ProteotoxomiRs: Diagnostic and pathologic miRNA signatures for reductive stress induced proteotoxic heart disease

• DOI: 10.1016/j.redox.2025.103525
• Publication Date: 2025-02-04T17:22:24Z
• Authors: Santhosh Kumar Ka...; Palanisamy Nallasamy; Jarrell Matthew C...; Ahila Arulmani; Ashvanthi Raveendran; Mariam Karimi; Mohammad Owais An...; Anil Kumar Challa; Moorthy P. Ponnusamy; Ivor J. Benjamin; Sooryanarayana Va...; Namakkal S. Rajas...
• Keywords: ProteotoxomiRs; Medicine (General); R5-920; Cardiomyopathy; QH301-705.5; Protein aggregation; Biology (General); Reductive stress; miRNA

Proteotoxic stress progressively leads to irreversible cardiac abnormalities. Using a mouse model of reductive stress-induced proteotoxic cardiomyopathy, we identified novel microRNA signatures, termed "ProteotoxomiRs," which reflect stage-specific and transgene-specific responses stress. Seven microRNAs were uniquely linked the human mutant R120G-αB-Crystallin transgene, indicating their direct association with pathogenic protein. Additionally, uncovered two distinct profiles associated early (pre-onset) late (cardiomyopathy/heart failure) stages disease progression. Early-stage signatures primarily modulate signaling pathways essential for health, including mTOR MAPK, while late-stage reveal regulatory disruptions in calcium autophagy insufficiency, driving damage caused by (RS) proteotoxicity transgenic mice. These findings miRNA biomarkers potential diagnostic prognostic value, offering new insights into molecular underpinnings disease. Moreover, our miRNA-mRNA interaction analysis targets unique transgene-specific, early, disease, several promising druggable candidates, warranting further validation translational applications.