2. Academic Validation
  3. Fyn deficiency drives pro-inflammatory macrophage activation to exacerbate septic acute lung injury

Fyn deficiency drives pro-inflammatory macrophage activation to exacerbate septic acute lung injury

  • Free Radic Biol Med. 2026 Mar 16:246:80-92. doi: 10.1016/j.freeradbiomed.2025.12.022.
Yi Liu 1,  Bangjun Xu 2,  Wuxiong Zhang 3,  Yifan Zuo 4,  Tinglv Fu 5,  Xiao Lu 3,  Xin Xing 3,  Qing Geng 3,  Bohao Liu 6,  Ning Li 7,  Qingsong Ye 8
Affiliations

Affiliations

  • 1 Center of Regenerative Medicine, Department of Stomatology, Renmin Hospital of Wuhan University, Wuhan, 430060, China; Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
  • 2 Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
  • 3 Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
  • 4 Department of Cardiovascular Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
  • 5 Department of Thoracic Surgery, The First Affiliated Hospital of Kunming Medical University, Kunming, 650000, China.
  • 6 Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, 130021, China. Electronic address: [email protected].
  • 7 Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China. Electronic address: [email protected].
  • 8 Center of Regenerative Medicine, Department of Stomatology, Renmin Hospital of Wuhan University, Wuhan, 430060, China. Electronic address: [email protected].
PMID: 41490764 DOI: 10.1016/j.freeradbiomed.2025.12.022
Abstract

Macrophage-driven inflammation is a hallmark of sepsis-associated acute lung injury (ALI). Fyn, a Src family kinase, plays a pivotal role in diverse cellular signaling pathways. While prior studies established that Toll-like Receptor (TLR) activation rapidly initiates Fyn activation, its precise immunoregulatory functions and role in sepsis-induced ALI remain contentious. In this study, we investigated the impact of Fyn deficiency on cecal ligation and puncture (CLP)-induced septic ALI. Furthermore, we utilized murine bone marrow-derived macrophages (BMDMs) and human THP-1-derived macrophages to elucidate the influence of Fyn on macrophage inflammatory responses. Fyn deficiency significantly exacerbated pulmonary inflammation and injury in ALI mice, as evidenced by histopathological analysis of lung tissue, elevated cytokine levels, and reduced survival. Notably, Fyn deficiency potentiated macrophage inflammatory responses. This effect was mediated through the suppression of TNF receptor-associated factor 6 (TRAF6) ubiquitination and degradation, thereby augmenting TLR4-NF-κB signaling. Consequently, Fyn deficiency led to excessive macrophage cytokine production and exacerbated ALI severity. Collectively, these findings underscore Fyn as a critical immunomodulator and highlight its potential as a therapeutic target for immunomodulation and anti-inflammatory strategies in sepsis-induced ALI and related acute inflammatory disorders.

Keywords

Acute lung injury; Fyn; Macrophage; Sepsis; TRAF6.

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