{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE328nnn/GSE328627/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Transcriptomics"],"species":["Homo sapiens"],"gds_type":["Expression profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE328627"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"Clinically approved HIF‑PHIs modulate redox metabolism, cell growth, and angiogenesis independent of HIF‑1α/HIF‑2α","description":"HIF-prolyl hydroxylase inhibitors are used to treat anemia in chronic kidney disease. These drugs stabilize hypoxia-inducible factors HIF-1α and HIF-2α, which activate erythropoiesis and iron metabolism pathways. Clinically approved HIF-PHIs including roxadustat and molidustat exhibit distinct molecular structures and selectivity profiles, yet their HIF-independent effects remain poorly understood. Here we show that roxadustat and molidustat modulate mitochondrial function, oxidative stress, lysosomal activity, and lipid accumulation, resulting in distinct cellular phenotypes in HIF-null cells. Notably, roxadustat exhibited anti-proliferative and anti-angiogenic activity in HIF-null cells, contradicting expectations of VEGF-driven angiogenesis via HIF stabilization. RNA sequencing and pathway analysis revealed compound-specific off-target gene regulation affecting cellular processes beyond canonical hypoxia responses including energy metabolism and immune signaling. These findings illuminate mechanisms underlying potential adverse effects- such as thrombosis- and identify alternative therapeutic pathways, providing a framework for optimizing HIF-PHI safety profiles and expanding their clinical applications in oncology and metabolic disorders.","dates":{"publication":"2026/05/21"},"accession":"GSE328627","cross_references":{"GSM":["GSM9686194","GSM9686195","GSM9686196","GSM9686197","GSM9686198","GSM9686199","GSM9686200","GSM9686201"],"GPL":["16791"],"GSE":["328627"],"taxon":["Homo sapiens"],"PMID":["[42150425]"]}}