2. Academic Validation
  3. Suppression of Skp2 contributes to sepsis-induced acute lung injury by enhancing ferroptosis through the ubiquitination of SLC3A2

Suppression of Skp2 contributes to sepsis-induced acute lung injury by enhancing ferroptosis through the ubiquitination of SLC3A2

  • Cell Mol Life Sci. 2024 Jul 30;81(1):325. doi: 10.1007/s00018-024-05348-3.
Zhaoyuan Chen # 1 2,  Jie Zhang # 1 2,  Shenjia Gao # 1 2,  Yi Jiang 1 2,  Mengdi Qu 1 2,  Jiahui Gu 1 2,  Han Wu 1 2,  Ke Nan 1 2,  Hao Zhang 1 2,  Jun Wang 3,  Wankun Chen 4 5 6,  Changhong Miao 7 8
Affiliations

Affiliations

  • 1 Department of Anesthesiology, Zhongshan Hospital, Fudan University, 180# Feng-Lin Road, Shanghai, 200032, China.
  • 2 Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China.
  • 3 Department of Integrative Medicine and Neurobiology, School of Basic Medical Science, Shanghai Medical College, Fudan University, Shanghai, 200032, China. jwangf@shmu.edu.cn.
  • 4 Department of Anesthesiology, Zhongshan Hospital, Fudan University, 180# Feng-Lin Road, Shanghai, 200032, China. chenwank@163.com.
  • 5 Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China. chenwank@163.com.
  • 6 Department of Anesthesiology, QingPu Branch of Zhongshan Hospital Affiliated to Fudan University, 1158# Gongyuan Dong Road, Shanghai, 201700, China. chenwank@163.com.
  • 7 Department of Anesthesiology, Zhongshan Hospital, Fudan University, 180# Feng-Lin Road, Shanghai, 200032, China. miaochangh@163.com.
  • 8 Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China. miaochangh@163.com.
  • # Contributed equally.
PMID: 39079969 DOI: 10.1007/s00018-024-05348-3
Abstract

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to Infection. The inflammatory cytokine storm causes systemic organ damage, especially acute lung injury in sepsis. In this study, we found that the expression of S-phase kinase-associated protein 2 (Skp2) was significantly decreased in sepsis-induced acute lung injury (ALI). Sepsis activated the MEK/ERK pathway and inhibited Skp2 expression in the pulmonary epithelium, resulting in a reduction of K48 ubiquitination of solute carrier family 3 member 2 (SLC3A2), thereby impairing its membrane localization and cystine/glutamate exchange function. Consequently, the dysregulated intracellular redox reactions induced Ferroptosis in pulmonary epithelial cells, leading to lung injury. Finally, we demonstrated that intravenous administration of Skp2 mRNA-encapsulating lipid nanoparticles (LNPs) inhibited Ferroptosis in the pulmonary epithelium and alleviated lung injury in septic mice. Taken together, these data provide an innovative understanding of the underlying mechanisms of sepsis-induced ALI and a promising therapeutic strategy for sepsis.

Keywords

Cytokine storm; Ferroptosis; SLC3A2; Sepsis; Skp2.

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