Nobiletin Modulates Transcriptomic and Metabolomic Alterations in Aβ42-Induced Primary Rat Astrocytes: Implications for Alzheimer's Disease.

Beta-amyloid (Aβ) aggregates interact with glial cells, particularly astrocytes, leading to altered morphology, disrupted homeostasis, and ultimately contributing to neurodegeneration in Alzheimer's disease (AD). Astrocytes, once considered passive support cells, are now recognized as active participants in neuroinflammatory and neurodegenerative cascades. Recent research has highlighted profound transcriptomic and metabolomic disturbances in astrocytes under AD pathology, implicating them as key players in disease progression. Nobiletin (NOB), a polymethoxylated flavonoid abundantly found in citrus peels, is known for its anti-inflammatory, antioxidant, and neuroprotective properties. However, its effects on the integrated transcriptomic and metabolomic landscape of Aβ42-induced primary rat astrocytes (PRAs) have not been fully elucidated. In this study, PRAs were treated with Aβ42 (4 µM) in the presence or absence of NOB (20 and 40 µM), for 50 min and 24 h, followed by high-throughput RNA sequencing and comprehensive metabolomic profiling. NOB significantly modulated several AD-associated molecular pathways, including acetate utilization, chemokine- and cytokine-mediated inflammatory signaling, and cholesterol biosynthesis. Additionally, metabolomic analysis revealed notable alterations in cytidine, guanosine, S-lactoylglutathione, and 2'-deoxycytidine. Integrated analysis of transcriptomic and metabolomic data showed that NOB influenced crucial pathways such as ABC transporters, steroid biosynthesis, and amino acid metabolism, including glycine, serine, and threonine metabolism and alanine, aspartate, and glutamate metabolism. These findings demonstrate that NOB might modulate transcriptional and metabolomic alterations induced by Aβ42 exposure in astrocytes, offering new insights into its multitargeted neuroprotective actions. This study supports the potential of NOB as a promising therapeutic candidate for mitigating astrocyte-mediated neuroinflammation and metabolic dysfunction in AD.