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

Abstract

Sepsis-associated lung injury (SALI) remains a critical clinical challenge, partly driven by ferroptosis-induced endothelial dysfunction. The pathological interaction between FUN14 domain-containing protein 1 (FUNDC1) and glutathione peroxidase 4 (GPX4) promotes ferroptosis and disrupts mitophagic flux. Magnesium lithospermate B (MLB), an active compound derived from Salvia miltiorrhiza, possesses anti-inflammatory and antioxidant properties and exhibits potential for vascular protection. Here, it is demonstrated that MLB mitigates sepsis-associated pulmonary vascular injury by suppressing ferroptosis and restoring mitochondrial homeostasis. Mechanistically, MLB directly binds GPX4 at Gly79, thereby disrupting the GPX4-FUNDC1 interaction, stabilizing GPX4 enzymatic activity, and preventing its FUNDC1-mediated mitophagic degradation. To enhance pulmonary targeting, P-selectin-binding peptide-engineered adipose-derived stem cell extracellular vesicles were constructed to deliver MLB, substantially improving its therapeutic efficacy in SALI. Furthermore, a silver-citrate nanostructure-based surface-enhanced Raman spectroscopy platform was developed, enabling precise identification of MLB's Raman fingerprint spectrum with nanogram-level sensitivity and time-resolved in vivo biodistribution profiling. Collectively, these findings reveal a novel therapeutic mechanism and efficacy of MLB in SALI, highlighting a promising translational strategy that integrates targeted drug delivery with molecular detection for potential clinical applications.