2. Academic Validation
  3. Plasma apolipoprotein E protein attenuates pulmonary fibrosis through LRP1 and PLAU dual receptor-mediated TGF-β/Smad inhibition

Plasma apolipoprotein E protein attenuates pulmonary fibrosis through LRP1 and PLAU dual receptor-mediated TGF-β/Smad inhibition

  • J Adv Res. 2025 Dec 29:S2090-1232(25)01035-5. doi: 10.1016/j.jare.2025.12.045.
Haiyang Zhang 1,  Yu Xie 1,  Gang Wei 2,  Juan Liu 1,  Wenru Shang 3,  Manyi Pan 1,  Yuxin Zou 1,  Lifeng Yan 1,  Tianyu Zhou 1,  Jiachang Chi 4,  Wangrui Liu 4,  Kai Zhang 5,  Yi Wang 6,  Weining Xiong 7,  Huaqi Guo 8
Affiliations

Affiliations

  • 1 Department of Pulmonary and Critical Care Medicine, Shanghai Key Laboratory of Tissue Engineering, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200011, China.
  • 2 Beijing Key Laboratory of Diabetes Research and Care, Department of Endocrinology, Beijing Diabetes Institute, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China.
  • 3 Research Center for Hospital Management, Shanghai Sixth People's Hospital, Shanghai 200233, China; Shanghai Shenkang Hospital Research Institute, Shanghai 200233, China.
  • 4 Department of Thoracic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
  • 5 Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing 100191, China. Electronic address: [email protected].
  • 6 Department of Pulmonary and Critical Care Medicine, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan 430030 Hubei, China. Electronic address: [email protected].
  • 7 Department of Pulmonary and Critical Care Medicine, Shanghai Key Laboratory of Tissue Engineering, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200011, China. Electronic address: [email protected].
  • 8 Department of Pulmonary and Critical Care Medicine, Shanghai Key Laboratory of Tissue Engineering, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200011, China; School of Medicine, Shanghai University, Shanghai 200444, China. Electronic address: [email protected].
PMID: 41475664 DOI: 10.1016/j.jare.2025.12.045
Abstract

Introduction: Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease with limited therapeutic options, thus necessitating novel strategies targeting upstream fibrogenic drivers; the exact impact of Apolipoprotein E (apoE) on IPF and its therapeutic potential remain unexplored.

Objectives: This study aims to identify novel therapeutic targets for pulmonary fibrosis and elucidate the mechanism by which plasma apoE alleviates this condition.

Methods: We conducted an integrated meta-analysis of seven plasma cohorts and two-sample Mendelian randomization to assess apoE's association with IPF risk. CRISPR-engineered APOE-deficient canines and apoE‒/‒ mice were studied for pulmonary fibrosis. Mechanistic studies employed single-cell transcriptomics to identify fibroblast-enriched apoE receptors and SPIDER technology coupled with surface plasmon resonance (SPR) to characterize novel apoE interactors. Therapeutic potential was tested using the LXR Agonist RGX-104 in murine models and human precision-cut lung slices.

Results: Plasma apoE was identified as a robust protective factor against IPF, with genetically elevated levels correlating with improved pulmonary function, and its deficiency in plasma showed potential diagnostic value for IPF. APOE-deficient canines developed spontaneous pulmonary fibrosis, and apoE‒/‒ mice exhibited exacerbated bleomycin-induced pulmonary fibrosis, reversible by tail vein injection of recombinant apoE protein. Fibroblast-specific enrichment of LRP1 and identification of PLAU as a high-affinity apoE interactor were observed. Mechanistically, apoE suppressed TGF-β/Smad-driven fibroblast activation via dual LRP1/PLAU co-engagement, attenuating α-SMA, Collagen 1, and fibronectin. Pharmacological LXR activation (RGX-104) rescued apoE expression, reduced Collagen deposition in vivo, and mitigated fibrosis in human precision-cut lung slices.

Conclusions: Plasma apoE is a causal guardian against pulmonary fibrogenesis, inhibiting TGF-β/Smad signaling through dual receptor (LRP1/PLAU) engagement. Cross-species validation and mechanistic elucidation position RGX-104, a small-molecule LXR Agonist, as a potential therapeutic candidate for clinical translation in IPF.

Keywords

Apolipoprotein E; Fibroblasts; Idiopathic pulmonary fibrosis; Mendelian randomization; RGX-104.

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