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Redefining the Role of lysosomal membrane permeabilization (LMP) inDoxorubicin-induced Cardiotoxicity

Award Number: R15HL179642
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/15/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2029

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Redefining the Role of lysosomal membrane permeabilization (LMP) inDoxorubicin-induced Cardiotoxicity - PROJECT SUMMARY Doxorubicin (DOX) is a powerful drug used for cancer treatment, but it can cause heart failure due to cardiotoxicity, which is a significant challenge in cancer therapy. Although the numerous mechanisms of DOX- induced cardiotoxicity have been studied extensively, recent research indicates that lysosomal dysfunction plays a crucial role in this process. Specifically, lysosomal membrane permeabilization (LMP) is a central mechanism affecting cardiomyocytes survival and death . Unlike previous studies that focused on lysosomal protease release into the cytoplasm to trigger cell death, our research emphasizes the importance of DOX-induced lysosomal luminal environment degradation in maintaining cardiac homeostasis. LMP reduces the acidity of lysosomes and impairs their ability to digest. This condition can worsen when lysosomal hydrolases, specifically cathepsin D (CTSD), are disrupted. Since CTSD is crucial for the maturation and function of other lysosomal enzymes, if CTSD activity is inadequate, it can result in insufficient lysosomal degradation, leading to cardiac injury. Our initial findings show that DOX treatment can induce LMP in cardiomyocytes, which results in a significant increase in CTSD expression but a decrease in its enzymatic activity. Surprisingly, knocking down CTSD or inhibiting its activity worsens DOX cardiotoxicity. Based on these findings, we hypothesize that cardiac dysfunction and DOX-induced cardiotoxicity can result from heightened LMP and subsequent functional insufficiency of CTSD. We have two aims to test this hypothesis: Aim 1 is to evaluate the impact of lysosomal membrane permeabilization (LMP) on DOX-induced cardiac injury using our novel LMP reporter and Lyso-tag system. We will apply novel interventions such as imidazoline drugs, ApoM, and SMURF1 to protect lysosomal membrane integrity and determine if DOX-induced LMP and cardiac damage can be mitigated. In Aim 2, we will investigate the impact of CTSD insufficiency in DOX-induced cardiac injury. We will use transgenic mice with increased cardiac CTSD activity to test if CTSD upregulation rescues DOX-induced cardiac dysfunction. Additionally, CTSD knockout mice and a CTSD inhibitor will help determine if CTSD is essential for cardiac homeostasis during DOX treatment. We will explore if CTSD deficiency arises from LMP or contributes by employing strategies like Imidazoline agonist treatment or prosaposin (PSAP) overexpression to restore CTSD maturation and lysosomal function, assessing their impact on interventions protecting lysosomal membrane integrity. Our innovative approach shifts focus from LMP-induced lysosomal enzyme release to its functional role in DOX-induced cardiotoxicity. To better understand lysosomal dysfunction in cardiac injury during DOX treatment, we use novel LMP reporter systems, Lyso-tag technology for quantitative LMP analysis, and super- resolution imaging. This projects completion could challenge current views on DOX -induced cardiotoxicity and suggest new strategies to mitigate it, improving life quality for cancer survivors treated with DOX.


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 = $573,750 )
2026	2026	NEW YORK INSTITUTE OF TECHNOLOGY	1855 BROADWAY	NEW YORK	NY	10023	NEW YORK	USA	Cardiovascular Diseases Research	000	1	7/7/2026	NEW	$573,750
														Subtotal = $573,750

Grand Total All Awards = $573,750

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Redefining the Role of lysosomal membrane permeabilization (LMP) inDoxorubicin-induced Cardiotoxicity

Award Number: R15HL179642

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/15/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2029

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