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. 2025 Sep 9;152(10):661-681.
doi: 10.1161/CIRCULATIONAHA.124.071217. Epub 2025 Aug 14.

Human Single-Nucleus RNA Sequencing Identifies CD47 as a Therapeutic Target for Doxorubicin-Induced Cardiomyopathy

Zhen Guo #  1 , Anahita Ataran #  1 , Pan Ma  1 , Wenjing Yu  1 , Hamidreza Hajirezaei  1 , Carla Valenzuela Ripoll  1 , Lauren N Pedersen  1 , Omid Rashidi  1 , Mandy M Chan  1 , Mengcheng Shen  1   2 , Shannon Kelley  3 , Alireza Sargazi  1 , Mualla Ozcan  1 , Aynaz Lotfinaghsh  1 , Yoonje Cho  1 , Ahmed Diab  1 , Felicia Grogan  4 , Amanda Klaas  4 , Alexander Pompian  1 , Adnan Imam  1 , Rehman Lodhi  1 , Amen Bekele Zelleke  1 , Attila Kovacs  1 , Kenneth B Margulies  5 , Jeff Szymanski  4 , Marco Sardiello  6 , Babak Razani  7 , Aarti Asnani  8 , Benjamin J Kopecky  9 , Pierre E Signore  10 , B Alexander Yi  10 , Craig T Basson  4   10 , Kodi S Ravichandran  3 , Sumanth D Prabhu  1 , Carmen Bergom  4 , Joel D Schilling  1 , Kory J Lavine  1 , Ali Javaheri  1   11
Affiliations

Human Single-Nucleus RNA Sequencing Identifies CD47 as a Therapeutic Target for Doxorubicin-Induced Cardiomyopathy

Zhen Guo et al. Circulation. .

Abstract

Background: Doxorubicin cardiomyopathy (DoxCM) remains a significant clinical problem, but its underlying mechanisms remain incompletely understood. Identifying DoxCM mechanisms can lead to therapeutic interventions that improve patient outcomes.

Methods: We performed single-nucleus RNA sequencing on left ventricular myocardial tissue from patients with DoxCM versus nonischemic cardiomyopathy and nonfailing donors. This approach aimed to uncover the transcriptional changes associated with DoxCM. Additionally, we conducted immunostaining, flow cytometry, antibody neutralization, and cell depletion studies to validate our findings and define in vivo mechanisms.

Results: Compared with nonfailing donors and patients with nonischemic cardiomyopathy, left ventricular myocardium from patients with DoxCM exhibited increased POSTN (periostin)+ activated fibroblasts, downregulation of genes involved in phagocytosis, and increased expression of the antiphagocytic molecule CD47. Immunostaining of human cardiac sections and murine studies demonstrated increased POSTN+ cells and CD47 in DoxCM and in a murine breast cancer model. CD47 antibody neutralization both prevented and treated doxorubicin-induced reduction in left ventricular ejection fraction and fibrosis. Mechanistically, depletion of resident cardiac macrophages blocked the cardioprotective effects of CD47 neutralization and clearance of cardiac fibroblasts.

Conclusions: Our data support CD47 as a disease-specific target and promising therapeutic approach for mitigating cardiac dysfunction in DoxCM.

Keywords: CD47; activated fibroblasts; doxorubicin cardiomyopathy; resident macrophage.

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Conflict of interest statement

Dr Javaheri has a pending patent for fusion protein nanodiscs for the treatment of heart failure and eye disease, is a member of the scientific advisory board of Mobius Scientific, and received research funding from AstraZeneca unrelated to the studies in this manuscript. Dr Javaheri received contract research funding for this study from Bitterroot Bio, which approved the submission of this study. Drs Signore, Yi, and Basson are employees of Bitterroot Bio, which develops anti-CD47 therapies.