Targeting Neuroinflammation in Depression: The Integrative Role of Sigma‐1 Receptor Modulation

Depression is a leading cause of global disability, yet remains insufficiently treated by conventional monoaminergic antidepressants, which are limited by their delayed onset, variable efficacy, and significant side effects. Accumulating evidence positions neuroinflammation, driven by glial dysfunction, peripheral-central immune crosstalk, and associated cellular stress pathways as a pivotal upstream mechanism in the pathogenesis of depression, contributing to both neurotransmitter dysregulation and impaired synaptic plasticity. This review examines the integrative role of the Sigma-1 receptor (Sig-1R), a ligand-operated chaperone predominantly localized at the mitochondria-associated endoplasmic reticulum membrane (MAM), as a promising therapeutic target for mitigating this neuroinflammatory cascade. We systematically synthesize preclinical evidence demonstrating that pharmacological activation of Sig-1R produces broad anti-neuroinflammatory effects, including the promotion of microglial homeostasis and a shift toward an anti-inflammatory phenotype, attenuation of reactive astrogliosis, suppression of key pro-inflammatory signaling hubs such as NF-κB and the NLRP3 inflammasome, and mitigation of oligodendrocyte dysfunction. Beyond immunomodulation, Sig-1R activation alleviates endoplasmic reticulum stress, enhances autophagic and mitophagic clearance, supports mitochondrial bioenergetics, and strengthens endogenous antioxidant defenses. Together, these actions disrupt the vicious cycle linking cellular stress, inflammation, and synaptic impairment. We also evaluate advances in representative Sig-1R agonists and review available clinical trial data, including results on the novel multi-target agent AXS-05. Genetic and pharmacological loss-of-function studies further emphasize the essential role of Sig-1R in mood regulation and stress resilience. In summary, the Sigma-1 receptor serves as a key regulator of cellular homeostasis and adaptation. Its agonists represent a promising therapeutic strategy that moves beyond symptomatic monoaminergic modulation to mechanistically target the core inflammatory and proteostatic disturbances in depression, offering the potential for improved treatment efficacy.