Objective:

To synthesize mechanisms underlying inflammation-associated fatigue across various chronic inflammatory conditions, including ME/CFS, post-COVID syndrome, and autoimmune diseases, focusing on immunometabolism, GPCR signaling, and epigenetic modifications.

Key Findings:

• Chronic fatigue is linked to inflammation-driven mechanisms across conditions like ME/CFS, post-COVID syndrome, and autoimmune diseases.
• Metabolic dysfunction, including mitochondrial impairment and altered glycolysis, contributes to persistent fatigue.
• GPCR signaling and epigenetic modifications play crucial roles in regulating immune and metabolic responses related to fatigue.
• Evidence linking GPCR pathways to fatigue is primarily indirect, derived from cellular and animal studies rather than direct human evidence.

Interpretation:

The interplay between inflammation, metabolism, and immune signaling provides a comprehensive framework for understanding chronic fatigue, suggesting potential biomarkers and therapeutic targets that could guide future research.

Limitations:

• Direct causal evidence in human fatigue syndromes remains limited, which may hinder the development of targeted therapies.
• Much of the current understanding is based on indirect evidence from cellular and animal models, necessitating further validation in human studies.

Conclusion:

A multidimensional approach is essential for understanding chronic inflammation-driven fatigue, highlighting the need for further mechanistic and translational research to address existing gaps.