GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE336nnn/GSE336868/primaryOK200TranscriptomicsMus musculusExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE336868GEOGSEfalseHMGCS2-PPARα signaling activates the prolongevity gene CISD2 to delay liver agingAging 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.2026/08/09GSE336868GSM9843920GSM9843921GSM9843922GSM9843923GSM9843924GSM9843925GSM9843926GSM9843927GSM9843939GSM9843917GSM9843918GSM9843919GSM9843930GSM9843931GSM9843932GSM9843933GSM9843934GSM9843935GSM9843936GSM9843915GSM9843937GSM9843938GSM9843916GSM9843928GSM98439291702121626336868Mus musculus