Chronic non-communicable diseases are conventionally classified as distinct clinical entities, yet multimorbidity has become the dominant phenotype in modern populations. Converging experimental, clinical and epidemiological evidence indicates that metabolic overload—characterised by persistent hyperinsulinaemia, insulin resistance and nutrient-driven anabolic signalling—acts as a central amplifier of conserved stress-response systems and chronic low-grade inflammatory signalling.
Under contemporary exposome conditions, sustained metabolic stress chronically engages sympathetic and renin–angiotensin–aldosterone signalling, oxidative stress pathways and innate immune activation, establishing a tightly coupled feed-forward network that stabilises pathological states across organ systems. Here, I synthesise mechanistic data from endocrinology, immunometabolism, vascular biology and ageing research to propose a unified stress-signalling architecture linking systemic stress axes to shared intracellular integration hubs.
These include inflammatory transcriptional regulators (NF-κB, AP-1), stress-activated kinases (MAPKs), and nutrient- and oxygen-sensing pathways centred on PI3K–Akt–mTOR and HIF-1α, with additional modulation by Notch signalling.
Frontiers in Immunology published a clinical update in Infectious Disease on 07 May 2026.
The item focuses on A shared stress-inflammation signalling architecture underlying chronic disease and multimorbidity.
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