LRP1 activated by AT2 cell-secreted MDK inhibits fibrotic ferroptosis in idiopathic pulmonary fibrosis

  • iScience. 2026 Jun 4;29(6):116212. doi: 10.1016/j.isci.2026.116212.
Wenjie Hua  1 ,  Zitao Wang  2 ,  Zhenhang Dai  2 ,  Zhenyu Zhang  3 ,  Xiaoshan Li  3 ,  Bo Wu  3 ,  Man Huang  4 ,  Jingyu Chen  1  2  3
Affiliations
  • 1. Wuxi School of Medicine, Jiangnan University, NO.1800, Lihu Avenue, Wuxi 214122, China.
  • 2. Lung Transplantation Department, Second Affiliated Hospital of Zhejiang University, NO.1511, Jianghong Road, Hangzhou 310052, China.
  • 3. Lung Transplantation Department, The Affiliated Wuxi People's Hospital of Nanjing Medical University, NO 299, Qingyang Road, Wuxi 214023, China.
  • 4. General Intensive Care Unit, Second Affiliated Hospital of Zhejiang University, NO.1511, Jianghong Road, Hangzhou 310052, China.
PMID: 42305620 DOI: 10.1016/j.isci.2026.116212
Abstract

Idiopathic pulmonary fibrosis (IPF) is characterized by alveolar injury and pathological fibroblast expansion. Our study investigated the aberrant intercellular communication underlying this process. By analyzing single-cell Sequencing from GEO database and experimentally validating the results in vivo and in vitro, we demonstrated that the abnormally regulated alveolar type 2 (AT2) cells secrete midkine (MDK) to activate the low-density lipoprotein receptor-related protein 1 (LRP1) receptor in CTHRC1+ fibroblasts, which inhibits fibroblast Ferroptosis. Mechanistically, LRP1 signaling upregulates the Deubiquitinase OTUB1, which binds to and stabilizes the Ferroptosis inhibitor SLC7A11. This molecular pathway was verified in an in vitro cell co-culture model and in vivo mouse models subjected to adenovirus-mediated overexpression and knockdown. Collectively, these results elucidate a novel pathway of disease progression in IPF that could potentially be targeted for the diagnosis or intervention.

Keywords
biological sciences; cell biology; molecular biology.
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