{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T05:04:45Z","timestamp":1783919085983,"version":"3.55.0"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T00:00:00Z","timestamp":1783900800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012521","name":"Universitas Gadjah Mada","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100012521","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Inborn errors of metabolism (IEM) are a heterogeneous group of genetic disorders characterized by metabolic dysregulation and high mortality. Despite extensive genetic discoveries, the molecular mechanisms underlying severe disease progression remain incompletely understood. Increasing evidence suggests that host metabolic states, particularly lipid dysregulation, can profoundly influence immune cell function and may contribute to impaired responses against intracellular pathogens.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We integrated genomic data from four high-confidence databases (GWAS Catalog, CTD, Open Targets, and ClinVar) and identified 1,288 IEM-associated genes. Disease ontology enrichment, multi-parametric functional annotation, and cell-type enrichment analyses were performed using Open-XGR, WebGestalt, and Tabula Sapiens. Bioinformatics findings were interpreted alongside clinical and cytomorphological observations from a pair of one-year-old twins with suspected IEM and macrophage activation syndrome. No patient-specific genetic or molecular validation of APOE was available.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Functional annotation identified APOE as the highest-scoring gene across seven biological categories, with enrichment in lipid metabolism- and macrophage-related pathways. Cell-type enrichment demonstrated an overrepresentation of IEM-associated genes in macrophage-related reference signatures, including datasets annotated as M2 macrophages. APOE was the only gene consistently represented across macrophage, M2 macrophage, protein\u2013lipid complex, and vasculature-associated macrophage categories. Clinical evaluation of the twin cases showed persistent hyperbilirubinemia, elevated transaminases, cholestasis, and macrophage activation. Bone marrow and cerebrospinal fluid cytology demonstrated lipid-laden monocyte\/macrophage morphology. These clinical observations are concordant with lipid-handling abnormalities in macrophages but do not establish an APOE-dependent mechanism or macrophage polarization state.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study identifies APOE as a highly prioritized candidate gene associated with lipid metabolism pathways and macrophage-related signatures in IEM. These findings support the hypothesis that APOE-associated lipid dysregulation may contribute to macrophage dysfunction and warrant further experimental validation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1880997","type":"journal-article","created":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T04:23:09Z","timestamp":1783916589000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrative bioinformatics analysis identifies APOE as a candidate link between lipid dysregulation and macrophage activation in inborn errors of metabolism"],"prefix":"10.3389","volume":"17","author":[{"given":"Rahmat Dani","family":"Satria","sequence":"first","affiliation":[{"name":"Clinical Pathology and Laboratory Medicine, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada","place":["Yogyakarta, Indonesia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riswan 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