Rescuing anxiety by targeting the neuronal-astrocytic iron signaling axis in male mice.

Anxiety disorders affect more than one-quarter of the global population, but current first-line therapies suffer from slow onset and limited efficacy, highlighting the urgent need for novel pathogenic targets. Psychological stress disrupts iron homeostasis in the brain and alters neural circuit excitability; however, the mechanism underlying these two processes remains elusive. Here, we identify a cell type-specific iron signaling pathway between neurons and astrocytes that mediates stress-induced anxiety by regulating synaptic iron transport in the ventral hippocampal-medial prefrontal cortex circuit. In a chronic restraint stress model in male mice, stress induces activity-dependent HMGB1 expression and release from medial prefrontal cortex pyramidal neurons, which bind to astrocytic TLR4 to stimulate local hepcidin secretion. Hepcidin degrades ferroportin at ventral hippocampal-medial prefrontal cortex axonal terminals in a retrograde manner, blocking presynaptic iron efflux. The resultant iron accumulation in ventral hippocampal-medial prefrontal cortex projection neurons increases their intrinsic excitability via a ferroplasticity mechanism and anxiety-like behaviors. Notably, intranasal administration of HMGB1/TLR4 antagonists efficiently restored synaptic iron flux and alleviated anxiety in both stress-induced and innate high-anxiety models. Collectively, our findings define a retrograde ferrosynaptic neuroglial coupling mechanism through which stress induces anxiety independently of classical synaptic transmission. This work establishes the HMGB1-TLR4-hepcidin-FPN axis as a druggable therapeutic target and provides a conceptual framework for understanding how iron metabolism operates as a transcellular social coordination system in emotional regulation.