The dynamic expression of YAP is essential for the development of male germ cells derived from human embryonic stem cells.

YAP plays a vital role in controlling growth and differentiation in various cell lineages. Although the expression of YAP in mice testicular and spermatogenic cells suggests its role in mammalian spermatogenesis, the role of YAP in the development of human male germ cells has not yet been determined. Using an in vitro model and a gene editing approach, we generated human spermatogonia stem cell-like cells (hSSLCs) from human embryonic stem cells (hESCs) and investigated the role of YAP in human spermatogenesis. The results showed that reducing YAP expression during the early stage of spermatogenic differentiation increased the number of PLZF+ hSSLCs and haploid spermatid-like cells. We also demonstrated that the up-regulation of YAP is essential for maintaining spermatogenic cell survival during the later stages of spermatogenic differentiation. The expression of YAP that deviates from this pattern results in a lower number of hSSLCs and an increased level of spermatogenic cell death. Taken together, our result demonstrates that the dynamic expression pattern of YAP is essential for human spermatogenesis. Modulating the level of YAP during human spermatogenesis could improve the production yield of male germ cells derived from hESCs, which could provide the optimization method for in vitro gametogenesis and gain insight into the application in the treatment of male infertility.

NEDD8 enhances Hippo signaling by mediating YAP1 neddylation.

The Hippo-YAP signaling pathway plays a central role in many biological processes such as regulating cell fate, organ size and tissue growth, and its key components are spatiotemporally expressed and post-translationally modified during these processes. Neddylation is a post-translational modification that involves the covalent attachment of NEDD8 to target proteins by NEDD8-specific E1-E2-E3 enzymes. Whether neddylation is involved in Hippo-YAP signaling remains poorly understood. Here, we provide evidence supporting the critical role of NEDD8 in facilitating the Hippo-YAP signaling pathway by mediating neddylation of the transcriptional coactivator Yes-associated protein 1 (YAP1). Overexpression of NEDD8 induces YAP1 neddylation and enhances YAP1 transactivity, but inhibition of neddylation suppresses YAP1 transactivity and attenuates YAP1 nuclear accumulation. Furthermore, inhibition of YAP1 signaling promotes MLN4924-induced GCs apoptosis and disruption of nedd8 in zebrafish results in downregulation of yap1-activated genes and upregulation of yap1-repressed genes. Further assays show that the xiap ligase promotes nedd8 conjugates to yap1 and that yap1 neddylation. In addition, we identify lysine 159 as a major neddylation site on YAP1. These findings reveal a novel mechanism for neddylation in the regulation of Hippo-YAP signaling.

WWC1 upregulation accelerates hyperuricemia by reduction of renal uric acid excretion through Hippo signaling pathway.

Hyperuricemia (HUA) is a metabolic disorder characterized by elevated serum uric acid (UA), primarily attributed to the hepatic overproduction and renal underexcretion of UA. Despite the elucidation of molecular pathways associated with this underexcretion, the etiology of HUA remains largely unknown. In our study, using by Uox knockout rats, HUA mouse and cell line models, we discovered that the increased WWC1 levels were associated with decreased renal UA excretion. Additionally, using by knockdown and overexpression approaches, we found that WWC1 inhibited UA excretion in renal tubular epithelial cells. Mechanistically, WWC1 activated the Hippo pathway, leading to phosphorylation and subsequent degradation of the downstream transcription factor YAP1, thereby impairing the ABCG2 and OAT3 expression through transcriptional regulation. Consequently, this reduction leaded to a decrease in UA excretion in renal tubular epithelial cells. In conclusion, our study has elucidated the role of upregulated WWC1 in renal tubular epithelial cells inhibiting the excretion of UA in the kidneys and causing HUA.

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The core components of the Hippo signaling pathway encompass upstream regulatory molecules, core kinase cascade complexes, and downstream transcriptional regulation complexes. This pathway modulates cellular biological behaviors by influencing the effector molecules of its core components and plays a pivotal role in immune regulation. Effector molecules,such as Yes-associated protein (YAP), transcriptional coactivator with PDZ-binding motif (TAZ), transcriptional enhanced associate domain transcriptional factor (TEAD), monopolar spindle-one binder (MOB1), large tumor suppressor (LATS), can stimulate fibroblast-like synovial cell migration and invasion in rheumatoid arthritis, regulate osteoarthritis disease progression, promote pathological new bone formation in ankylosing spondylitis, sustain submandibular gland development while delaying Sjogren's syndrome progression, mediate alpha-smooth muscle actin in systemic sclerosis, and refine the regulation of target genes associated with pulmonary fibrosis. This article provides an overview of the regulatory mechanisms involving Hippo signaling pathway-related effector molecules in the pathogenesis and progression of rheumatic immune system diseases, to serve as a reference for exploring novel therapeutic targets of rheumatic immune system diseases.

