ICA69 aggravates ferroptosis causing septic cardiac dysfunction via STING trafficking

Area of Science:

• Cardiovascular Biology
• Immunology
• Cellular Pathology

Background:

• Sepsis-induced cardiomyopathy (SIC) involves cardiomyocyte apoptosis, ferroptosis, and inflammation.
• The role of Islet cell autoantigen 69 (ICA69) in cardiovascular disease, especially SIC, remains unclear.
• ICA69 is known to regulate inflammation and immune responses in various diseases.

Purpose of the Study:

• To investigate the function of ICA69 in sepsis-induced cardiomyopathy.
• To determine the impact of ICA69 deficiency on cardiac function and pathology during sepsis.
• To elucidate the molecular mechanisms by which ICA69 influences ferroptosis and inflammation in SIC.

Main Methods:

• Utilized lipopolysaccharide (LPS)-induced mouse models and isolated macrophages and cardiomyocytes.
• Assessed survival rates, cardiac function, inflammatory cytokines, reactive oxygen species (ROS), and ferroptosis biomarkers.
• Investigated the role of STING signaling in ICA69-mediated ferroptosis.

Main Results:

• LPS administration increased ICA69 expression in mice, macrophages, and cardiomyocytes.
• ICA69 knockout significantly improved survival and cardiac function in LPS-induced mice.
• ICA69 deficiency reduced cardiac inflammation, ROS, and ferroptosis biomarkers, independent of xCT.
• Elevated ICA69 levels were observed in peripheral blood mononuclear cells (PBMCs) of septic patients.

Conclusions:

• ICA69 deficiency alleviates inflammation and ferroptosis in the heart during sepsis.
• Targeting ICA69 presents a promising therapeutic strategy for sepsis-induced cardiomyopathy.
• ICA69 promotes ferroptosis and heart injury via STING-mediated lipid peroxidation.