Gulf War Illness (GWI) is a multi-symptom disorder affecting 1990–1991 Persian Gulf War veterans and is characterized by post-exertional malaise, neurological symptoms, immune deregulation, and exhaustion. Causation is not understood, and effective diagnostics and therapies have not yet been developed. In this work, we analyzed stress-related, sex-specific transcriptomic shifts in GWI subjects and healthy controls through RNA sequencing of peripheral blood mononuclear cells (PBMCs). Blood samples at baseline (T0), at maximal exertion (T1), and four hours post-exertion (T2) were analyzed. In female subjects with GWI, pathways associated with pro-inflammatory processes were found to be deregulated, and in male GWI subjects, pathways related to IL-12 signaling and lymphocytic activation were deregulated at T1 compared to T0. During recovery from stress, pathways corresponding to immune responses and microglial cell activation were altered in female GWI subjects, and apoptotic signaling changed in males with GWI. Documented sex-specific immune deregulation leads to finding better biomarkers. Targeting sex-specific transcriptomic markers of the disease could lead to new therapies for GWI.

Gulf War Illness (GWI) is a multi-symptom disorder affecting 1990–1991 Persian Gulf War veterans and is characterized by post-exertional malaise, neurological symptoms, immune deregulation, and exhaustion. Causation is not understood, and effective diagnostics and therapies have not yet been developed. In this work, we analyzed stress-related, sex-specific transcriptomic shifts in GWI subjects and healthy controls through RNA sequencing of peripheral blood mononuclear cells (PBMCs). Blood samples at baseline (T0), at maximal exertion (T1), and four hours post-exertion (T2) were analyzed. In female sub-jects with GWI proinflammatory processes, and in male subjects IL-12 signaling and lymphocytic activation were deregulated at T1compared to T0. During recovery from stress, HCMV activity and microglia activation increased in female GWI subjects, and apoptotic signaling changed in males with GWI. Documented sex-specific immune deregulation warrants personalized markers and therapies. Targeting sex-specific transcriptomic markers of disease could lead to new therapies for GWI.

Gulf War Illness (GWI) is a neuroinflammation- and immune-dysfunction-related chronic disease. Corticosteroids, a class of steroid hormones with potent anti-inflammatory and immunosuppressive properties, have been studied for their role in GWI pathophysiology. Eight corticosteroid effect studies were evaluated in this systematic review. Preclinical models showed exacerbation of neuroinflammation, oxidative stress, and epigenetic changes with exposure to CORT in addition to Gulf War neurotoxicants, which induced pro-inflammatory cytokine expression (Tumor Necrosis Factor Alpha (TNF-α), Interleukin-6 (IL-6), C-C motif chemokine ligand 2 (CCL2)). Such findings suggest that corticosteroids can exacerbate symptoms of GWI and need further clinical research to clarify their role in neuroinflammatory processes.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating, multi-system disease characterized by profound fatigue, post-exertional malaise (PEM), and a constellation of immune, neurological, and autonomic symptoms. Despite its global prevalence, the pathophysiology of ME/CFS remains elusive, and there are no FDA-approved treatments targeting the underlying mechanisms. Symptom-based pharmacologic management is often complicated by hypersensitivity reactions and mitochondrial toxicity. Non-pharmacologic interventions, such as energy conservation, autonomic regulation, and nutritional strategies, are frequently employed to mitigate symptom burden. Emerging research points to mitochondrial dysfunction as a core contributor to ME/CFS pathology, marked by impaired ATP production, oxidative stress, and bioenergetic failure. Mitochondrial-derived peptides (MDPs), particularly MOTS-c, offer a novel therapeutic avenue by enhancing mitochondrial biogenesis, reducing oxidative damage, and modulating inflammatory responses through AMPK and NRF2 activation. Preclinical evidence suggests that MOTS-c improves glucose metabolism, increases mitochondrial density, and enhances fatigue resistance. However, safety and efficacy data in humans are lacking. Future investigations are needed to evaluate MOTS-c's potential as a disease-modifying therapy in ME/CFS.