Identification of biomarkers in myocardial hypertrophy and fibrosis via integrated transcriptomic and phosphoproteomic profiling.

Myocardial hypertrophy and fibrosis (MHF) are key structural changes in adverse cardiac remodeling. They are commonly observed in hypertension, metabolic disorders, and cardiomyopathies. These processes contribute to heart failure and sudden death, yet their molecular mechanisms remain unclear. We established in vivo and in vitro models of MHF and performed transcriptomic and label-free phosphoproteomic sequencing. These data were integrated with public single-cell RNA sequencing datasets. This multi-tier strategy enabled us to move beyond bulk-tissue signals and prioritize candidates based on cross-omics concordance and cell-type-specific expression. We identified five candidate biomarkers, CLIP2, PLA2G4A, PRRX1, SLAIN2, and XPO1. These candidates showed coordinated upregulation or downregulation at both the transcriptomic and phosphoproteomic levels. They were also specifically enriched in disease-relevant cardiac cell populations, including cardiomyocytes and fibroblasts. PRRX1 and PLA2G4A were enriched in fibrogenic fibroblast subsets and increased along activation trajectories. XPO1 and SLAIN2 were downregulated in cardiomyocytes and fibroblasts, suggesting impaired nuclear export and cytoskeletal regulation. Molecular docking revealed flurandrenolide and selinexor as potential modulators of PLA2G4A and XPO1 respectively. However, their cardiovascular safety and efficiency remain uncertain. Notably, the therapeutic implications of XPO1 modulation appear context-dependent, warranting careful evaluation of its functional role in specific MHF etiologies. Overall, these findings highlight novel targets and provide mechanistic insights into MHF progression.