EGFR and Hippo signaling pathways are involved in organophosphate esters-induced proliferation and migration of triple-negative breast cancer cells.

The widespread application of organophosphate flame retardants has led to pervasive exposure to organophosphate esters (OPEs), prompting considerable concerns regarding their potential health risk to humans. Despite hints from previous research about OPEs' association with breast cancer, their specific effects and underlying mechanisms of triple-negative breast cancer (TNBC) remain unclear. In this study, we investigated the effects of four representative OPEs on cell proliferation, cell cycle regulation, migration, and the expression of genes and proteins associated with the epidermal growth factor receptor (EGFR) and Hippo signaling pathways in TNBC (MDA-MB-231) cells. Our findings revealed that treatment with 1-25 µM triphenyl phosphate (TPHP) and tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) induced TNBC cell proliferation and accelerated cell cycle progression, with upregulation in MYC, CCND1, and BRCA1 mRNA. Moreover, exposure to 1-25 µM TPHP, 10-25 µM TDCIPP, and 1-10 µM tris (2-chloroethyl) phosphate (TCEP) induced MMP2/9 mRNA expression and enhanced migratory capacity, except for 2-ethylhexyl diphenyl phosphate (EHDPP). Mechanistically, four OPEs treatments activated the EGFR-ERK1/2 and EGFR-PI3K/AKT signaling pathways by increasing the transcript of EGFR, ERK1/2, PI3K, and AKT mRNA. OPEs treatment also suppressed the Hippo signaling pathway by inhibiting the expression of MST1 mRNA and phosphorylation of LATS1, leading to the overactivation of YAP1 protein, thereby promoting TNBC cell proliferation and migration. In summary, our study elucidated that activation of the EGFR signaling pathway and suppression of the Hippo signaling pathway contributed to the proliferation, cell cycle dysregulation, and migration of TNBC cells following exposure to OPEs.

Circular RNA HSDL2 promotes breast cancer progression via miR-7978 ZNF704 axis and regulating hippo signaling pathway.

Circular RNAs (circRNAs) are a new group of endogenous RNAs recently found to be involved in the development of various diseases, including their confirmed involvement in the progression of several types of cancers. Unluckily, the abnormal expression and functions of circRNAs in breast cancer shall be further investigated. This work aims to elucidate the action and molecular mechanism of circHSDL2 in the malignant progression of breast cancer. Differential expression profiles of circRNAs in breast cancer tissues relative to normal breast tissues and in the exosomes of breast cancer patients compared to healthy women were analyzed from databases to identify potentially functional circRNAs. CircHSDL2 was selected for further investigation. Cell proliferation, migration and invasion assays were done to assess the effect of circHSDL2 overexpression on breast cancer cells. Bioinformatics test and dual-luciferase reporter experiments were done to explore the interaction between circHSDL2 and miRNA. Downstream target genes were further investigated through proteomics analysis and Western blotting. The influence of circHSDL2 on breast cancer in vivo was evaluated through xenograft experiments in nude mice. Functional analysis demonstrated circHSDL2 overexpression promoted the division, movement, and invasion of breast cancer cells both in vivo and in vitro. Mechanistically, circHSDL2 acted as a sponge for miR-7978 to affect ZNF704 expression and thereby regulate the Hippo pathway in breast cancer cells. In conclusion, circHSDL2 regulates the Hippo pathway through the miR-7978/ZNF704 axis to facilitate the malignancy of breast cancer. This may be a potential biomarker and treatment target.

Molecular Pathways and Animal Models of Hypoplastic Left Heart Syndrome.

