Circulating biomarkers in serum from aortic valve stenosis patients predict sex-specific drug responses in valve myofibroblasts

Aortic valve stenosis (AVS) is a prevalent, sexually dimorphic cardiovascular disease characterized by fibro-calcification of the aortic valve leaflet. Sex differences in AVS arise in part from sexually dimorphic serum composition that differentially regulate valvular interstitial cell (VIC) myofibroblast activation. However, how individual serum factors contribute to sex-specific drug responses targeting VIC myofibroblast activation remains unknown. Here, we integrate serum proteomic profiling with in vitro drug screening using hydrogel biomaterials to identify sex-specific regulators of antifibrotic drug efficacy. We found that Insulin-like Growth Factor Binding Protein 2 (IGFBP2) serum levels are associated with resistance to the antifibrotic drug Evogliptin only in female VICs cultured with female AVS serum. This mechanism is driven by IGFBP2-mediated activation of Rho/ROCK and focal adhesion kinase signaling pathways that counteract Evogliptin treatment. Our findings reveal a sex-specific, serum-mediated mechanism of Evogliptin resistance and highlight IGFBP2 as a candidate biomarker for stratifying female AVS patients for Evogliptin treatment. More broadly, these findings underscore the importance of incorporating sex-stratified biomarker analyses into AVS therapeutic development to improve patient-specific treatment recommendations.