Molecular mechanisms of perimenopausal cognitive impairment in a rat model: multi-omics integration reveals the Adgrl2-Camk2d-TRPV1 signaling axis mediating calcium homeostasis disruption and neuroinflammation

Background Perimenopause represents a pivotal transitional stage in female reproductive aging, often accompanied by neurological disorders such as cognitive decline. However, the underlying molecular mechanisms remain incompletely understood. Methods In this study, a total of 18 eight-week-old female Sprague–Dawley (SD) rats were randomly divided into the control group and the perimenopausal syndrome (PMS) model group induced by bilateral ovariectomy (OVX). We systematically investigated the regulatory mechanisms of perimenopausal cognitive impairment by integrating behavioral assessments, histopathological examinations, biochemical and molecular validation, as well as multi-omics approaches, including transcriptomics, metabolomics, and ionomics. Results The results showed that PMS rats displayed marked cognitive deficits alongside evident pathological alterations in hippocampal neurons. Differentially expressed genes were enriched in the inflammatory mediator regulation of transient receptor potential (TRP) channels pathway. Adhesion G protein-coupled receptor L2 (Adgrl2) and calcium/calmodulin-dependent protein kinase II delta (Camk2d) were synergistically upregulated, driving activation of the transient receptor potential vanilloid 1 (TRPV1) channel, which induced Ca 2+ homeostasis imbalance and calcium overload. Adgrl2 was specifically highly expressed in microglia, accompanied by elevated levels of interleukin-6 (IL-6) and tumor necrosis factor- α (TNF-α), forming a vicious cycle of Ca 2+ -inflammation. Metabolomics analysis also revealed widespread metabolic disorders involving pathways such as amino acid and energy metabolism. Conclusion The Adgrl2-Camk2d-TRPV1 signaling axis is a core driver pathway of perimenopausal cognitive impairment, exacerbating neuronal damage by mediating calcium overload, neuroinflammation, and metabolic disorders. This discovery provides a novel pathological mechanism for perimenopausal cognitive impairment, identifies Adgrl2 and TRPV1 as potential therapeutic targets, and designates Ca 2+ as an ideal diagnostic biomarker, offering significant support for clinical diagnosis, treatment, and related theoretical research.