PVN mechanisms in OSA comorbidities: from intermittent hypoxia-stress to therapy.

Obstructive Sleep Apnea (OSA) is a common sleep-disordered breathing condition characterized by recurrent upper airway collapse, chronic intermittent hypoxia (CIH), and sleep fragmentation. Beyond daytime dysfunction, OSA is strongly associated with cardiovascular and neuropsychiatric comorbidities, particularly hypertension and depression. The paraventricular nucleus of the hypothalamus (PVN), a central hub for autonomic regulation and stress integration, plays a pivotal role in mediating these outcomes. This review synthesizes recent evidence on the synergistic interplay between CIH and chronic stress within the PVN. We highlight three core mechanisms-neuronal plasticity, neuroinflammation and oxidative stress, and epigenetic reprogramming-that collectively drive sustained sympathetic overactivation and hypothalamic-pituitary-adrenal (HPA) axis dysregulation. These central alterations form the neurobiological basis of OSA-related hypertension and contribute to shared pathways with mood disorders, including oxidative stress and ferroptosis. Finally, we summarize emerging diagnostic and therapeutic advances, such as non-invasive biomarkers, phenotype-specific pharmacotherapies, and precision neuromodulation approaches. Future directions include the development of composite animal models, targeted epigenetic interventions, and circuit-specific modulation strategies. Together, these insights provide a framework for mechanism-based and stratified management of OSA and its comorbidities.