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

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: 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: 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.