reduced UA levels and lower IGF1R expression with the risk and severity of myasthenia gravis. While IGF1R emerges as a promising biomarker and therapeutic target, further experimental studies are necessary to validate these findings.

Reference

Shen Y, Pang L, Wang H, et al. Comprehensive Analysis of Uric Acid and Myasthenia Gravis: IGF1R as a Protective Factor and Potential Therapeutic Target. CNS Neurosci Ther. 2025;31(3):e70361. doi:10.1111/cns.70361