Network Physiology provides a unifying framework for understanding how molecular, cellular, and organ-level systems integrate as a network to generate distinct physiological states and sustain human function. Spaceflight offers a unique environment-characterized by microgravity, radiation, isolation, and circadian disruption-that perturbs interconnected physiological systems and networks. Network Physiology in Space, an emerging area of research and clinical practice within the multidisciplinary field of Network Physiology, examines how multiscale interactions, from genomic and metabolic pathways to organ system dynamics, adapt and reorganize in response to spaceflight stressors to maintain homeostasis at the organism level. Using systems biology, multi-omics, nonlinear analyses of physiological systems dynamics, computational modeling, and AI-enhanced analysis, researchers have traditionally focused on individual systems to investigate regulatory mechanisms underpinning adaptations to spaceflight, including muscle and bone loss, cardio-vascular and cardio-respiratory deconditioning, immune function shifts, neuro-vestibular dysregulation, circadian, and sleep fragmentation. However, physiological systems and organs continuously interact across levels to synchronize dynamics and coordinate functions. Changes in a system in response to perturbations are often interlinked with other systems, leading to diversity of effects, which underscores the need for an integrative framework capable of linking molecular signals to system-level physiological function and crew functionality. In this context, Network Physiology provides a unifying theoretical and analytical approach to identify, quantify and model dynamic interactions among physiological systems across spatio-temporal scales, integrating multi-omics, physiological, and behavioral data into dynamical network representations. This systems-level perspective enables spaceflight-induced adaptations to be interpreted as coordinated reconfigurations of interacting physiological networks, rather than isolated responses of individual components. As many adaptations are common with disuse pathology, spaceflight becomes a living laboratory for probing frailty and resilience, revealing principles relevant to aging, metabolic and immune disorders, neurodegeneration, and rehabilitation on Earth. Recent methodological advances in inferring functional forms of coupling and causality in dynamic systems interactions, and novel integrative and adaptive network approaches in Network Physiology offer new perspectives to human and animal studies in space or analogue environments, for the development of translational applications to clinical practice and hybrid mechanistic-machine-learning models that simulate system-wide responses and guide personalized countermeasures strategies and personalized medicine.
