{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T05:26:40Z","timestamp":1787030800850,"version":"build-2736575974"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:00:00Z","timestamp":1787011200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Aberrant tissue repair and relentless fibroblast activation are hallmark features of idiopathic pulmonary fibrosis (IPF). Although IPF and Alzheimer\u2019s disease (AD) share underlying aging-related pathologies, including immune and metabolic dysregulation, the putative genetic mechanisms linking AD susceptibility to pathogenic macrophage remodeling in the fibrotic niche are not fully established.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We performed a two-sample Mendelian randomization (MR) analysis to assess the genetic association and potential causal relationship between AD and IPF. Shared hub genes were identified via protein interaction networks. To characterize macrophage heterogeneity and intercellular crosstalk within the IPF microenvironment, we interrogated scRNA-seq data (GSE122960) utilizing Monocle 3 and CellChat algorithms. The functional essentiality of APOE was evaluated bridging computational virtual knockout (scTenifoldKnk) with laboratory\n                      <jats:italic>in vitro<\/jats:italic>\n                      assays. Specifically, downstream transcriptomic shifts and fibroblast activation capacities were validated using APOE-silenced THP-1 macrophages and a Transwell co-culture model with MRC-5 cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      MR estimates indicated that genetic liability to AD is associated with a lower risk of developing IPF. Integrated profiling identified the lipid-metabolism gene APOE as a central hub, specifically enriched in lung macrophages. Pseudotime modeling captured a pathogenic bifurcation in IPF, where macrophages evolve toward a terminal state marked by profound oxidative phosphorylation defects and massive SPP1 secretion. These SPP1+ macrophages primarily activate fibroblasts via CD44 and integrin signaling axes. Furthermore, both virtual simulations and\n                      <jats:italic>in vitro<\/jats:italic>\n                      THP-1 experiments demonstrated that loss of APOE function triggers the hyperactivation of complement (C1QA) and antigen-presentation (HLA-DR) pathways. Co-culture assays ultimately confirmed that APOE ablation in macrophages strongly exacerbates myofibroblast differentiation (elevated \u03b1-SMA and collagen I) in adjacent MRC-5 cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      APOE functions as a vital metabolic barrier against pro-fibrotic macrophage polarization in the lung. Disruption of this specific lipid metabolic network is strongly associated with SPP1-driven fibroblast activation and local immune imbalance, providing a theoretical framework that strictly warrants future\n                      <jats:italic>in vivo<\/jats:italic>\n                      investigation to determine its clinical relevance.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1904638","type":"journal-article","created":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:28:00Z","timestamp":1787027280000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Multi-omics integration identifies APOE as a metabolic regulator of macrophage-fibroblast crosstalk in idiopathic pulmonary fibrosis"],"prefix":"10.3389","volume":"17","author":[{"given":"Bing","family":"Bai","sequence":"first","affiliation":[{"name":"Department of General Practice, Fuhua Street Community Health 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