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

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

  • Adv Sci (Weinh). 2026 Apr;13(20):e16488. doi: 10.1002/advs.202516488.
Zhixi Li 1 2 3 4,  Chang Liu 2 3 4 5,  Zhaoxue Ma 1 2,  Dongyou Zheng 1 2,  Renkai Wang 1 2,  Yongjing Yu 1 2,  Guangmin Chen 6,  Chenglong Li 7,  Yue Bu 2 8,  Hang Cao 1 2,  Bing Zhang 1 2
Affiliations

Affiliations

  • 1 Department of Anesthesiology, Second Affiliated Hospital of Harbin Medical University, Harbin, P. R. China.
  • 2 The Key Laboratory of Anesthesiology and Intensive Care Research of Heilongjiang Province, Harbin, P. R. China.
  • 3 The Key Laboratory of Myocardial Ischemia Organization, Chinese Ministry of Education, Harbin, P. R. China.
  • 4 State Key Laboratory of Frigid Zone Cardiovascular Diseases, Harbin, P. R. China.
  • 5 Department of Anesthesiology, Harbin Medical University Cancer Hospital, Harbin, P. R. China.
  • 6 Department of Anesthesiology, First Affiliated Hospital of Harbin Medical University, Harbin, P. R. China.
  • 7 Department of Anesthesiology, Fourth Affiliated Hospital of Harbin Medical University, Harbin, P. R. China.
  • 8 Department of Pain Medicine, Second Affiliated Hospital of Harbin Medical University, Harbin, P. R. China.
PMID: 41616122 DOI: 10.1002/advs.202516488
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.

Keywords

endothelial cells; ferroptosis; lung injury; mitophagy; sepsis.

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