To appreciate why this claim matters, it helps to understand what the Hippo pathway actually does. First characterised in Drosophila, where its effector protein was colourfully named Yorkie, the pathway is an evolutionarily conserved kinase cascade that regulates organ size by balancing cell proliferation against cell death. In mammals, upstream kinases such as MST1 and MST2 activate LATS1 and LATS2, which in turn phosphorylate the transcriptional co-activators YAP and TAZ. When phosphorylated, YAP and TAZ are retained in the cytoplasm and degraded; when the pathway is off, they slip into the nucleus and bind TEAD transcription factors to switch on genes governing growth, survival, and regeneration. The pathway is exquisitely sensitive to mechanical cues, responding to the stiffness of the extracellular matrix, cell shape, and fluid shear stress, which makes it a kind of molecular barometer of the tissue environment.

In the brain, this barometer reads far more than mechanical pressure. The review assembles evidence that Hippo–YAP/TAZ signalling governs neuronal survival, maintains neural stem and progenitor cells, shapes synaptic plasticity, and preserves the integrity of the neurovascular unit. During development, YAP and TAZ sustain the proliferative capacity of radial glial cells and are required for the cerebellar scaffold to form properly, while transcription factors of the TEAD family are involved in neural tube closure. In adulthood, the same machinery appears to regulate the fate choices of oligodendrocyte precursor cells and the ependymal cells that line the brain’s fluid-filled ventricles. KIBRA, a pathway-associated protein, has even been linked to human memory performance in genetic studies, hinting that the pathway’s reach extends into cognition itself.

What happens when this system drifts out of tune with age? According to the review, dysregulation of Hippo signalling contributes to cellular senescence, impaired tissue repair, and progressive neurodegeneration. Ageing brains accumulate oxidative stress, mitochondrial dysfunction, and DNA damage, and YAP/TAZ sit at several of these crossroads simultaneously. In Alzheimer’s disease models, age-dependent reduction of YAP1 worsens pathology through an Nr4a1–AKT/GSK-3β axis, while YAP loss in astrocytes promotes premature senescence and cognitive decline via CDK6 signalling. Conversely, inhibiting the LATS kinases in 5xFAD mice increased neuronal resilience against ferroptosis, an iron-dependent form of cell death, and protected against cognitive decline. In Huntington’s disease, a distinctive form of TEAD/YAP-transcription-dependent necrosis dubbed TRIAD occurs in early stages, and the pathway is measurably dysregulated in human Huntington’s brains and neuronal stem cells.

Parkinson’s disease offers another instructive case. Deficiency of the guidance molecule netrin-1 activates MST1 through the UNC5B receptor, promoting apoptotic death of dopaminergic neurons, and progressive loss of prosurvival YAP isoforms has been documented in the spinal cords of SOD1 mutant mice modelling ALS. On the therapeutic side, a LATS inhibitor protected against 6-OHDA-induced neuronal death both in vitro and in vivo, and astrocytic YAP was shown to shield degenerating neurons in C9orf72 poly-GA mice through Wnt/β-catenin/EAAT2 signalling, a mechanism of self-protection the authors highlight as previously unrecognised. Adding to the picture, recent work indicates that YAP helps maintain the liquid dynamics of TDP-43 condensates and opposes the pathological aggregates characteristic of ALS and frontotemporal dementia.

One of the review’s central themes is crosstalk. Hippo signalling does not operate in isolation but is interwoven with the major pathways that define the ageing brain. It intersects with the insulin/IGF-1 and mTOR axes that regulate lifespan, with Wnt/β-catenin signalling through YAP/TAZ incorporation into the β-catenin destruction complex, and with the AMPK–Sirtuin 1–YAP axis that controls autophagy flux. MST1 is a known regulator of autophagy and mitophagy, and glucose sensing enters the picture through O-GlcNAcylation, which modifies Hippo pathway components in response to nutrient state. A landmark Nature study cited in the review showed that YAP/TAZ activity in stromal cells prevents ageing by controlling the cGAS–STING innate immune pathway, positioning the pathway as a genuine hub where mechanical, metabolic, and inflammatory signals converge.