Hypoplastic left heart syndrome (HLHS) is a severe congenital heart disease (CHD) with underdevelopment of left-sided heart structures. While previously uniformly fatal, surgical advances now provide highly effective palliation that allows most HLHS patients to survive their critical CHD. Nevertheless, there remains high morbidity and mortality with high risk of heart failure. As hemodynamic compromise from restricted aortic blood flow has been suggested to underlie the poor LV growth, this suggests the possibility of prenatal fetal intervention to recover LV growth. As such interventions have yielded ambiguous results, the optimization of therapy will require more mechanistic insights into the developmental etiology for HLHS. Clinical studies have shown high heritability for HLHS, with an oligogenic etiology indicated in conjunction with genetic heterogeneity. This is corroborated with the recent recovery of mutant mice with HLHS. With availability-induced pluripotent stem cell (iPSC)-derived cardiomyocytes from HLHS mice and patients, new insights have emerged into the cellular and molecular etiology for the LV hypoplasia in HLHS. Cell proliferation defects were observed in conjunction with metaphase arrest and the disturbance of Hippo-YAP signaling. The left-sided restriction of the ventricular hypoplasia may result from epigenetic perturbation of pathways regulating left-right patterning. These findings suggest new avenues for fetal interventions with therapies using existing drugs that target the Hippo-YAP pathway and/or modulate epigenetic regulation.

Acetylcytidine modification of Amotl1 by N-acetyltransferase 10 contributes to cardiac fibrotic expansion in mice after myocardial infarction.

Cardiac fibrosis is a pathological scarring process that impairs cardiac function. N-acetyltransferase 10 (Nat10) is recently identified as the key enzyme for the N4-acetylcytidine (ac4C) modification of mRNAs. In this study, we investigated the role of Nat10 in cardiac fibrosis following myocardial infarction (MI) and the related mechanisms. MI was induced in mice by ligation of the left anterior descending coronary artery; cardiac function was assessed with echocardiography. We showed that both the mRNA and protein expression levels of Nat10 were significantly increased in the infarct zone and border zone 4 weeks post-MI, and the expression of Nat10 in cardiac fibroblasts was significantly higher compared with that in cardiomyocytes after MI. Fibroblast-specific overexpression of Nat10 promoted collagen deposition and induced cardiac systolic dysfunction post-MI in mice. Conversely, fibroblast-specific knockout of Nat10 markedly relieved cardiac function impairment and extracellular matrix remodeling following MI. We then conducted ac4C-RNA binding protein immunoprecipitation-sequencing (RIP-seq) in cardiac fibroblasts transfected with Nat10 siRNA, and revealed that angiomotin-like 1 (Amotl1), an upstream regulator of the Hippo signaling pathway, was the target gene of Nat10. We demonstrated that Nat10-mediated ac4C modification of Amotl1 increased its mRNA stability and translation in neonatal cardiac fibroblasts, thereby increasing the interaction of Amotl1 with yes-associated protein 1 (Yap) and facilitating Yap translocation into the nucleus. Intriguingly, silencing of Amotl1 or Yap, as well as treatment with verteporfin, a selective and potent Yap inhibitor, attenuated the Nat10 overexpression-induced proliferation of cardiac fibroblasts and prevented their differentiation into myofibroblasts in vitro. In conclusion, this study highlights Nat10 as a crucial regulator of myocardial fibrosis following MI injury through ac4C modification of upstream activators within the Hippo/Yap signaling pathway.

Hippo signaling modulation and its biological implications in urological malignancies.

Although cancer diagnosis and treatment have rapidly advanced in recent decades, urological malignancies, which have high morbidity and mortality rates, are among the most difficult diseases to treat. The Hippo signaling is an evolutionarily conserved pathway in organ size control and tissue homeostasis maintenance. Its downstream effectors, Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), are key modulators of numerous physiological and pathological processes. Recent work clearly indicates that Hippo signaling is frequently altered in human urological malignancies. In this review, we discuss the disparate viewpoints on the upstream regulators of YAP/TAZ and their downstream targets and systematically summarize the biological implications. More importantly, we highlight the molecular mechanisms involved in Hippo-YAP signaling to improve our understanding of its role in every stage of prostate cancer, bladder cancer and kidney cancer progression. A better understanding of the biological outcomes of YAP/TAZ modulation will contribute to the establishment of future therapeutic approaches.

Lats1 and Lats2 regulate YAP and TAZ activity to control the development of mouse Sertoli cells.

