Pharmacotherapeutic opportunities within the Hippo signaling pathway

Abstract

The Hippo pathway is a master of cellular regulation. It modulates intricate mechanisms that govern organ size, tissue homeostasis, and regeneration. Guo et al (2025) dissect the pathway’s multifaceted nature. Their article discusses the complex interactions between kinase cascades, transcriptional machinery, and upstream regulators that orchestrate this elaborate network of signaling cascades. The authors elegantly discuss the delicate balance that lies at the heart of the Hippo pathway (Guo et al, 2025). Two kinases, namely MST1/2 and LATS1/2, form the core and modulate the activity of YAP/TAZ transcriptional coactivators through a series of phosphorylation events, finely tuned to respond to a range of intracellular and extracellular signals. These signals include cellular energy levels, cell density, hormonal cues, and mechanical forces, which collectively modulate the pathway’s output and influence cellular behavior in response to an ever-changing environment. As the authors aptly note, one of the critical factors in the function of the Hippo pathway is its spatial organization (Guo et al, 2025). Indeed, it is this spatial regulation that ensures signaling fidelity and specificity, allowing for the precise control of YAP/TAZ activity in response to diverse stimuli. Recent discoveries have unveiled an additional layer of complexity, revealing that biomolecular condensation plays a critical regulatory role. This phenomenon of liquid-liquid phase separation introduces dynamic and reversible mechanisms for compartmentalizing and modulating pathway components, offering new insights into how cells achieve spatiotemporal control over signaling events. The authors remind us that the implications of Hippo pathway dysregulation are far-reaching, with cancer standing at the forefront. Aberrant regulation in YAP/TAZ activity contributes to tumorigenesis and drug resistance. This realization opens new avenues for targeted therapeutics. Indeed, modulating the Hippo pathway holds promise for both cancer treatment and regenerative medicine. The article also explores the complex posttranslational modifications governing YAP/TAZ activity. Phosphorylation, being essential, largely determines subcellular localization and stability. Other modifications are also pivotal. For instance, monomethylation, O-GlcNAcylation, and lactylation further modulate the YAP/TAZ function. These modifications respond to metabolic cues and link cellular energetics to Hippo signaling. The Hippo pathway’s upstream regulators are diverse and multifaceted. These regulators integrate various signals, including cell-cell contact, mechanical cues, and soluble factors. Together, these inputs converge on the core kinase cascade and fine-tune its activity with remarkable precision. Moreover, another critical regulatory hub is the striatin-interacting phosphatase and kinase complex. It modulates MST1/2 and MAP4K activity and indeed exemplifies the intricate balance of phosphorylation and dephosphorylation events that govern Hippo signaling. Its function underscores the importance of negative regulation in pathway control. Beyond its canonical role in organ size control, the Hippo pathway’s functions are extensive. For instance, in addition to its ability to govern embryonic development, regulate cell differentiation, and maintain tissue homeostasis, it plays a role in immune responses, aging processes, and cellular metabolism. This wide-ranging influence underscores the Hippo pathway’s central role in integrating diverse cellular processes. Therefore, it is not surprising that the therapeutic potential of targeting the Hippo pathway is significant. In cancer, strategies aim to suppress YAP/TAZ signaling.