The HIPPO signaling pathway is a conserved molecular cascade that controls organ size and tissue homeostasis by regulating cell proliferation and apoptosis, with YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif) as key downstream effectors that, when activated, promote gene expression driving cell growth and survival. Gastric cancer (GC) ranks as the fifth most common malignancy and the third leading cause of cancer mortality globally, with over 1 million annual cases [1] . H. pylori, a Class I carcinogen, is the primary risk factor, initiating a cascade from chronic gastritis to adenocarcinoma [2] . The HIPPO pathway, conserved across species, is hijacked in H. pylori-driven oncogenesis, promoting epithelial-mesenchymal transition (EMT), metaplasia, and tumor progression [3] . H. pylori infects over 50% of the global population, with higher prevalence in developing countries. Chronic infection increases GC risk 2 - 6 fold, influenced by host genetics, diet, and bacterial virulence, particularly cagA-positive strains [4] . Persistent inflammation and oxidative stress from H. pylori drive genomic instability and oncogenic signaling [5] . Discovered in the 2000s, the HIPPO pathway inhibits YAP/TAZ to maintain tissue homeostasis. Its dysregulation in cancers, including GC, correlates with aggressive phenotypes and poor survival [6] . In H. pylori infection, HIPPO inactivation fosters stemness and EMT, making it a critical therapeutic target [7] . This article reviews how H. pylori modulates the HIPPO pathway and identifies therapeutic targets to improve clinical outcomes.

The HIPPO pathway integrates mechanical and biochemical signals to control cellular fate through a kinase cascade and transcriptional effectors. Upstream regulators, such as Merlin/NF2 and G-protein-coupled receptors, sense cell polarity and cytoskeletal dynamics, often disrupted in GC by inflammatory stress [8] . Core kinases MST1/2 phosphorylate LATS1/2, which then phosphorylates YAP/TAZ at serine residues (e.g., S127 in YAP), promoting 14-3-3 binding and cytoplasmic retention or proteasomal degradation [9] . H. pylori CagA inhibits LATS2, allowing unphosphorylated YAP/TAZ to enter the nucleus and bind TEAD1–4, driving expression of oncogenic genes like CTGF, CYR61, and SOX9 [10] . In GC, YAP/TAZ hyperactivation promotes proliferation, survival, and metastasis, with studies showing elevated YAP levels in H. pylori-positive tumors correlating with advanced stages [11] .

H. pylori colonizes the gastric mucosa, evading immune responses and inducing chronic inflammation. Its virulence factors, notably CagA and VacA, disrupt host signaling. CagA, delivered via the type IV secretion system, mimics host proteins to activate pathways like PI3K/AKT, while VacA causes vacuolation and inhibits apoptosis [12] [13] . Chronic infection triggers NF-κB-mediated cytokine release (e.g., IL-1β, TNF-α), creating a protumorigenic microenvironment that suppresses HIPPO kinases and activates YAP [14] [15] . This inflammatory milieu also induces DNA damage and epigenetic alterations, fostering metaplasia and adenocarcinoma [16] . Studies in H. pylori-infected gastric organoids demonstrate enhanced stem cell-like properties, driven by HIPPO dysregulation, which precede malignant transformation [17] .

H. pylori disrupts the HIPPO pathway through direct, epigenetic, and indirect mechanisms, amplifying oncogenic potential.

Targeting the HIPPO pathway offers promising avenues for H. pylori-associated GC, with strategies focusing on YAP/TAZ inhibition, kinase activation, and combination therapies. The following table summarizes key HIPPO-targeted agents, their mechanisms, and development stages:

The HIPPO pathway’s dysregulation is a cornerstone of H. pylori-driven gastric carcinogenesis, mediating the transition from infection to malignancy through complex molecular and epigenetic mechanisms. Targeting YAP/TAZ and upstream regulators offers transformative potential, with emerging therapies like verteporfin, statins, and novel inhibitors showing promise in preclinical and early clinical studies. However, strain heterogeneity in H. pylori virulence factors, such as variable CagA expression, and host genetic polymorphisms affecting inflammatory responses may influence HIPPO activation and therapeutic outcomes, complicating standardized treatments. These limitations underscore the need for personalized therapeutic strategies. Despite progress, challenges persist in targeting the HIPPO pathway. YAP/TAZ inhibitors often face resistance due to compensatory pathways, such as EGFR or PI3K activation [41] . Biomarker development is critical to identify patients likely to benefit from HIPPO-targeted therapies, with YAP nuclear localization and TEAD4 expression proposed as candidates [42] . Multi-omics approaches, integrating genomics, epigenomics, and transcriptomics, can uncover novel targets and resistance mechanisms [43] . Artificial intelligence-driven modeling of HIPPO interactions could optimize drug design and predict therapeutic responses [44] . Future research should focus on personalized medicine, combining HIPPO inhibitors like IAG933 with H. pylori eradication and immunotherapy to address tumor heterogeneity and improve outcomes, with preclinical studies paving the way [45] .

*Corresponding author.