# Type I Interferon Responses in the Pathobiology of Anthracycline-induced Cardiotoxicity

> **NIH NIH R01** · TEXAS A&M UNIVERSITY · 2020 · $371,015

## Abstract

Anthracycline chemotherapeutics, such as doxorubicin (Doxo), are among the most effective and widely used
antineoplastic drugs, yet their clinical application is limited by the damaging cardiac side effects that occur in
many patients. Anthracycline-induced cardiotoxicity (AIC) can manifest acutely during cancer treatment, but can
also cause life threatening cardiomyopathy and heart failure that develops years after the cessation of
chemotherapy. Despite significant effort, the underlying mechanisms responsible for AIC are not fully defined,
and it remains impossible to predict which patients will experience cardiotoxicity. Thus, there is an urgent need
to advance mechanistic understanding in order to discover novel treatments and/or predictive biomarkers for this
devastating condition. The overall objective of this proposal is to comprehensively define how type I interferon
(IFNab) signaling, a pleiotropic innate immune pathway, potentiates the cardiotoxic effects of Doxo
chemotherapy. The central hypothesis is that Doxo-induced cardiac DNA damage triggers the Stimulator of
Interferon Genes (STING)-dependent production of IFNab, in turn driving a self-propagating cycle of
mitochondrial dysfunction, reactive oxygen species (ROS) production, and cardiomyocyte death that contributes
to cardiac remodeling and failure. In support of this hypothesis, ongoing studies have revealed that Doxo robustly
engages STING to upregulate IFNab responses in cardiac cells and tissue. Strikingly, both male and female
mice lacking STING or IFNab signaling are protected from Doxo-induced cardiac mitochondrial damage,
myocardial remodeling, and left ventricle dysfunction. Conversely, treating melanoma-bearing mice with adjuvant
IFNa in addition to Doxo results in enhanced cardiac fibrosis and contractility defects relative to tumor-bearing
mice receiving Doxo alone. To gain additional insight into what appears to be an unappreciated yet fundamental
driver of AIC, three related, but independent, aims are proposed. Aim 1 will employ single-cell approaches, a
novel IFNab reporter mouse, and conditional knockout lines to define the kinetics of IFNab production in the
heart and determine that STING-IFNab signaling in cardiac myeloid and myocyte populations contributes to AIC.
Aim 2 will test the hypothesis that STING-IFNab signaling amplifies the cardiotoxicity of anthracyclines by
potentiating mitochondrial dysfunction, iron overload, and oxidative stress. Finally, Aim 3 will establish that the
IFNab-mediated upregulation of Z-DNA binding protein 1 (ZBP1) enhances sensing of cardiac DNA damage and
promotes cardiac necroptosis to sustain inflammatory responses during and after Doxo chemotherapy. This
proposal is innovative because it expands the current paradigms of AIC and defines the IFNab-mitochondrial
nexus as a fundamental pathway contributing to myocardial damage. In addition, this research will contribute
significant new information on how cardiac innate immune respo...

## Key facts

- **NIH application ID:** 10051737
- **Project number:** 1R01HL148153-01A1
- **Recipient organization:** TEXAS A&M UNIVERSITY
- **Principal Investigator:** Andrew Phillip West
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $371,015
- **Award type:** 1
- **Project period:** 2020-08-05 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10051737

## Citation

> US National Institutes of Health, RePORTER application 10051737, Type I Interferon Responses in the Pathobiology of Anthracycline-induced Cardiotoxicity (1R01HL148153-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10051737. Licensed CC0.

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