# Sex Differences in Metabolite–Immune Circuits of Neuroinflammation

## TL;DR

This paper explores how sex differences influence immune and metabolic processes in the brain, contributing to neuroinflammation and disease.

## Contribution

The paper proposes a new framework linking sex-biased immunometabolism to neuroimmune disease risk and progression.

## Key findings

- Sex-defining factors interact with age and environment to shape metabolite–immune circuits.
- Metabolic pathways influence immune responses and CNS resilience in a sex-dependent manner.

## Abstract

Sex is a fundamental yet underexplored determinant of human neuroinflammation. Across autoimmune, neurodegenerative, and post‐infectious neurological syndromes, males and females exhibit consistent differences in disease vulnerability, progression, and immune tone. While sex hormones and chromosomes strongly shape immune development and function in health and disease, they do not fully explain the magnitude or disease‐specific patterns of these disparities, nor do they provide sufficient mechanistic information for developing novel therapeutics. Emerging evidence suggests that sex‐defining factors interact with age and environment to shape downstream metabolite–immune circuits, networks in which metabolic enzymes, metabolites, and immune cells tune inflammatory set points. Pathways spanning purine metabolism, glycolytic remodeling, lipid sensing, mitochondrial stress, and nucleic‐acid sensing can recalibrate microglial activation thresholds, T‐cell cytokine programs, innate type I interferon antiviral responses, and shape overall CNS resilience in a sex‐dependent manner. Here, we synthesize mechanistic and human systems‐level studies to propose an integrated framework in which sex‐biased immunometabolism serves as a mechanistic bridge between biological sex and neuroimmune disease risk, progression, and responses to injury. We highlight key knowledge gaps and discuss how targeting metabolite–immune pathways may enable sex‐informed biomarkers and therapeutic strategies in neuroinflammatory disease.