Antimicrobial Peptide CRAMP/LL-37 Protected Heart Cells from Iron-Dependent Death After Heart Attack | Research

The takeaway

The antimicrobial peptide CRAMP (and its human equivalent LL-37) protected heart muscle cells from ferroptosis — a form of iron-dependent cell death — by inhibiting cathepsin L, and improved heart function after heart attacks in mice.

Cardiac function improved in vivo
Both CRAMP overexpression and direct peptide administration reduced myocardial injury in mice after heart attacks by blocking the ferroptosis pathway

What the researchers found

CRAMP levels were reduced in infarcted cardiac tissue and in cardiomyocytes exposed to ferroptosis inducers. Overexpressing CRAMP or pretreating cells with LL-37 peptide alleviated ferroptosis, while CRAMP knockdown worsened cell death. The mechanism involves CRAMP inhibiting cathepsin L (CTSL) activity, which preserves PDIA4 — a protein that suppresses ferroptosis. In the mouse myocardial infarction model, both CRAMP overexpression and direct CRAMP peptide administration significantly reduced myocardial injury and improved cardiac function.

Why it matters

Heart attacks remain the leading cause of death worldwide, and ferroptosis is increasingly recognized as a major driver of heart muscle loss after ischemic injury. Discovering that a natural antimicrobial peptide can protect the heart from ferroptosis opens a completely new therapeutic approach — repurposing CRAMP/LL-37 from infection defense to cardiac protection.

The numbers in context

CRAMP reduced in infarcted tissue · overexpression alleviated ferroptosis · knockdown worsened cell death · CTSL elevated under ferroptotic stress · PDIA4 pathway identified · in vivo cardiac function improved

How the study worked

Combined in vitro and in vivo study. In vitro: cardiomyocytes were treated with ferroptosis inducers, with CRAMP overexpressed or knocked down to test its role. CTSL activity and PDIA4 expression were measured. In vivo: mouse myocardial infarction model with CRAMP overexpression and CRAMP peptide administration. Protein interactions were identified using database screening.

Who was studied

Mouse cardiomyocytes (in vitro) and mouse myocardial infarction model (in vivo)

What this study cannot tell us

Preclinical mouse study — translation to human cardiac disease is uncertain. The abstract does not provide specific quantitative outcome data (e.g., infarct size reduction, ejection fraction numbers). The mechanism was primarily established in cell culture with in vivo confirmation, but the pharmacokinetics and optimal dosing of CRAMP peptide for cardiac protection were not detailed.

How to read the evidence

Well-designed preclinical study combining in vitro mechanistic work with in vivo validation in a mouse myocardial infarction model. The full signaling pathway (CRAMP → CTSL → PDIA4 → ferroptosis) was delineated. However, all data is from animal models with no human clinical evidence.

When this study was published

Published in 2025, this is cutting-edge research connecting two rapidly growing fields — antimicrobial peptides and ferroptosis — in the context of cardiac injury.

The bigger picture

Cathelicidin/LL-37 is one of the most studied antimicrobial peptides, primarily known for immune defense. This study reveals an unexpected cardioprotective role through ferroptosis regulation, expanding the known functions of this peptide family beyond infection control into cardiovascular medicine. As ferroptosis-targeted therapies gain traction, CRAMP/LL-37 could emerge as a novel therapeutic agent.

Questions still open

Could LL-37 or synthetic cathelicidin analogs be administered during or after heart attacks to reduce infarct size in humans?
Does CRAMP/LL-37 protect against ferroptosis in other organs like the brain (stroke) or kidneys?
What is the optimal route, dose, and timing for CRAMP peptide administration to maximize cardiac protection?

Common questions

What is ferroptosis and why does it matter for heart attacks?

Ferroptosis is a recently discovered form of cell death caused by iron-dependent lipid damage (oxidative stress). During a heart attack, iron accumulates in damaged tissue and triggers ferroptosis, killing heart muscle cells. Unlike other forms of cell death, ferroptosis can potentially be blocked by specific interventions — like this antimicrobial peptide.

How is an antimicrobial peptide related to heart protection?

CRAMP (cathelicidin-related antimicrobial peptide) was originally known for fighting infections, but this study reveals it also regulates oxidative stress and iron metabolism in heart cells. By inhibiting cathepsin L, CRAMP prevents the cascade that leads to iron-dependent cell death, showing that immune defense peptides can have unexpected protective roles in other organs.

Read the original research

Antimicrobial peptide CRAMP/LL-37 mediates ferroptosis resistance in cardiomyocytes by inhibiting cathepsin L.

Basic research in cardiology, 120(5), 1011-1025

View on PubMed ↗Publisher’s paper ↗

Citation

Liu, Zhantao; Zhang, Qingsong; Su, Dan; Chen, Hong; Wang, Bowen; Ye, Lin; Wang, Peiyan; Wu, Jingnan; Jia, Wencan; Liu, Lijun; Wang, Jianxun; Miao, Shuo. (2025). Antimicrobial peptide CRAMP/LL-37 mediates ferroptosis resistance in cardiomyocytes by inhibiting cathepsin L.. Basic research in cardiology, 120(5), 1011-1025. https://doi.org/10.1007/s00395-025-01122-z