Essential Oils From the Fruit of Amomum villosum Lour. Alleviate LPS ‐Induced Neuroinflammation by Repressing PI3K ‐Akt and MAPK Signaling Pathways

ABSTRACT Amomum villosum Lour. has been traditionally valued in various cultures for its health benefits. Here, we show that the neuroprotective effects of the essential oils extracted from the fruit of Amomum villosum Lour. (AVEO) and elucidate its underlying mechanisms in lipopolysaccharide (LPS)‐induced neuroinflammation. The main compounds of AVEO can cross the blood–brain barrier and significantly improve cognitive and behavioral dysfunction in LPS‐induced mice, leading to a 50% enhancement in Morris water maze performance, a 60% and 80% reduction in immobility time in the tail suspension test and forced swimming test, respectively. Moreover, AVEO mitigates neuron loss and suppresses the expression of pro‐inflammatory mediators, including TNF‐α, IL‐1β, and IL‐6, while upregulating the anti‐inflammatory cytokine IL‐10 in brain tissue. RNA‐seq and metabonomics analyses reveal that AVEO modulates multiple inflammation‐related pathways and restore metabolic homeostasis in brain tissue. Remarkably, AVEO attenuates hyperactivation of the PI3K‐Akt and MAPK signaling pathways in LPS‐induced microglia and improves neuronal damage in LPS‐induced microglia–neuron co‐culture system. Altogether, our findings suggest that AVEO alleviates neural dysfunction by modulating PI3K‐Akt and MAPK signaling cascades and promoting metabolic reprogramming upon neuroinflammation, thereby revealing the therapeutic potential of AVEO in several neurological disorders.