Recent reports suggest that the Hippo signaling pathway regulates testis development, though its exact roles in Sertoli cell differentiation remain unknown. Here, we examined the functions of the main Hippo pathway kinases, large tumor suppressor homolog kinases 1 and 2 (Lats1 and Lats2) in developing mouse Sertoli cells. Conditional inactivation of Lats1/2 in Sertoli cells resulted in the disorganization and overgrowth of the testis cords, the induction of a testicular inflammatory response and germ cell apoptosis. Stimulated by retinoic acid 8 (STRA8) expression in germ cells additionally suggested that germ cells may have been preparing to enter meiosis prior to their loss. Gene expression analyses of the developing testes of conditional knockout animals further suggested impaired Sertoli cell differentiation, epithelial-to-mesenchymal transition, and the induction of a specific set of genes associated with Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ)-mediated integrin signaling. Finally, the involvement of YAP/TAZ in Sertoli cell differentiation was confirmed by concomitantly inactivating Yap/Taz in Lats1/2 conditional knockout model, which resulted in a partial rescue of the testicular phenotypic changes. Taken together, these results identify Hippo signaling as a crucial pathway for Sertoli cell development and provide novel insight into Sertoli cell fate maintenance.

Emerging Perspectives of YAP/TAZ in Human Skin Epidermal and Dermal Aging.

Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are key downstream effectors of the Hippo signaling pathway, which plays a central role in tissue homeostasis, organ development, and regeneration. While the dysregulation of YAP/TAZ has been linked to various human diseases, their involvement in the aging of human skin has only recently begun to manifest. In the skin, the YAP/TAZ effectors emerge as central regulators in maintaining homeostasis of epidermal stem cells and dermal extracellular matrix, and thus intimately linked to skin aging processes. This review underscores recent molecular breakthroughs highlighting how age-related decline of YAP/TAZ activity impacts human epidermal and dermal aging. Gaining insight into the evolving roles of YAP/TAZ in human skin aging presents a promising avenue for the development of innovative therapeutic approaches aimed at enhancing skin health and addressing age-related skin conditions.

Exposure to microcystin-LR promotes astrocyte proliferation both in vitro and in vivo via Hippo signaling pathway.

Microcystins (MCs) are toxic to the central nervous system of mammals. However, the direct toxicity of MCs on mammalian brain cells and the involved molecular mechanisms are not fully elucidated. Here, we incubated primary astrocytes, the major glial cell-type in the brain, with 0-12.5 µM concentrations of MC-LR for 48 h, and the impairment was evaluated. We found that MC-LR caused significant increases in the cell viability at the range of 0.05-1 µM concentrations with the highest density at 0.1 µM concentration. Treatment with 0.1 µM MC-LR induced YAP nuclear translocation and decreased the ratio of p-YAP to YAP. It also decreased mRNA levels of the upstream regulator (AMOT), and enhanced expressions of YAP interacted genes (Egfr, Tead1, and Ctgf) in primary astrocytes. Overexpression of AMOT significantly attenuated the increase of MC-LR-induced astrocyte proliferation and the expression of YAP downstream genes. These results indicate that Hippo signaling contributed to MC-LR-caused astrocyte proliferation. Further, reactive astrogliosis was observed in the mice brain after MC-LR exposure to environmentally relevant concentrations (20 or 100 µg/L) through drinking water for 16 weeks. Pathological observations revealed that 100 µg/L MC-LR exposure caused neuronal damages with characteristics of shrunken or vacuolation in the region of the cerebral cortex, striatum and cerebellum. These results were accompanied with increased oxidative stress and inflammatory response. Our data reveal the potential astrocytic mechanisms in MC-induced neurotoxicity and raise an alarm for neurodegenerative disease risk following daily exposure to MC-LR.

Construction and validation of a rat model of acute necrotizing pancreatitis-associated intestinal injury.

Acute pancreatitis (AP) is an acute inflammatory reaction of the pancreatic tissue, which involves auto-digestion, edema, hemorrhage, and necrosis. AP can be categorized into mild, moderately severe, and severe AP, with severe pancreatitis also referred to as acute necrotizing pancreatitis (ANP). ANP is characterized by the accumulation of necrotic material in the peritoneal cavity. This can result in intestinal injury. However, the mechanism of ANP-associated intestinal injury remains unclear. We established an ANP-associated intestinal injury rat model (ANP-IR model) by injecting pancreatitis-associated ascites fluid (PAAF) and necrotic pancreatic tissue at various proportions into the triangular area formed by the left renal artery and ureter. The feasibility of the ANP-IR model was verified by comparing the similar changes in indicators of intestinal inflammation and barrier function between the two rat models. In addition, we detected changes in apoptosis levels and YAP protein expression in the ileal tissues of rats in each group and validated them in vitro in rat epithelial crypt cells (IEC-6) to further explore the potential injury mechanisms of ANP-associated intestinal injury. We also collected clinical data from patients with ANP to validate the effects of PAAF and pancreatic necrosis on intestinal injury. Our findings offer a theoretical basis for restricting the buildup of peritoneal necrosis in individuals with ANP, thus promoting the restoration of intestinal function and enhancing treatment efficacy. The use of the ANP-IR model in further studies can help us better understand the mechanism and treatment of ANP-associated intestinal injury.NEW & NOTEWORTHY We constructed a rat model of acute necrotizing pancreatitis-associated intestinal injury and verified its feasibility. In addition, we identified the mechanism by which necrotic pancreatic tissue and pancreatitis-associated ascites fluid (PAAF) cause intestinal injury through the HIPPO signaling pathway.

