Physical activity and the renin-angiotensin system LBP-centered immunometabolic network in sepsis from multiomics to functional validation
Lizhi Li, Jianbin Wang, Zhiwei Li, Ling Zhang, Dunyan Chen, Jianwei Wang, Ying Chen, Yansong GuoBackground
The immunometabolic mechanisms behind the protective association between physical activity and reduced sepsis risk remain poorly understood.
Methods
We combined global epidemiological data, Mendelian randomization, bulk and single-cell transcriptomics, machine learning, clinical analyses and macrophage functional experiments to explore how physical activity modulates sepsis susceptibility.
Results
Physical inactivity, metabolic dysfunction and high BMI substantially contribute to global sepsis burden. Mendelian randomization indicated a causal protective effect of physical activity partially mediated by metabolic pathways. The renin-angiotensin system (RAS), represented by the ACE/ACE2 ratio, acts as a core regulatory network linking physical activity to sepsis. Macrophages are key effector cells, with ACE, ACE2, GLUT4, TLR4, CHPT1 and LBP identified as core immunometabolic regulators. Asparagine alleviated inflammasome-triggered macrophage injury in an LBP-dependent manner. Clinical data showed RAS inhibitor use was associated with improved 28-day survival in sepsis patients.
Conclusion
Physical activity reduces sepsis risk through renin-angiotensin system and LBP-centered immunometabolic regulation, providing potential preventive and therapeutic targets.