A phenotypic screen identified KEAP1-kelch domain blockade as a mechanism to restore cardiac function in the setting of chronic severe hemodynamic stress

2025 · doi:10.1101/2025.09.24.678104
preprint OA: closed
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⚙ AI-generated summary by claude@2026-07, 2026-07-05 ⓘ

This study identified KEAP1-kelch domain blockade as a mechanism that restores cardiac function under chronic severe hemodynamic stress.

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⚙ AI-generated deep summary by claude@2026-07, 2026-07-05 · read from full text ⓘ

The paper used a bespoke gene-expression–based small-molecule phenotypic screen in human induced pluripotent stem cell–derived cardiomyocytes to identify targets and pathways capable of reversing heart failure–related pathologic gene expression signatures and decompensated phenotypes. Using a composite human–murine HF gene expression signature, a target-annotated compound set, and a reversal scoring algorithm, they identified KEAP1 kelch domain blockers as lead candidates that restored contractile function in models of oxidant stress and pressure overload–induced cardiac dysfunction, supported by compound characterization including rodent HF studies and iPSC-CM contractility assays. The abstract does not state specific limitations, but the key caveats implied by the design are that the screening and efficacy evaluation rely on cardiomyocyte systems and pressure- or oxidant-stress HF models. The paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.

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Abstract

A bespoke gene expression (GE) based small molecule screen in human induced pluripotent stem cell derived cardiomyocytes (iPSC-CM) was conducted with the aim of identifying drug targets and pathways with the potential to reverse heart failure (HF) pathologic GE and the resultant decompensated HF phenotype. The screen utilized a composite human-murine HF gene expression signature, a target annotated compound set, and a HF gene expression reversal scoring algorithm to identify small molecules and their associated targets as potential modulators of HF pathologic GE. Following hit triage, a lead optimization program, and compound characterization in preclinical rodent models of HF and human iPSC-CM contractility assays, KEAP1 kelch domain blockers were identified as potent efficacious agents in the restoration of contractile function in the setting of oxidant stress and pressure overload induced cardiac dysfunction.
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Abstract A bespoke gene expression (GE) based small molecule screen in human induced pluripotent stem cell derived cardiomyocytes (iPSC-CM) was conducted with the aim of identifying drug targets and pathways with the potential to reverse heart failure (HF) pathologic GE and the resultant decompensated HF phenotype. The screen utilized a composite human-murine HF gene expression signature, a target annotated compound set, and a HF gene expression reversal scoring algorithm to identify small molecules and their associated targets as potential modulators of HF pathologic GE. Following hit triage, a lead optimization program, and compound characterization in preclinical rodent models of HF and human iPSC-CM contractility assays, KEAP1 kelch domain blockers were identified as potent efficacious agents in the restoration of contractile function in the setting of oxidant stress and pressure overload induced cardiac dysfunction. Competing Interest Statement The authors have declared no competing interest.

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last seen: 2026-05-20T01:45:00.602351+00:00