Abstract
Background: The neuroendocrine and immune systems operate as deeply integrated regulatory networks, jointly modulating host responses to infectious agents and metabolic perturbations. Disruptions in the hypothalamic-pituitary-adrenal (HPA) axis frequently coincide with pathological oxidative stress, creating a self-amplifying cycle of immunological dysfunction, hormonal imbalance, and cellular damage. Emerging evidence further implicates mitochondrial dysfunction, ferroptosis, and immunometabolic reprogramming as critical mechanistic intermediaries.
Objective: This review critically examines the bidirectional relationship between immunoendocrine signaling and oxidative stress across infectious and metabolic diseases, with emphasis on the Nrf2/NF-κB axis, NLRP3 inflammasome, ferroptosis, immunometabolic reprogramming, and the microbiome-endocrine-immune interface.
Key Findings: Cortisol, thyroid hormones, melatonin, and insulin orchestrate pro- and anti-inflammatory immune activity. ROS generated during infection and metabolic disease amplify cytokine cascades, impair antioxidant enzyme systems (SOD, CAT, GPx), and suppress endocrine feedback loops. Mitochondrial ROS trigger NLRP3 inflammasome activation, while ferroptosis—an iron-dependent, GPX4-regulated cell death pathway—emerges as a critical tissue injury mechanism in diabetes and severe infections. The Warburg-shifted immunometabolic reprogramming of activated immune cells further amplifies inflammatory cascades.
Conclusion: Multi-target therapeutic strategies simultaneously addressing endocrine dysregulation, ferroptosis, mitochondrial dysfunction, and oxidative burden represent the most promising approach for managing complex infectious and metabolic pathologies. Sex-stratified multiomics investigations and AI-assisted biomarker integration are urgently needed.
Objective: This review critically examines the bidirectional relationship between immunoendocrine signaling and oxidative stress across infectious and metabolic diseases, with emphasis on the Nrf2/NF-κB axis, NLRP3 inflammasome, ferroptosis, immunometabolic reprogramming, and the microbiome-endocrine-immune interface.
Key Findings: Cortisol, thyroid hormones, melatonin, and insulin orchestrate pro- and anti-inflammatory immune activity. ROS generated during infection and metabolic disease amplify cytokine cascades, impair antioxidant enzyme systems (SOD, CAT, GPx), and suppress endocrine feedback loops. Mitochondrial ROS trigger NLRP3 inflammasome activation, while ferroptosis—an iron-dependent, GPX4-regulated cell death pathway—emerges as a critical tissue injury mechanism in diabetes and severe infections. The Warburg-shifted immunometabolic reprogramming of activated immune cells further amplifies inflammatory cascades.
Conclusion: Multi-target therapeutic strategies simultaneously addressing endocrine dysregulation, ferroptosis, mitochondrial dysfunction, and oxidative burden represent the most promising approach for managing complex infectious and metabolic pathologies. Sex-stratified multiomics investigations and AI-assisted biomarker integration are urgently needed.
Keywords
immunoendocrine interactions; HPA axis; oxidative stress; reactive oxygen species; Nrf2/NF-κB; ferroptosis; mitochondrial dysfunction; immunometabolism; infectious diseases; metabolic syndrome