Pharmacological Research · Nov 2, 2026

The Hypothalamic Paraventricular Nucleus as an Integrative Hub of Circadian Regulation and a Therapeutic Target in Disease

By Yao LJ, Qi T, Li X et al.

Circadian rhythms are endogenous, approximately 24-hour oscillations that align physiology and behavior with the environmental light–dark cycle and support homeostasis. In mammals, the suprachiasmatic nucleus (SCN) serves as the central circadian pacemaker, but its neuronal projections are restricted to a relatively small set of hypothalamic targets. The hypothalamic paraventricular nucleus (PVN) is an important downstream integrative node that receives direct and indirect temporal signals from the SCN and integrates them with metabolic, visceral, stress-related, and limbic inputs. Through functionally distinct neuroendocrine, autonomic, and central-projecting neuronal populations, the PVN contributes to the temporal regulation of hypothalamic-pituitary-adrenal axis activity, glucose metabolism, feeding behavior, nociceptive sensitivity, and cardiovascular function. Cell-type-specific genetic and transcriptomic studies further indicate that PVN neuronal populations exhibit distinct clock-related molecular programs. Studies predominantly in nocturnal rodent models have linked disruption of PVN clocks or rhythmic output to aging-associated decline, metabolic dysfunction, altered tumor immunity, neurodegenerative disease, and pain-related phenotypes. Human post-mortem studies have reported heterogeneous PVN changes in Alzheimer’s disease, but direct evidence of PVN clock or SCN–PVN circuit dysfunction in humans remains limited. This review integrates circuit-, cellular-, and molecular-level evidence for the PVN’s role in circadian regulation, evaluates interventions spanning timed drug delivery, meal timing, light exposure, and PVN-focused experimental manipulation, and outlines the challenges of translating preclinical findings into clinical practice.

doi.org/10.1016/j.phrs.2026.109728Open accessPubMed 42971417Mechanisms