Hippo-YAP/TAZ signalling at the crossroads of brain ageing and neurological disorders: mechanisms, crosstalk, and therapeutic prospects.

As life expectancy increases globally, ageing has emerged as the main risk factor driving the increasing burden of neurological disorders. Although advances have been made in understanding their pathogenesis, current therapies remain largely symptomatic and do not prevent disease progression. There is a growing body of evidence that these disorders share common molecular mechanisms, including oxidative stress, mitochondrial dysfunction, neuroinflammation, impaired autophagy, ferroptosis, and blood-brain barrier disruption. Recently, the Hippo signalling pathway has been identified as a key regulator of these processes through its downstream effectors Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ). In addition to its well-characterised functions in the regulation of organ size and tissue regeneration, Hippo signalling has crucial roles in neuronal survival, maintenance of neural stem cells, synaptic plasticity, neurovascular integrity and cellular responses to metabolic and mechanical stress. Dysregulation of this pathway in aging contributes to cellular senescence, impaired tissue repair and progressive neurodegeneration. This review summarizes the physiological functions of Hippo-YAP/TAZ signaling in the aging brain and discusses its mechanistic involvement in major neurological disorders. We further highlight the extensive crosstalk between Hippo signalling and key pathways regulating inflammation, oxidative stress, autophagy, and mitochondrial homeostasis. Finally, recent advances in therapeutic strategies targeting Hippo signalling, including small-molecule modulators, drug-repurposing approaches, and natural bioactive compounds, are discussed along with current challenges and future perspectives. Collectively, the available evidence positions the Hippo-YAP/TAZ pathway as a promising therapeutic target for developing disease-modifying interventions against ageing-associated neurological disorders.