Annexin A1 as a Molecular Bridge Between Stress Signaling and Brain Homeostasis: Neuroprotective Mechanisms and Therapeutic Potential

Abstract

Depression is globally recognised as the most common mental health problem, and it can lead to considerable personal, social, and economic losses. Central to its pathophysiology are stress and dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, with hypercortisolemia resulting in neuronal injury and impaired feedback control. Glucocorticoid-regulated protein, Annexin A1 (ANXA1) is highly expressed in the brain and immune system and can regulate HPA axis feedback, maintain blood-brain barrier integrity, and exhibit potent anti-inflammatory and neuroprotective effects. The existing preclinical data indicates that ANXA1 might have a role in mitigating stress-induced neuronal dysfunction. As clinical studies on ANXA1 in depression is lacking, future studies need to delineate if it could be a major mediator in stress signaling, immune modulation, and neurovascular integrity, and thus its potential as a biomarker and therapeutic candidate in major depressive disorder (MDD). This review presents the current knowledge on the molecular mechanisms of ANXA1 and proposes a plausible mechanistic pathway in MDD. It further discusses its translational relevance, therapeutic approaches using ANXA1-derived peptides, and identifies major challenges and gaps that must be addressed to advance ANXA1 from mechanistic insight to clinical application. As a prominent molecule that could link glucocorticoid signaling, neurovascular integrity, and neuroimmune modulation, further research on ANXA1 integrating translational strategies might pave the way for precision approaches in depression and related neuropsychiatric disorders. Graphical Abstract Physiological role of Annexin A1 in stress signaling and brain homeostasis. (1) HPA axis regulation. Under normal conditions, stress activates the hypothalamic–pituitary–adrenal (HPA) axis: the hypothalamus releases corticotropin-releasing hormone (CRH), the anterior pituitary secretes adrenocorticotropic hormone (ACTH), and the adrenal cortex produces cortisol. Cortisol binds to glucocorticoid receptors (GR) and provides negative feedback at the hypothalamus and pituitary. Activated GR in the cells translocates to the nucleus, binds glucocorticoid response elements (GREs), and induces expression of Annexin A1 (ANXA1). (2) Anti-inflammatory signaling of ANXA1. ANXA1 binds to the formyl peptide receptor 2 (FPR2). Activation of FPR2 suppresses NF-κB and MAPK signaling pathways, thereby reducing the production of pro-inflammatory mediators. (3) BBB integrity. ANXA1 maintains blood-brain barrier (BBB) integrity by stabilizing the actin cytoskeleton and upregulating important endothelial tight junction proteins, thereby reinforcing the structural framework. Created in BioRender. K V, A. (2026) https://BioRender.com/63qm7nv .