Postnatal deletion of ZIP9 leads to premature mortality and hippocampal-dependent cognitive decline with disrupted brain–gut–lipid homeostasis

Background Androgen decline during aging contributes to cognitive impairment; androgen supplementation can improve these conditions. The zinc transporter ZIP9 has been identified as a membrane androgen receptor; however, its role in brain health remains poorly understood, particularly in in vivo models. Methods Hippocampal ZIP9 conditional knockout mice were generated. Behavior experiments were performed and key genes involved in synaptic plasticity was assessed to evaluate brain function. Hippocampal neuroinflammatory cytokine levels were quantified using ELISA. Mechanistic insights were derived from hippocampal bulk RNA sequencing, integrated with gut microbiome 16S rRNA sequencing, serum and hippocampal metabolomic profiles. Results Hippocampal ZIP9 knockout shortened the lifespan of mice, induced memory deficits, neuroinflammation and reduced synaptic PSD95 levels. Hippocampal ZIP9 expression declined with age in naturally aged mice. Multi-omics analysis revealed differential gene expression (downregulation of Adcyap1, Ddc, Pla2g2f, Galnt15, Hspb1 , upregulation of Tac2, Cd44 and Akr1b8 ) like aged brain, altered gut microbiota characterized by an enrichment of Tyzzerella and reductions in Lachnospiraceae_NK4A136_group , and hippocampal lipid remodeling, notably in cardiolipin levels. Conclusions Conditional hippocampal ZIP9 deletion accelerates brain aging, promoting cognitive decline, neuroinflammation and synaptic impairment, and leads to premature mortality. These alterations are associated with gut microbiota shifts and lipid dysregulation. Our findings suggest that ZIP9 may link brain, gut, and lipid homeostasis during aging, providing a foundation for future mechanistic studies to dissect the causal relationships within this network.