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Cell stem cell

IF: 19.8
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CRISPRi/a screens in human iPSC-cardiomyocytes identify glycolytic activation as a druggable target for doxorubicin-induced cardiotoxicity

Published:7 November 2024 DOI:
Chun Liu, Mengcheng Shen, Yanxia Liu, Amit Manhas, Shane Rui Zhao, Mao Zhang, Nadjet Belbachir, Lu Ren, Joe Z. Zhang, Arianne Caudal, Masataka Nishiga, Dilip Thomas, Angela Zhang, Huaxiao Yang, Yang Zhou, Mohamed Ameen, Nazish Sayed, June-Wha Rhee, Lei S. Qi, Joseph C. Wu

Abstract

Doxorubicin is limited in its therapeutic utility due to its life-threatening cardiovascular side effects. Here, we present an integrated drug discovery pipeline combining human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iCMs), CRISPR interference and activation (CRISPRi/a) bidirectional pooled screens, and a small-molecule screening to identify therapeutic targets mitigating doxorubicin-induced cardiotoxicity (DIC) without compromising its oncological effects. The screens revealed several previously unreported candidate genes contributing to DIC, including carbonic anhydrase 12 (CA12). Genetic inhibition of CA12 protected iCMs against DIC by improving cell survival, sarcomere structural integrity, contractile function, and calcium handling. Indisulam, a CA12 antagonist, can effectively attenuate DIC in iCMs, engineered heart tissue, and animal models. Mechanistically, doxorubicin-induced CA12 potentiated a glycolytic activation in cardiomyocytes, contributing to DIC by interfering with cellular metabolism and functions. Collectively, our study provides a roadmap for future drug discovery efforts, potentially leading to more targeted therapies with minimal off-target toxicity.

Substances (4)

Materials
Procduct Name CAS Molecular Formula Supplier Price
Indisulam 165668-41-7 C14H12ClN3O4S2 125 suppliers $21.00-$3955.00
Indisulam 165668-41-7 C14H12ClN3O4S2 125 suppliers $21.00-$3955.00
Indisulam 165668-41-7 C14H12ClN3O4S2 125 suppliers $21.00-$3955.00
Indisulam 165668-41-7 C14H12ClN3O4S2 125 suppliers $21.00-$3955.00

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