CRISPR/Cas9 Screens Implicate RARA and SPNS1 in Doxorubicin Cardiotoxicity.

ABSTRACT:

Background

Doxorubicin (DOX) causes cardiotoxicity and heart failure in a significant fraction of patients, but the molecular etiology is poorly understood.

Objectives

We adopted a functional genomics-based approach to probe the genetic basis for DOX-induced cardiotoxicity in an exhaustive and agnostic manner.

Methods

Genome-wide and targeted CRISPR/Cas9 screens were performed in immortalized cardiomyocytes and induced pluripotent stem cell-derived cardiomyocytes to identify genetic modifiers of DOX-induced cardiotoxicity.

Results

Our first screen revealed that loss of the Retinoic Acid Receptor Alpha gene (RARA) increased DOX-induced cell death. Conversely, pharmacological activation of RARA protein with tamibarotene reduced DOX-induced toxicity. RNA-Seq analy

SUBMITTER: McDermott-Roe C 

PROVIDER: S-EPMC12922622 | biostudies-literature | 2026 Feb

REPOSITORIES: biostudies-literature