Genome-Wide CRISPR Screen Identifies an NF2-Adherens Junction Mechanistic Dependency for Cardiac Lineage.

BACKGROUND: Cardiomyocyte differentiation involves a stepwise clearance of repressors and fate-restricting regulators through the modulation of BMP (bone morphogenic protein)/Wnt-signaling pathways. However, the mechanisms and how regulatory roadblocks are removed with specific developmental signaling pathways remain unclear. METHODS: We conducted a genome-wide CRISPR screen to uncover essential regulators of cardiomyocyte specification in human embryonic stem cells using a myosin heavy chain 6 (MYH6)-GFP (green fluorescence protein) reporter system. After an independent secondary single guide ribonucleic acid validation of 25 candidates, we identified NF2 (neurofibromin 2), a moesin-ezrin-radixin like (MERLIN) tumor suppressor, as an upstream driver of early cardiomyocyte lineage specification. Independent monoclonal NF2 knockouts were generated using CRISPR-Cas9, and cell states were inferred through bulk RNA sequencing and protein expression analysis across differentiation time points. Terminal lineage differentiation was assessed by using an in vitro 2-dimensional-micropatterned gastruloid model, trilineage differentiation, and cardiomyocyte differentiation. Protein interaction and post-translation modification of NF2 with its interacting partners were assessed using site-directed mutagenesis, coimmunoprecipitation, and proximity ligation assays. RESULTS: Transcriptional regulation and trajectory inference from NF2-null cells reveal the loss of cardiomyocyte identity and the acquisition of nonmesodermal identity. Sustained elevation of early mesoderm lineage repressor SOX2 and upregulation of late anticardiac regulators CDX2 and MSX1 in NF2 knockout cells reflect a necessary role for NF2 in removing regulatory roadblocks. Furthermore, we found that NF2 and AMOT (angiomotin) cooperatively bind to YAP (yes-associated protein) during mesendoderm formation, thereby preventing YAP activation, independent of canonical MST (mammalian sterile 20-like serine-threonine protein kinase)-LATS (large tumor suppressor serine-threonine protein kinase) signaling. Mechanistically, cardiomyocyte lineage identity was rescued by wild-type and NF2 serine-518 phosphomutants, but not NF2 FERM (ezrin-radixin-meosin homology protein) domain blue-box mutants, demonstrating that the critical FERM domain-dependent formation of the AMOT-NF2-YAP scaffold complex at the adherens junction is required for early cardiomyocyte lineage differentiation. CONCLUSIONS: These results provide mechanistic insight into the essential role of NF2 during early epithelial-mesenchymal transition by sequestering the repressive effect of YAP and relieving regulatory roadblocks en route to cardiomyocytes.

Biomolecular condensates: hubs of Hippo-YAP/TAZ signaling in cancer.

Biomolecular condensates, the membraneless cellular compartments formed by liquid-liquid phase separation (LLPS), represent an important mechanism for physiological and tumorigenic processes. Recent studies have advanced our understanding of how these condensates formed in the cytoplasm or nucleus regulate Hippo signaling, a central player in organogenesis and tumorigenesis. Here, we review recent findings on the dynamic formation and function of biomolecular condensates in regulating the Hippo-yes-associated protein (YAP)/transcription coactivator with PDZ-binding motif (TAZ) signaling pathway under physiological and pathological processes. We further discuss how the nuclear condensates of YAP- or TAZ-fusion oncoproteins compartmentalize crucial transcriptional co-activators and alter chromatin architecture to promote oncogenic programs. Finally, we highlight key questions regarding how these findings may pave the way for novel therapeutics to target cancer.

