Activation of immune cells in adipose tissues and liver contributes to IR progression through ER stress induction.This is evidenced by activated macrophages and NK cells promoting the secretion of proinflammatory cytokines, thereby aggravating ER stress and insulin resistance.Elevated levels of Secreted Phosphoprotein 1/Osteopontin (SPP1) upregulate ER stress markers, triggering insulin resistance. SPP1 promotes macrophage infiltration and the M1 inflammatory phenotype, leading to elevated cytokine levels (e.g., TNF-α, IL-6), which interfere with insulin signaling. The gene discussed is INS; the disease is Insulin resistance.