Lithium carbonate induces myofibroblast necroptosis to reverse pulmonary fibrosis

Pulmonary fibrosis (PF) is a fatal disease with limited therapeutic options. Myofibroblasts, central to the pathogenesis of PF, are the primary collagen-producing cells that drive fibrosis. However, therapeutic targeting of myofibroblasts faces formidable challenges owing to their autonomous activation, persistent proliferation, and resistance to apoptosis. Here, we show that lithium carbonate (LC), a clinically approved mood stabilizer, effectively depletes myofibroblasts during fibrosis progression. Mechanistically, LC promotes alveolar macrophages (AMs) to produce TNF-α, which activates pro-caspase-8 signaling without inducing myofibroblast apoptosis. LC directly binds to and inactivates pro-caspase-8, inducing to RIP1/RIP3/MLKL-dependent necroptosis of myofibroblasts. These mechanistic insights have enabled the repurposing of LC as a therapeutic strategy to reverse established lung fibrosis in mouse models. Our findings provide a myofibroblast-targeting strategy and highlight its potential in PF treatment.

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Publication Details

Journal
Immunity & Inflammation
Published
2025-09-03
DOI
https://doi.org/10.1007/s44466-025-00002-4
Citations
2
Primary Topic
Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
Type
article
Field-Weighted Citation Impact
3.04

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article

Lithium carbonate induces myofibroblast necroptosis to reverse pulmonary fibrosis

Qing Lin, Shuai Tong, Huafeng Zhang, Yuhan Bian et al.
2 citations
Immunity & Inflammation
Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
3.04
article

Lithium carbonate induces myofibroblast necroptosis to reverse pulmonary fibrosis

Qing Lin, Shuai Tong, Huafeng Zhang, Yuhan Bian, Keke Wei, Jiadi Lv, Xin Zhang, Simin Liu, Bo Huang, Tao Zhu, Ke Tang, Jingxuan Xiao, Sha Wu, Liang Tang, Jingwei Ma, Runze Zhang, Yuan Ma
article en
2 citations

Abstract

Pulmonary fibrosis (PF) is a fatal disease with limited therapeutic options. Myofibroblasts, central to the pathogenesis of PF, are the primary collagen-producing cells that drive fibrosis. However, therapeutic targeting of myofibroblasts faces formidable challenges owing to their autonomous activation, persistent proliferation, and resistance to apoptosis. Here, we show that lithium carbonate (LC), a clinically approved mood stabilizer, effectively depletes myofibroblasts during fibrosis progression. Mechanistically, LC promotes alveolar macrophages (AMs) to produce TNF-α, which activates pro-caspase-8 signaling without inducing myofibroblast apoptosis. LC directly binds to and inactivates pro-caspase-8, inducing to RIP1/RIP3/MLKL-dependent necroptosis of myofibroblasts. These mechanistic insights have enabled the repurposing of LC as a therapeutic strategy to reverse established lung fibrosis in mouse models. Our findings provide a myofibroblast-targeting strategy and highlight its potential in PF treatment.

Immunity & InflammationVol. 1(1)
Chinese Academy of Medical Sciences & Peking Union Medical College (CN), Huazhong University of Science and Technology (CN), Southern Medical University (CN)
National Natural Science Foundation of China, China Postdoctoral Science Foundation, National Key Research and Development Program of China
Openalex Percentile: Top 8%
Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
3.04
DOIOpen Access PDFOpenAlex
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