Alzheimer’s disease (AD) is a catastrophic neurodegenerative disorder marked by progressive decline of cognitive function, memory loss, and neuronal death. Its pathology is characterized by the formation of extracellular amyloid-beta (Aβ) plaques and intracellular neurofibrillary tangles from tau hyperphosphorylation. Despite extensive research, current treatments are limited to symptomatic relief and are associated with significant side effects. This accentuates the critical need for alternative therapeutic strategies with potent neuroprotective effects and minimal toxicity. This study investigates the neuroprotective potential of glycyrrhizic acid, as the precise molecular mechanisms by which it might improve AD pathology remain poorly understood. Using an Aβ₄₂-induced IMR-32 cell model of AD, our research revealed that Aβ₄₂ treatment caused significant protein alterations associated with AD pathology, mitochondrial dysfunction, cell cycle re-entry, and synaptic activity. Co-treatment with glycyrrhizic acid not only restored these protein levels, but also mitigated the hyperactivation of several key signaling pathways and rescued neurons from apoptosis. These findings suggest that glycyrrhizic acid exerts neuroprotective effects by preventing mitochondrial dysfunction and apoptosis via modulation of critical signaling pathways. This study provides strong evidence for glycyrrhizic acid’s neuroprotective properties in AD, paving the way for further research into its potential as a promising therapeutic agent for Alzheimer’s disease.

Phosphorylation driven dysregulation of intracellular signaling networks is a central feature of cancer initiation, progression, and therapeutic resistance. Although Annona muricata leaf extracts have demonstrated anticancer activity across multiple experimental models, the underlying molecular mechanisms particularly at the level of phosphorylation dependent signaling remain poorly understood. In this study, we employed a tandem mass tag TMT-based quantitative phosphoproteomic approach to systematically characterize signaling alterations induced by methanolic Annona muricata leaf extract (AME) in oral squamous cell carcinoma (OSCC) CAL-27 cells. Functional assays revealed that AME significantly inhibited cell proliferation, migration, and clonogenic survival. Global phosphoproteomic profiling identified 6,362 phosphopeptides corresponding to 1,964 unique phosphorylation sites across nearly 7,000 phosphoproteins. AME treatment induced widespread, time-dependent hypophosphorylation, indicating a coordinated suppression of oncogenic signaling networks. Pathway and network analyses revealed marked inhibition of signaling pathways associated with key oncogenic kinases, including cyclin-dependent kinases (CDKs), mitogen-activated protein kinases (MAPKs), and signaling modules linked to EGFR and mTOR pathways. Kinase-substrate enrichment and kinome mapping further demonstrated reduced inferred activity of CDK and MAPK driven signaling, accompanied by suppression of cell cycle progression, mitosis, and checkpoint regulation. Collectively, these findings demonstrate that AME induces systems-level remodeling of phosphorylation dependent signaling networks, enforcing a growth-restrictive cellular state in OSCC cells. This study highlights quantitative phosphoproteomics as a powerful strategy for dissecting natural product mediated regulation of oncogenic signaling and provides mechanistic insight into the anticancer potential of Annona muricata .