{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE336nnn/GSE336868/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Transcriptomics"],"species":["Mus musculus"],"gds_type":["Expression profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE336868"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"HMGCS2-PPARα signaling activates the prolongevity gene CISD2 to delay liver aging","description":"Aging is a major risk factor for metabolic liver disorders, yet the molecular mechanisms driving hepatic aging remain incompletely understood. Here, we identify an HMGCS2-PPARα signaling pathway that regulates the prolongevity gene CISD2 and liver aging. Using naturally aged mice, we show that late-life administration of the citrus flavonoid hesperetin restores hepatic CISD2 expression, improves liver pathology, and partially reverses aging-associated transcriptomic alterations. Mechanistically, we identify HMGCS2 as a molecular target of hesperetin and demonstrate that HMGCS2 interacts with PPARα to activate CISD2 transcription through a PPAR response element (PPRE) in the CISD2 promoter. Genetic and transcriptomic analyses reveal that the protective effects of hesperetin are largely CISD2-dependent, as they are significantly attenuated in hepatocyte-specific Cisd2 knockout mice. Consistent with these findings, PPARα and CISD2 expression decline with age in human liver tissues. Together, our results define a signaling axis linking HMGCS2, PPARα, and CISD2 that regulates liver aging and suggest that targeting this pathway may represent a strategy to mitigate age-associated hepatic dysfunction.","dates":{"publication":"2026/08/09"},"accession":"GSE336868","cross_references":{"GSM":["GSM9843920","GSM9843921","GSM9843922","GSM9843923","GSM9843924","GSM9843925","GSM9843926","GSM9843927","GSM9843939","GSM9843917","GSM9843918","GSM9843919","GSM9843930","GSM9843931","GSM9843932","GSM9843933","GSM9843934","GSM9843935","GSM9843936","GSM9843915","GSM9843937","GSM9843916","GSM9843938","GSM9843928","GSM9843929"],"GPL":["17021","21626"],"GSE":["336868"],"taxon":["Mus musculus"]}}