The Hippo pathway terminal effector TAZ/WWTR1 mediates oxaliplatin sensitivity in p53 proficient colon cancer cells.

YAP and TAZ, the Hippo pathway terminal transcriptional activators, are frequently upregulated in cancers. In tumor cells, they have been mainly associated with increased tumorigenesis controlling different aspects from cell cycle regulation, stemness, or resistance to chemotherapies. In fewer cases, they have also been shown to oppose cancer progression, including by promoting cell death through the action of the p73/YAP transcriptional complex, in particular after chemotherapeutic drug exposure. Using HCT116 cells, we show here that oxaliplatin treatment led to core Hippo pathway down-regulation and nuclear accumulation of TAZ. We further show that TAZ was required for the increased sensitivity of HCT116 cells to oxaliplatin, an effect that appeared independent of p73, but which required the nuclear relocalization of TAZ. Accordingly, Verteporfin and CA3, two drugs affecting the activity of YAP and TAZ, showed antagonistic effects with oxaliplatin in co-treatments. Importantly, using several colorectal cell lines, we show that the sensitizing action of TAZ to oxaliplatin is dependent on the p53 status of the cells. Our results support thus an early action of TAZ to sensitize cells to oxaliplatin, consistent with a model in which nuclear TAZ in the context of DNA damage and p53 activity pushes cells towards apoptosis.

Role of angiomotin family members in human diseases (Review).

Angiomotin (Amot) family members, including Amot, Amot-like protein 1 (Amotl1) and Amot-like protein 2 (Amotl2), have been found to interact with angiostatins. In addition, Amot family members are involved in various physiological and pathological functions such as embryonic development, angiogenesis and tumorigenesis. Some studies have also demonstrated its regulation in signaling pathways such as the Hippo signaling pathway, AMPK signaling pathway and mTOR signaling pathways. Amot family members play an important role in neural stem cell differentiation, dendritic formation and synaptic maturation. In addition, an increasing number of studies have focused on their function in promoting and/or suppressing cancer, but the underlying mechanisms remain to be elucidated. The present review integrated relevant studies on upstream regulation and downstream signals of Amot family members, as well as the latest progress in physiological and pathological functions and clinical applications, hoping to offer important ideas for further research.

MST1 selective inhibitor Xmu-mp-1 ameliorates neuropathological changes in a rat model of sporadic Alzheimer's Disease by modulating Hippo-Wnt signaling crosstalk.

Alzheimer's disease (AD), the most prevalent form of dementia, is characterized by progressive cognitive impairment accompanied by aberrant neuronal apoptosis. Reports suggest that the pro-apoptotic mammalian set20-like kinase 1/2 (MST1/2) instigates neuronal apoptosis via activating the Hippo signaling pathway under various stress conditions, including AD. However, whether inhibiting MST1/2 has any therapeutic benefits in AD remains unknown. Thus, we tested the therapeutic effects of intervening MST1/2 activation via the pharmacological inhibitor Xmu-mp-1 in a sporadic AD rat model. Sporadic AD was established in adult rats by intracerebroventricular streptozotocin (ICV-STZ) injection (3 mg/kg body weight). Xmu-mp-1 (0.5 mg/kg/body weight) was administered once every 48 h for two weeks, and Donepezil (5 mg/kg body weight) was used as a reference standard drug. The therapeutic effects of Xmu-mp-1 on ICV-STZ rats were determined through various behavioral, biochemical, histopathological, and molecular tests. At the behavioral level, Xmu-mp-1 improved cognitive deficits in sporadic AD rats. Further, Xmu-mp-1 treatment reduced STZ-associated tau phosphorylation, amyloid-beta deposition, oxidative stress, neurotoxicity, neuroinflammation, synaptic dysfunction, neuronal apoptosis, and neurodegeneration. Mechanistically, Xmu-mp-1 exerted these neuroprotective actions by inactivating the Hippo signaling while potentiating the Wnt/ß-Catenin signaling in the AD rats. Together, the results of the present study provide compelling support that Xmu-mp-1 negated the neuronal dysregulation in the rat model of sporadic AD. Therefore, inhibiting MST/Hippo signaling and modulating its crosstalk with the Wnt/ß-Catenin pathway can be a promising alternative treatment strategy against AD pathology. This is the first study providing novel mechanistic insights into the therapeutic use of Xmu-mp-1 in sporadic AD.