Hesperetin activates the Hmgcs2-Pparα-Cisd2 signaling axis and delays liver aging

Aging is a major risk factor for metabolic liver disorders, yet the molecular mechanisms driving hepatic aging remain incompletely understood. Here, we identify the 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 candidate 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.