GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE299nnn/GSE299164/primaryOK200TranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE299164GEOGSEfalsePharmacological Activation of the LXR-APOE Axis by RGX-104 Attenuates Pulmonary Fibrosis through LRP1 and PLAU Dual Receptor-Mediated TGF-β/Smad InhibitionIdiopathic pulmonary fibrosis (IPF), a fatal interstitial lung disease with limited therapeutic options, urgently requires novel strategies targeting upstream fibrogenic drivers. Through integrated meta-analysis of seven plasma cohorts and two-sample Mendelian randomization (MR), we identified apolipoprotein E (APOE) as a robust protective factor against IPF, with genetically elevated APOE levels correlating positively with pulmonary function. Plasma APOE depletion in IPF patients demonstrated superior diagnostic accuracy. CRISPR-engineered APOE-deficient canines spontaneously developed pulmonary fibrotic lesions, whereas Apoe‒/‒ mice exhibited exacerbated bleomycin-induced fibrosis, which was reversed by recombinant APOE protein administration. Single-cell transcriptomics revealed fibroblast-specific enrichment of the APOE receptor LRP1, and SPIDER technology coupled with surface plasmon resonance (SPR) identified PLAU as a novel high-affinity APOE interactor. Mechanistically, APOE suppressed TGF-β/Smad-driven fibroblast activation through dual receptor co-engagement (LRP1 and PLAU), attenuating α-SMA, collagen 1, and fibronectin expression. Pharmacological activation of the LXR‒APOE axis via RGX‒104, a small-molecule LXR agonist, rescued Apoe expression, reduced collagen deposition in murine models, and mitigated fibrotic marker expression in human precision-cut lung slices. This work establishes APOE as a causal guardian against fibrogenesis via LRP1/PLAU-mediated TGF-β/Smad inhibition, bridging genetic epidemiology with therapeutic discovery. Our cross-species validation and mechanistic elucidation position RGX-104 as a promising candidate for clinical translation in IPF.2026/09/09GSE299164GSM9034730GSM9034723GSM9034722GSM9034721GSM9034731GSM9034720GSM9034727GSM9034726GSM9034725GSM9034724GSM9034729GSM903472834284299164Homo sapiens[41475664]