The emerging role of the Hippo signaling pathway in interorgan crosstalk

Interorgan communication has emerged as a fundamental mechanism for maintaining systemic homeostasis, and its disruption contributes to the development of metabolic diseases, chronic inflammation, and cancer. The Hippo signaling pathway, traditionally known for controlling organ size, has recently been redefined as a context-dependent coordinator of systemic cues. By translating hormonal, metabolic, and microbial signals into coordinated cellular responses, Hippo signaling serves as a bidirectional communication hub that not only interprets systemic inputs but also generates “outputs” that connect multiple organ systems. In this review, we summarize how Hippo signaling integrates diverse stimuli within key interorgan axes (e.g., gut–liver, gut–pancreas, and adipose–peripheral organs), and how organ-specific Hippo activity, particularly in adipose tissue and skeletal muscle, generates systemic outputs influencing metabolism. This integration occurs through context-specific mechanisms, allowing Hippo signaling to adapt cellular programs to physiological or pathological conditions. Despite recent progress, the mechanisms by which Hippo signaling prioritizes and integrates multiple systemic inputs and transmits its effects across organs remain incompletely understood. Elucidating these processes will be crucial to establishing Hippo signaling as a unifying framework of interorgan communication and understanding its broader implications in systemic physiology and disease.