Inflammation is where this convergence becomes clinically vivid. Hippo/MST1 signalling mediates microglial activation after acute cerebral ischaemia–reperfusion injury, and recent work shows that regional, cell-type-specific activation of YAP/TAZ underlies glial responses in modelled neuroinflammation. Matrix stiffness regulates interleukin-10 secretion in human microglia through YAP-mediated mechanotransduction, meaning that the physical scarring of brain tissue may directly tune its inflammatory tone. In the vasculature, YAP/TAZ regulate sprouting angiogenesis and vascular barrier maturation; Hippo/YAP signalling mitigates blood–brain barrier disruption after ischaemic injury, and endothelial YAP/TAZ loss alters the chronic stroke lesion environment. Neuroprotective effects of insulin-like growth factor 1 after cerebral ischaemia appear to be mediated through the Hippo/YAP pathway via the PI3K/AKT cascade.

Translational prospects follow from this mechanistic map. The review surveys small-molecule modulators of the pathway, drug-repurposing strategies, and natural bioactive compounds. An Artemisia annua extract improved cognitive deficits and reversed Alzheimer-like pathology in models through YAP regulation, while the traditional formula Shengxian decoction alleviated experimental autoimmune myasthenia gravis by enhancing regulatory T-cell activity via the Hippo pathway, and Jiajian Shuyu pills ameliorated cerebral ischaemia–reperfusion injury by modulating Hippo signalling and the lipid metabolism–ferroptosis axis. There is even evidence that drugs used for bipolar disorder and schizophrenia transcriptionally modulate the pathway, raising repurposing possibilities. Inhibiting Hippo pathway kinases released WWC1 to promote AMPAR-dependent synaptic plasticity and long-term memory in mice, a result that directly ties the pathway to learning and memory mechanisms.

Yet the authors are candid about the challenges. YAP/TAZ are double-edged swords: the same co-activators that support neuronal survival and regeneration are amplified in medulloblastomas and drive ependymoma-like tumour formation in mice, so systemic activation carries oncogenic risk. Achieving the right dose, duration, and cell-type specificity of any intervention will be critical, particularly given the pathway’s divergent roles in neurons, astrocytes, microglia, endothelial cells, and neural stem cells. Most evidence remains preclinical, drawn from cell culture and animal models, and no Hippo-targeted therapy for a neurodegenerative disease has yet reached the clinic. Delivery across the blood–brain barrier adds a further layer of difficulty.

Even so, the synthesis is compelling. As global life expectancy rises, ageing has become the dominant risk factor for neurological disease, and current symptomatic therapies do not slow its march. A pathway that simultaneously touches senescence, ferroptosis, autophagy, mitochondrial homeostasis, neuroinflammation, and vascular integrity is exactly the kind of convergent target that field has been searching for. If the coming decade can deliver pathway modulators that are safe, brain-penetrant, and cell-type selective, the humble relay that once set the size of a fly’s wing may yet help set the trajectory of the ageing human brain, shifting neurology from managing decline toward preserving resilience.

Subject of Research: Role of Hippo–YAP/TAZ signalling in brain ageing and neurological disorders

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

Article References: Hippo–YAP/TAZ signalling at the crossroads of brain ageing and neurological disorders: mechanisms, crosstalk, and therapeutic prospects. (n.d.). https://doi.org/10.1007/s10522-026-10526-w

Image Credits: AI Generated

DOI: 10.1007/s10522-026-10526-w

Keywords: Hippo signalling, YAP/TAZ, brain ageing, neurodegeneration, Alzheimer's disease, Parkinson's disease, neuroinflammation, cellular senescence, ferroptosis, blood–brain barrier, autophagy, therapeutic targeting