This study investigates the metabolomic and immune alterations in long COVID (LC) patients with chronic fatigue syndrome (CFS). The researchers compared LC patients, recovered individuals (R), acute COVID-19 patients, and healthy controls (HCs) to understand the pathophysiology of LC, particularly CFS. Key findings include: 1. **Metabolomic Alterations**: LC patients exhibited distinct metabolomic profiles compared to R, HC, and acute COVID-19 patients. Altered pathways included tryptophan-kynurenine, Xanthine/hypoxanthine, and others. Notably, LC patients showed a significant reduction in ATP levels. 2. **Pro-Inflammatory Biomarkers**: LC patients had elevated levels of pro-inflammatory biomarkers such as IL-1α, IL-6, TNF-α, Flt-1, and sCD14, while showing a reduction in ATP levels. 3. **Sarcosine and Serine**: LC patients had significantly lower concentrations of sarcosine and serine, which were inversely correlated with cognitive dysfunction and depression scores. These findings suggest potential therapeutic implications for sarcosine and serine supplementation. 4. **Clinical Implications**: The study highlights the long-lasting impact of LC on organ function and the potential role of residual immune activation and mitochondrial dysfunction in the syndrome. 5. **Sex Differences**: LC disproportionately affected females, with nearly 70% of LC patients being female. The study provides a comprehensive understanding of the metabolomic and immune alterations in LC patients with CFS, offering insights into potential therapeutic targets and emphasizing the need for further research and clinical trials.This study investigates the metabolomic and immune alterations in long COVID (LC) patients with chronic fatigue syndrome (CFS). The researchers compared LC patients, recovered individuals (R), acute COVID-19 patients, and healthy controls (HCs) to understand the pathophysiology of LC, particularly CFS. Key findings include: 1. **Metabolomic Alterations**: LC patients exhibited distinct metabolomic profiles compared to R, HC, and acute COVID-19 patients. Altered pathways included tryptophan-kynurenine, Xanthine/hypoxanthine, and others. Notably, LC patients showed a significant reduction in ATP levels. 2. **Pro-Inflammatory Biomarkers**: LC patients had elevated levels of pro-inflammatory biomarkers such as IL-1α, IL-6, TNF-α, Flt-1, and sCD14, while showing a reduction in ATP levels. 3. **Sarcosine and Serine**: LC patients had significantly lower concentrations of sarcosine and serine, which were inversely correlated with cognitive dysfunction and depression scores. These findings suggest potential therapeutic implications for sarcosine and serine supplementation. 4. **Clinical Implications**: The study highlights the long-lasting impact of LC on organ function and the potential role of residual immune activation and mitochondrial dysfunction in the syndrome. 5. **Sex Differences**: LC disproportionately affected females, with nearly 70% of LC patients being female. The study provides a comprehensive understanding of the metabolomic and immune alterations in LC patients with CFS, offering insights into potential therapeutic targets and emphasizing the need for further research and clinical trials.