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. 2026 Apr 3;31(8):4690–4698. doi: 10.1038/s41380-026-03588-2

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© The Author(s) 2026

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.

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Fig. 3 — a HPA axis dysregulation: Depression can dysregulate HPA axis and increases serum glucocorticoids concentrations. Excessive activation of MRs on SMCs induces vascular stiffness, fibrosis, and inflammation. Binding of GRs initially upregulates anti-inflammatory factors and downregulate pro-inflammatory cytokines through NF-κB inhibition. However, depression has been found to be associated with hypermethylation at NR3C1 promoter, attenuating the overall GRs expression, which induces chronic inflammation (inflammaging). b Dopaminergic dysfunction. Depression is associated with enhanced expression of D2/D3 receptors, which suggests downregulation of the mesolimbic and nigrostriatal pathways. These result in reduced reward sensing and motivation of achieving goals, impaired motor and cognitive functions. c Allostatic load: An accumulation of physiological wear and tear results from exogenous stress such as depression. Studies suggest positive association between depressive symptoms and allostatic load in community-dwelling older adults, which in turn is associated with increased frailty, chronic inflammation, and cognitive decline. d CRF-1 coupling mechanism: CRF is hypersecreted in the context of depression. One target of CRF is CRF-1 receptors located at locus coeruleus. Higher proportion of binding of CRF to CRF-1 in females are coupled to G-protein coupled receptors, which activates cAMP PKA pathway that phosphorylates target genes, further increasing CRF sensitivity. Greater proportion of binding of CRF to CRF-1 in males are coupled to beta-arrestins that internalize CRF-1 receptors to increase CRF resilience under CRF hypersecretion. e DNMT expression differences: Expression of Dnmt1 was found to be lower in MDD patients regardless of sex, suggesting inability to maintain original methylation patterns. While Dnmt3B expression was increased in MDD patients, such extents were pronounced in females MDD, suggesting uneven de-novo methylation that altering transcription and function. HPA, Hypothalamic-pituitary-adrenal; SMC, smooth muscle cell; GRs, glucocorticoids receptors; MRs, mineralocorticoid receptors; CRF: corticotrophin releasing factor; cAMP-PKA: cyclic adenosine monophosphate-protein kinase A; DNMT: DNA methyltransferases. Figure generated in Biorender.