Trained Immunity in sepsis: Exploring the molecular link to long-term cardiometabolic disorders

Sepsis, a life-threatening systemic infection, has long been recognized for its immediate risks, but its long-term consequences on health are increasingly evident, particularly in predisposing survivors to chronic cardiometabolic disorders (CMDs) such as atherosclerosis, insulin resistance, and dyslipidemia. Central to this process is trained immunity, where innate immune cells like monocytes, macrophages, and neutrophils undergo long-lasting epigenetic reprogramming after sepsis. This reprogramming, sustained by molecular pathways such as NF-κB, mTOR, and altered lipid metabolism, drives chronic inflammation, oxidative stress, and metabolic dysfunction, contributing to long-term cardiovascular diseases (CVDs) and metabolic disorders post-sepsis. This review explores the key mechanisms through which trained immunity bridges sepsis and CMDs, particularly focusing on epigenetic modifications such as histone acetylation, DNA methylation, and mitochondrial alterations. We discuss how trained immunity enhances immune cell activation, leading to persistent low-grade inflammation, lipid dysregulation, and impaired insulin sensitivity, all of which predispose sepsis survivors to CVDs. Additionally, we highlight potential therapeutic approaches targeting trained immunity, including statins, which reduce inflammation and immune reprogramming; metformin, which restores metabolic balance by activating AMPK and reducing oxidative stress; dimethyl fumarate (DMF), a potent Nrf2 activator that counteracts inflammation; and probiotics, which help restore gut microbiota balance and limit endotoxin-driven inflammation. These therapies offer promising strategies to mitigate long-term metabolic dysfunction and reduce the incidence of CMDs following sepsis. Understanding these mechanisms and developing targeted interventions may ultimately help prevent chronic cardiovascular and metabolic diseases in sepsis survivors and improve long-term outcomes.