2. Academic Validation
  3. Targeting PARK7: Sodium 4-Phenylbutyrate shields endothelial cells from oxidative stress and GSDME-mediated Pyroptosis in acute lung injury

Targeting PARK7: Sodium 4-Phenylbutyrate shields endothelial cells from oxidative stress and GSDME-mediated Pyroptosis in acute lung injury

  • Int Immunopharmacol. 2025 Aug 19:164:115386. doi: 10.1016/j.intimp.2025.115386.
Jian Xu 1,  Tianchang Wei 1,  Yuhan Wang 2,  Cuiping Zhang 1,  Xiaoyan Chen 1,  Yufan Li 3,  Juan Song 1,  Weiqi Mao 1,  Qingyuan Xu 1,  Xu Wu 4,  Yuanlin Song 5
Affiliations

Affiliations

  • 1 Shanghai Key Laboratory of Lung Inflammation and Injury, Shanghai Respiratory Research Institute, Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
  • 2 Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai 200032, China.
  • 3 Shanghai Key Laboratory of Lung Inflammation and Injury, Shanghai Respiratory Research Institute, Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai 200032, China.
  • 4 Shanghai Key Laboratory of Lung Inflammation and Injury, Shanghai Respiratory Research Institute, Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China. Electronic address: wu.xu@zs-hospital.sh.cn.
  • 5 Shanghai Key Laboratory of Lung Inflammation and Injury, Shanghai Respiratory Research Institute, Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai 200032, China; National and Shanghai Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China; Key Laboratory of Chemical Injury, Emergency and Critical Medicine of Shanghai Municipal Health Commission, Center of Emergency and Critical Medicine, Jinshan Hospital of Fudan University, Shanghai 201508, China. Electronic address: ylsong70@163.com.
PMID: 40834532 DOI: 10.1016/j.intimp.2025.115386
Abstract

The mechanisms of endothelial cell injury in acute lung injury (ALI) remain unclear, and effective interventional strategies targeting endothelial cells are limited. Sodium 4-phenylbutyrate (Na-PBA), a histone deacetylase inhibitor, can potentially reduce oxidative damage. Its effects on Pyroptosis and its relationship with PARK7, a redox-regulating protein, remain unclear. Using a lipopolysaccharide (LPS)-induced ALI mouse model, we evaluated Na-PBA's effects on lung tissue damage, inflammatory markers, and endothelial Pyroptosis. In vitro, human umbilical vein endothelial cells (HUVECs) were treated with LPS, Nigericin, and Na-PBA to assess Pyroptosis and oxidative stress responses. RNA Sequencing, immunoblotting, gene knockdown, and overexpression were utilized to explore molecular mechanisms. Na-PBA pretreatment alleviated lung injury, reduced pulmonary edema, and lowered inflammatory cytokines in LPS-ALI mice. It significantly decreased oxidative stress and Pyroptosis of endothelial cells via the cytochrome c (Cyt c)-caspase9-caspase3-GSDME pathway in vivo and in vitro. Na-PBA pretreatment increased PARK7 expression in HUVECs. Na-PBA depended on PARK7 to protect against HUVEC injury and GSDME-mediated Pyroptosis in vitro and relied on PARK7 expression in endothelial cells to mitigate ALI in vivo. Na-PBA upregulated PARK7 through HDAC inhibition, which could be amplified through a positive feedback loop involving NRF2. Finally, upregulation of PARK7 may alleviate downstream Caspase activation and Pyroptosis by stabilizing mitochondria and inhibiting Cyt c leakage from mitochondria. In conclusion, Na-PBA alleviates ALI by modulating oxidative stress and Pyroptosis through the PARK7-dependent Cyt c-caspase9-caspase3-GSDME pathway. This study's results provide a novel therapeutic approach for mitigating endothelial cell injury in lung diseases.

Keywords

Acute lung injury; Endothelial cell; PARK7; Pyroptosis; Sodium 4-phenylbutyrate.

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