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<p>Acute lung injury (ALI) is a clinically prevalent condition characterized by excessive inflammatory activation leading to tissue damage, with high mortality rates. USP19, a deubiquitinase (DUB) known to play critical roles in skeletal muscle atrophy, antiviral responses, and stabilization of transmembrane endoplasmic reticulum-associated degradation (ERAD) substrates, has not been previously investigated in ALI pathogenesis. In this study, we established both in vivo (lipopolysaccharide (LPS)-challenged C57BL/6j mice) and in vitro (LPS-stimulated HULEC-5a cells) to simulate acute lung injury (ALI), demonstrating significant downregulation of USP19 expression during ALI progression. Functional studies revealed that genetic ablation of USP19 in mice exacerbated LPS-induced acute lung injury, manifesting as enhanced pulmonary tissue damage, increased vascular permeability, amplified inflammatory responses, and elevated cellular apoptosis. In HULEC-5a cells, USP19 overexpression attenuated LPS-induced cellular damage, inflammatory activation and apoptosis, while USP19 knockdown exacerbated these effects. These findings were recapitulated in USP19-knockout mouse lung microvascular endothelial cells. Mechanistically, we identified that USP19 exerts its protective effects by suppressing TAK1 phosphorylation, thereby inhibiting activation of the downstream JNK/p38 signaling pathway. These findings not only elucidate USP19 as a novel negative regulator of ALI through modulation of the TAK1-JNK/p38 axis, but also provide potential therapeutic targets and conceptual advances for ALI treatment strategies.</p>

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USP19 alleviates LPS-induced acute lung injury via inhibiting TAK1 activation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月13日

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  • Cong Li,
  • Kui Qin,
  • Youna Wang,
  • Yuqing Huang,
  • Jiangsong Zhang,
  • Hongbin Chen

摘要

Acute lung injury (ALI) is a clinically prevalent condition characterized by excessive inflammatory activation leading to tissue damage, with high mortality rates. USP19, a deubiquitinase (DUB) known to play critical roles in skeletal muscle atrophy, antiviral responses, and stabilization of transmembrane endoplasmic reticulum-associated degradation (ERAD) substrates, has not been previously investigated in ALI pathogenesis. In this study, we established both in vivo (lipopolysaccharide (LPS)-challenged C57BL/6j mice) and in vitro (LPS-stimulated HULEC-5a cells) to simulate acute lung injury (ALI), demonstrating significant downregulation of USP19 expression during ALI progression. Functional studies revealed that genetic ablation of USP19 in mice exacerbated LPS-induced acute lung injury, manifesting as enhanced pulmonary tissue damage, increased vascular permeability, amplified inflammatory responses, and elevated cellular apoptosis. In HULEC-5a cells, USP19 overexpression attenuated LPS-induced cellular damage, inflammatory activation and apoptosis, while USP19 knockdown exacerbated these effects. These findings were recapitulated in USP19-knockout mouse lung microvascular endothelial cells. Mechanistically, we identified that USP19 exerts its protective effects by suppressing TAK1 phosphorylation, thereby inhibiting activation of the downstream JNK/p38 signaling pathway. These findings not only elucidate USP19 as a novel negative regulator of ALI through modulation of the TAK1-JNK/p38 axis, but also provide potential therapeutic targets and conceptual advances for ALI treatment strategies.