Targeting the GPX4-FUNDC1 Interaction with Magnesium Lithospermate B Attenuates Sepsis-Associated Lung Injury

Area of Science:

• Biomedical Engineering
• Molecular Biology
• Pharmacology

Background:

• Sepsis-associated lung injury (SALI) involves endothelial dysfunction driven by ferroptosis.
• The interaction between FUNDC1 and GPX4 promotes ferroptosis and impairs mitophagic flux in SALI.
• Magnesium lithospermate B (MLB) shows anti-inflammatory and antioxidant potential for vascular protection.

Purpose of the Study:

• To investigate MLB's therapeutic effects on sepsis-associated pulmonary vascular injury.
• To elucidate the molecular mechanism of MLB in mitigating ferroptosis and restoring mitochondrial homeostasis.
• To develop a targeted drug delivery system and a sensitive detection platform for MLB in SALI treatment.

Main Methods:

• Investigated MLB's interaction with GPX4 and its effect on the GPX4-FUNDC1 complex.
• Engineered adipose-derived stem cell extracellular vesicles with P-selectin-binding peptides for pulmonary MLB delivery.
• Developed a silver-citrate nanostructure-based surface-enhanced Raman spectroscopy (SERS) platform for MLB detection and biodistribution.

Main Results:

• MLB suppressed ferroptosis and restored mitochondrial homeostasis in sepsis-induced lung injury.
• MLB directly binds GPX4, disrupting FUNDC1 interaction and preventing GPX4 degradation.
• Targeted delivery of MLB via engineered EVs significantly enhanced therapeutic efficacy.
• The SERS platform achieved nanogram-level sensitivity for MLB identification and in vivo tracking.

Conclusions:

• MLB demonstrates significant therapeutic potential for SALI by targeting ferroptosis and mitochondrial dysfunction.
• The developed targeted delivery system and SERS platform offer a promising integrated strategy for SALI treatment and monitoring.
• These findings support the clinical translation of MLB-based therapies for sepsis-induced lung injury.