Depression is the most common mental health problem worldwide, and a new open-access review argues that a single glucocorticoid-regulated protein, Annexin A1, may sit at the crossroads of the stress response, inflammation and blood-brain barrier maintenance that together shape the disorder. Writing in Cellular and Molecular Neurobiology, a team led by Anju Jose, Aishwarya Laxmi Krishnan, K. P. Lakshmi, Lalitha Biswas, Bindu Menon and K. V. Athira synthesises preclinical evidence on the molecular mechanisms of ANXA1 and proposes a plausible mechanistic pathway in major depressive disorder, while stressing that clinical studies on the protein in depression are still lacking.
The review’s starting point is the hypothalamic–pituitary–adrenal axis, the body’s central stress circuit. Under normal conditions, stress triggers the hypothalamus to release corticotropin-releasing hormone, the anterior pituitary to secrete adrenocorticotropic hormone, and the adrenal cortex to produce cortisol. Cortisol then binds glucocorticoid receptors and provides negative feedback at the hypothalamus and pituitary. In depression, the authors write, stress and dysregulation of this axis are central to pathophysiology, with hypercortisolemia resulting in neuronal injury and impaired feedback control. That failure of the braking system leaves the brain exposed to sustained cortisol levels that can damage neurons over time.
Where does ANXA1 enter this circuit? According to the graphical model presented in the paper, activated glucocorticoid receptors translocate to the nucleus, bind glucocorticoid response elements and induce expression of Annexin A1. In other words, the protein is a downstream product of the very hormone system that malfunctions in depression. Because ANXA1 is highly expressed in both the brain and the immune system, the authors argue it is well positioned to regulate HPA axis feedback, and the existing preclinical data indicate it might have a role in mitigating stress-induced neuronal dysfunction.
The anti-inflammatory arm of the model runs through a specific receptor. ANXA1 binds to formyl peptide receptor 2, and activation of FPR2 suppresses the NF-κB and MAPK signaling pathways, thereby reducing the production of pro-inflammatory mediators. This matters for depression because neuroimmune activation has been repeatedly implicated in the disorder, and a glucocorticoid-induced protein that dampens inflammatory signaling offers a mechanistic account of how the stress system and the immune system talk to each other. The review frames ANXA1 as a prominent molecule that could link glucocorticoid signaling, neurovascular integrity and neuroimmune modulation.
A third mechanism concerns the blood-brain barrier, the structural border that protects neural tissue from blood-borne insults. The review describes ANXA1 as maintaining barrier integrity by stabilising the actin cytoskeleton and upregulating important endothelial tight junction proteins, thereby reinforcing the structural framework of the barrier. If hypercortisolemia injures neurons and disrupts feedback control, a protein that both responds to glucocorticoids and shores up the barrier could determine how much damage the stress response ultimately inflicts on the brain.
Beyond basic mechanisms, the authors examine translational relevance, including therapeutic approaches using ANXA1-derived peptides. The abstract identifies major challenges and gaps that must be addressed to advance ANXA1 from mechanistic insight to clinical application, and the authors suggest that further research integrating translational strategies might pave the way for precision approaches in depression and related neuropsychiatric disorders. The protein is discussed as a potential biomarker as well as a therapeutic candidate in major depressive disorder, a dual role that would be unusual if borne out by future work.
The evidence base, however, remains preclinical. The review states explicitly that clinical studies on ANXA1 in depression are lacking, and that future studies need to delineate whether the protein is a major mediator in stress signaling, immune modulation and neurovascular integrity. The article is published as a peer-reviewed accepted manuscript shared early for faster access; the authors note this version is subject to further edits and will be replaced by the final Version of Record. Readers should therefore treat the proposed pathway as a hypothesis grounded in preclinical data rather than a validated clinical finding.
What the review does deliver is a testable framework. It presents current knowledge on the molecular mechanisms of ANXA1 and proposes a plausible mechanistic pathway in MDD, connecting cortisol signaling through receptor-mediated gene expression to anti-inflammatory action via FPR2 and barrier maintenance through cytoskeletal and tight-junction effects. Each node in that chain is individually supported by the preclinical literature the authors survey; what remains unproven is whether the integrated pathway operates in patients with depression, whether ANXA1 levels track disease state, and whether ANXA1-derived peptides can be developed safely as therapeutics.
For a field in which most depression research focuses on monoamines, ketamine or neurotrophic factors, a review centring a glucocorticoid-regulated, anti-inflammatory, barrier-protective protein offers a different angle on an old problem. The authors’ own conclusion is measured: ANXA1 could be a major mediator linking stress signaling to brain homeostasis, but only further research integrating translational strategies will show whether that promise survives contact with clinical reality. Until such studies are done, the protein remains a well-motivated candidate, not a validated target, in the biology of major depressive disorder.
Subject of Research: A review of the molecular mechanisms of Annexin A1 linking stress signaling, neuroimmune modulation and blood-brain barrier integrity in major depressive disorder.
Article Title: Annexin A1 as a Molecular Bridge Between Stress Signaling and Brain Homeostasis: Neuroprotective Mechanisms and Therapeutic Potential
Article References: Jose, A., Krishnan, A. L., Lakshmi, K. P., Biswas, L., Menon, B., & Athira, K. V. (2026). Annexin A1 as a Molecular Bridge Between Stress Signaling and Brain Homeostasis: Neuroprotective Mechanisms and Therapeutic Potential. Cellular and Molecular Neurobiology. https://doi.org/10.1007/s10571-026-01825-4
Image Credits: AI Generated
DOI: 10.1007/s10571-026-01825-4
Keywords: Annexin A1, major depressive disorder, HPA axis, glucocorticoids, cortisol, formyl peptide receptor 2, NF-kB, blood-brain barrier, tight junctions, neuroinflammation, ANXA1-derived peptides, biomarker
News Source: Cassandra Pierce. (October 30, 2026). Annexin A1 Emerges as a Candidate Link Between Stress Hormones and Brain Protection in Depression. Scienmag.
