Abstract 4359493: PRECISION TARGETING OF CORIN AND FURIN: A TRANSLATIONAL LEAP IN HEART FAILURE AND HYPERTENSION THERAPY

Background: Heart failure and hypertension remain leading causes of morbidity and mortality worldwide. Proteolytic regulation of natriuretic peptides (NPs) by corin and furin is essential for cardiovascular homeostasis. Dysregulation of these proteases, due to genetic variants or altered expression, contributes to salt-sensitive hypertension, myocardial fibrosis, and heart failure. Despite promising preclinical data, these enzymes remain underexplored as therapeutic targets. Hypothesis: Selective targeting of corin and furin, guided by integrative multi-omics and population-specific genotyping, can restore NP signaling and improve outcomes in heart failure and hypertension. Goals: This study aimed to (1) assess the translational potential of corin and furin modulation, (2) characterize therapeutic candidates including recombinant proteins and inhibitors, and (3) evaluate genotype-informed strategies for precision medicine. Methods: Multi-omics analyses of human cardiovascular tissues integrated transcriptomic, proteomic, and single-cell data to define cell-specific expression of corin and furin. Functional genomics and in silico modeling mapped substrate networks and predicted therapeutic responses. Preclinical hypertension and heart failure models evaluated corin replacement, furin inhibitors, and RNA-based silencing. Variant-specific effects were studied in stratified mouse cohorts expressing human CORIN alleles. Results: Corin deficiency impaired ANP processing, reduced cGMP, and raised blood pressure in mice; recombinant corin restored NP signaling and reduced hypertrophy. Furin inhibitors (α1-PDX, decanoyl-RVKR-CMK) decreased atherosclerosis and improved remodeling without toxicity. RNA interference against furin reduced monocyte proliferation and suppressed TGF-β1 activation. Human data confirmed cell-specific protease expression and high-frequency deleterious CORIN variants in African and Southeast Asian populations. Multi-omics network analysis predicted enhanced efficacy of ENaC blockers in corin-deficient phenotypes. Conclusion(s): Targeted modulation of corin and furin offers a novel, mechanism-based approach for heart failure and hypertension. Recombinant corin, furin inhibitors, RNA therapeutics, and gene editing show strong preclinical potential. Integration of multi-omics and genotyping supports personalized therapy and rapid translational development of corin- and furin-based precision interventions.