Omics · study · 2026
Pharmacological Activation of the LXR-APOE Axis by RGX-104 Attenuates Pulmonary Fibrosis through LRP1 and PLAU Dual Receptor-Mediated TGF-β/Smad Inhibition
Listed in NCBI GEO
Idiopathic pulmonary fibrosis (IPF), a fatal interstitial lung disease with limited therapeutic options, urgently requires novel strategies targeting upstream fibrogenic drivers.
Description
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.
Read the rest (2 more)
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.
Links
Get the data
- GEO FTP directory ftp.ncbi.nlm.nih.gov/geo/series/GSE299nnn/GSE299164 ↗
download · from NCBI GEO
Where it is published
- GEO accession page ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE299164 ↗
landing page · from NCBI GEO
Documentation and papers
- PRJNA1273007 ncbi.nlm.nih.gov/bioproject/PRJNA1273007 ↗
project · from NCBI GEO
- PubMed 41475664 pubmed.ncbi.nlm.nih.gov/41475664 ↗
publication · from NCBI GEO
Topics
- Stated by source
- Expression profiling by high throughput sequencing · Homo sapiens
- From keywords
- Life Sciences
- Inferred from text
- Disease 75%
Provenance · 1 source records, 8 field assertions
| Source | Key | Last seen | Raw |
|---|---|---|---|
| NCBI GEO | GSE299164 | 15 d ago | JSON v1 |
| Field | Assertion | Extractor | Evidence |
|---|---|---|---|
| access_level | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[disease].local:disease:disease | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (75%) |
| concepts[field].local:field:life-sciences | mapping · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[method].geo_series_type:expression-profiling-by-high-throughput-sequencing | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /gdstype |
| concepts[organism].NCBITaxon:9606 | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /taxon |
| description | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /summary |
| publication_date | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| title | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /title |