Aortic valve stenosis serum IGFBP2 mediates female-specific Evogliptin resistance in valve myofibroblasts

Sex differences in AVS arise in part from sexually dimorphic serum composition that differentially regulates valvular interstitial cell (VIC) myofibroblast activation. However, how individual serum factors contribute to sex-specific drug responses 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 serum Insulin-like Growth Factor Binding Protein 2 (IGFBP2) mediates Evogliptin resistance in female VICs cultured with female AVS serum through the activation of Rho/ROCK and focal adhesion kinase signaling. Our findings highlight IGFBP2 as a candidate biomarker for stratifying female AVS patients for Evogliptin treatment, underscoring the need to incorporate sex as a biological variable in determining AVS treatments.