Sangkyun Cho, PhD
Johns Hopkins University
Precision Mechanotherapies for Treating Cardiovascular Fibrosis
Fibrosis is a major contributor to virtually all forms of cardiovascular disease, yet effective therapies remain elusive, in part due to: (i) the lack of fibroblast-specific druggable targets, and (ii) an often-overlooked feedback loop in which the stiffened scar microenvironment perpetuates the activation of fibroblasts—the very cells that drive fibrotic remodeling. Here, we present a strategy that addresses these two critical bottlenecks simultaneously. We first identify SRC as a new druggable mechanosensor that is uniquely enriched in cardiac fibroblasts and is activated ~8-fold in the fibrotic myocardium. Using an AI-assisted in silico drug screen of >10,000 compounds, we pinpoint the orphan drug, saracatinib, as a top candidate SRC inhibitor. When combined with existing drugs targeting TGF-beta, saracatinib treatment in myofibroblasts potentiates a robust transcriptomic, metabolic, and morphological reversal towards quiescence, mimicking the effects of dynamic light-induced hydrogel softening. Importantly, the drug combination’s effects are synergistic, attributable to its acute inhibition of the MRTFA-SRF pathway. Beyond modulation of fibroblast states, this two-hit treatment suppresses fibrosis and restores contractile function in 3D engineered tissues and in pressure-overloaded mouse hearts. Our findings thus point to joint inhibition of SRC-mediated stromal mechanosensing and TGF-beta signaling as a potential mechanotherapeutic strategy for treating cardiac fibrosis.
Fibrosis is a major contributor to virtually all forms of cardiovascular disease, yet effective therapies remain elusive, in part due to: (i) the lack of fibroblast-specific druggable targets, and (ii) an often-overlooked feedback loop in which the stiffened scar microenvironment perpetuates the activation of fibroblasts—the very cells that drive fibrotic remodeling. Here, we present a strategy that addresses these two critical bottlenecks simultaneously. We first identify SRC as a new druggable mechanosensor that is uniquely enriched in cardiac fibroblasts and is activated ~8-fold in the fibrotic myocardium. Using an AI-assisted in silico drug screen of >10,000 compounds, we pinpoint the orphan drug, saracatinib, as a top candidate SRC inhibitor. When combined with existing drugs targeting TGF-beta, saracatinib treatment in myofibroblasts potentiates a robust transcriptomic, metabolic, and morphological reversal towards quiescence, mimicking the effects of dynamic light-induced hydrogel softening. Importantly, the drug combination’s effects are synergistic, attributable to its acute inhibition of the MRTFA-SRF pathway. Beyond modulation of fibroblast states, this two-hit treatment suppresses fibrosis and restores contractile function in 3D engineered tissues and in pressure-overloaded mouse hearts. Our findings thus point to joint inhibition of SRC-mediated stromal mechanosensing and TGF-beta signaling as a potential mechanotherapeutic strategy for treating cardiac fibrosis.
