In the study published in the BMC Cardiovascular Disorders, researchers from Peking University have identified potential therapeutic candidates for CryAB(R120G)-related cardiomyopathy. This is a genetic condition characterized by protein misfolding, fibrosis, and heart failure. In this study, a transgenic mouse model was used to combine transcriptomic profiling with in-silico drug screening.

The CryAB(R120G) mutation leads to the accumulation of insoluble protein aggregates in cardiac tissue, impairing heart function and triggering remodeling. RNA sequencing of affected mice revealed 174 differentially expressed genes, with disruptions in pathways regulating circulation, metabolism, and muscle fiber regulation. Protein-protein interaction analysis shortlisted nine hub genes, including SCN5A, DHTKD1, and HSPA1B, as critical regulators of disease progression.

The Connectivity Map database was used to screen compounds capable of reversing the pathological gene expression profile. Out of 68 promising drugs, nortriptyline ranked highest, showing strong binding affinity with SCN5A in molecular docking simulations. Torin-1, an mTOR inhibitor, and cilostazol, a PDE3 inhibitor, also showed therapeutic potential. It was found that phosphodiesterase (PDE) family proteins emerged as the most frequent targets.  This indicates their central role in modulating protein homeostasis and cardiac remodeling.

While nortriptyline displayed the most favorable interaction, it has known cardiac risks, including arrhythmia. Therefore, further research is needed to evaluate its safety and confirm its efficacy.