TNF and endothelial dysfunction: Systemic inflammation promotes insulin resistance and atherogenesis through several well-described mechanisms: pro-inflammatory cytokines (such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6)) induce serine phosphorylation of insulin receptor substrate proteins and impair downstream insulin signaling, promote lipolysis and ectopic lipid deposition, and increase oxidative stress; concurrently, inflammation drives endothelial dysfunction, monocyte recruitment, macrophage foam cell formation, and matrix remodeling that accelerate plaque formation and instability.