Sex Differences in Molecular Mechanisms Linking Neuronal Stress and Inflammation

Dear Colleagues,

Neuroinflammatory diseases increasingly reveal sex-specific patters in incidence, progression, and treatment response; however, underlying cellular and molecular determinants remain unclear or poorly defined. Emerging evidence indicates that neurons act as dynamic regulators of neuroimmune activation rather than passive participants, particularly through stress response pathways. This Special Issue will focus on how neuronal stresses such as ER stress, mitochondrial dysfunction, oxidative dysfunction, and altered proteostasis drive neuroinflammation through various downstream mechanisms. A primary emphasis will be placed on identifying and dissecting sex-dependent mechanisms that alter these pathways and contribute to differential vulnerability or resilience across CNS disorders.

We invite the submission of original research articles, reviews, and short communications that address the following themes:

• Sex-specific molecular pathways linking neuronal stress to neuroimmune activation;
• Cell stress response in male vs. female neurons;
• Neuron-derived DAMPs, PRR signaling, and inflammatory crosstalk with glia or peripheral immune cells;
• Single-cell, spatial, or multi-omics analyses revealing sex differences in neuro-immune interactions;
• Mechanisms of neuronal injury, dysfunction, or death that differentiate sexes during CNS inflammation;
• Translation studies identifying sex-specific biomarkers or therapeutic targets related to neuronal stress and neuroinflammation.

This Special Issue will integrate cellular, molecular, and systems-level insights to advance our understanding of sex as a critical biological variable in neuroinflammation. By highlighting neuron-centric mechanisms, we seek to stimulate new strategies for sex-informed therapeutic development in CNS diseases.

Dr. John R. Bethea
Dr. Kayla Lee Nguyen
Guest Editors

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