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.