2. Academic Validation
  3. FN14 promotes ventilator-induced lung injury by regulating pyroptosis via the ANXA2/ERK1/2 axis

FN14 promotes ventilator-induced lung injury by regulating pyroptosis via the ANXA2/ERK1/2 axis

  • Int Immunopharmacol. 2025 Sep 23:162:114500. doi: 10.1016/j.intimp.2025.114500.
Ke Wu 1,  Chunyu Li 2,  Jun Lv 3,  Jing Wang 4,  Zongyu Chen 2,  Qian Zhu 1,  Jiayi Zhang 1,  Siyu Lian 1,  Li Wang 1,  Xianming Zhang 5
Affiliations

Affiliations

  • 1 Department of Respiratory and Critical Medicine, the Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China; School of Clinical Medicine, Guizhou Medical University, Guiyang, Guizhou, China.
  • 2 Department of Respiratory and Critical Medicine, the Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China.
  • 3 Jinan Obstetrics and Gynecology Hospital, Jinan, Shandong, China.
  • 4 Department of Infectious and Respiratory Critical Care Medicine, Xinxiang Central Hospital, The Fourth Clinical College of Xinxiang Medical University, Xinxiang, China.
  • 5 Department of Respiratory and Critical Medicine, the Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China. Electronic address: zhangxianming@gmc.edu.cn.
PMID: 40744784 DOI: 10.1016/j.intimp.2025.114500
Abstract

Background: Uncontrollable inflammatory cascade is a key factor in the development of Ventilator-induced lung injury (VILI). Studies have shown that FN14 is involved in the pathophysiological processes of various acute inflammatory diseases. However, its mechanism of action in VILI has not been elucidated.

Methods: We established rat and cell models of VILI. Hematoxylin and eosin (H&E) staining were used to assess lung injury. Real-time quantitative polymerase chain reactions (qRT-PCR) and Western blot were used to detect the expressions of FN14, AnxA2, ERK1/2, p-ERK1/2, GSDMD, GSDMD-N, IL-1β and IL-18. Immunohistochemistry was used to assess the expressions of GSDMD and GSDMD-N. Molecular docking, mass spectrometry analysis, co-immunoprecipitation and immunofluorescence were used to verify the binding of FN14 and AnxA2. In addition, we further investigated the regulatory relationship of the FN14/AnxA2/ERK1/2 axis through rescue experiments.

Results: FN14 expression was up-regulated in VILI rat lung tissues and ATII cells. After inhibiting FN14, the lung tissue injury was alleviated and the Pyroptosis of lung was significantly reduced, while these phenomena were obviously reversed by Ro 67-7476. In ATII cells, overexpression FN14 boosted the production of pyroptosis-related effectors GSDMD, GSDMD-N and pro-inflammatory factors IL-1β, IL18. Conversely, knockdown of FN14 resulted in decreased expression of pyroptosis-related proteins and pro-inflammatory factors. Mechanically, upregulated FN14 enhanced the binding to AnxA2 and promoted phosphorylation at Tyr24 of AnxA2, thereby inducing the activation of ERK1/2.

Conclusions: We revealed that FN14 is triggered in response to VILI and promotes VILI by regulating Pyroptosis via the AnxA2/ERK1/2 axis.

Keywords

ANXA2; FN14; Gasdermin D; Phosphorylation; Pyroptosis; Ventilator-induced lung injury.

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