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Targeting ATF4 in radiation-induced myocardial fibrosis

Award Number: R01HL187931
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/17/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2030

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Targeting ATF4 in radiation-induced myocardial fibrosis - PROJECT SUMMARY In patients with breast, lung, and esophageal cancers, incidental exposure of the heart or vascular structures to radiation therapy (RT) has been associated with long-term cardiovascular side effects. A well-documented pathological consequence of this incidental radiation exposure is the development of radiation-induced myocardial fibrosis (RIMF). RIMF is characterized by the deposition of collagen in the extracellular matrix, leading to myocardial ischemia and fibrosis, and the potential development of conditions such as pericarditis, cardiomyopathy, and, in some cases, congestive heart failure. Our published and preliminary findings indicate that the activating transcription factor 4 (ATF4) plays a central role in regulating myocardial fibrosis in mouse hearts treated with RT. Our research demonstrates that localized single-dose and fractionated irradiation of the cardiac apex significantly increases ATF4 expression, which in turn affects the interleukin-4 (IL-4)/signal transducer and activator of transcription 6 (STAT6) signaling pathway in macrophages. This interaction leads to the M2 polarization of macrophages, which enhances the production of transforming growth factor-beta 1 (TGF- 1). Depleting macrophages with clodronate liposomes revealed that macrophages are the primary source of TGF-1 secretion in the damaged myocardium following RT. Elevated TGF-1 promotes fibroblast-to- myofibroblast transformation, enhancing collagen production and subsequently impairing cardiac function. Genetic deletion of ATF4 or its chemical inhibition with ISRIB (a highly specific ATF4 inhibitor) effectively reduces cardiac damage and myocardial fibrosis and preserves cardiac function in RT-treated mice. Furthermore, ISRIB pretreatment of human macrophages significantly reduces IL-4–induced M2 polarization. Based on these findings, we hypothesize that targeting ATF4 will alleviate RIMF by inhibiting macrophage-dependent TGF-1 secretion, reducing fibroblast-to-myofibroblast transformation, and decreasing collagen synthesis. To test this hypothesis, we have established the following Specific Aims: Aim 1, to investigate the mechanism by which ATF4 regulates the M2 polarization of macrophages; Aim 2, to elucidate the role of macrophage-secreted TGF- 1 in ATF4-mediated fibrosis in RIMF; and Aim 3, to explore the therapeutic potential of ATF4 inhibition in the treatment of RIMF. With the proposed study, we aim to identify ATF4 as a central regulator of cardiac fibrosis pathophysiology and propose ATF4 inhibition as a potential therapeutic strategy for RIMF.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $757,729 )
2026	2026	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cardiovascular Diseases Research	000	1	8/19/2026	NEW	$757,729
														Subtotal = $757,729

Grand Total All Awards = $757,729

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Targeting ATF4 in radiation-induced myocardial fibrosis

Award Number: R01HL187931

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/17/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2030

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