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Background Aging is a well-established risk factor for non-alcoholic fatty liver disease (NAFLD). This study tested the hypothesis that age-associated immunoglobulin G (IgG) accumulation exacerbates susceptibility to hepatic steatosis and identified macrophage SASP as a critical mechanistic link—where IgG triggers macrophage senescence, leading to paracrine disruption of hepatocyte lipid homeostasis.Methods Liver tissues were harvested from young (3 months) and aged (24 months) male C57BL/6 mice under standardized conditions. To assess in vivo susceptibility to diet-induced steatosis, HFD-fed mice received weekly intraperitoneal injections of purified murine IgG or vehicle control for 10 weeks. In vitro, bone marrow–derived macrophages (BMDMs) were treated with IgG to evaluate senescence markers (e.g., SA-β-gal activity, p21CIP1, and SASP factors). To investigate paracrine effects on hepatocytes, immortalized mouse hepatocyte line AML12 and primary mouse hepatocytes were exposed to conditioned medium (CM) collected from IgG-treated BMDMs; lipid accumulation was quantified by intracellular triglyceride assays.Results Aged mice displayed significantly elevated hepatic IgG levels ( IDDF2026-ABS-0121 Figure 1(A,B) Age-associated IgG accumulation exacerbates diet-induced hepatic steatosis). Notably, intraperitoneal administration of IgG on HFD-fed mice markedly exacerbated hepatic steatosis and histopathological injury relative to the vehicle-treated HFD control group (IDDF2026-ABS-0121 Figure 1(C-E) Age-associated IgG accumulation exacerbates diet-induced hepatic steatosis). At the cellular level, IgG treatment induced macrophage senescence, as evidenced by upregulation of the Senescence-Associated Secretory Phenotype (SASP) (IDDF2026-ABS-0121 Figure 2(A,B) IgG-mediated macrophage senescence promotes hepatocyte steatosis through paracrine signaling). Moreover, AML12 and primary hepatocytes exposed to CM derived from IgG-treated macrophages exhibited significantly increased intracellular lipid accumulation (IDDF2026-ABS-0121 Figure 2(C,D) IgG-mediated macrophage senescence promotes hepatocyte steatosis through paracrine signaling), demonstrating that SASP factors secreted by senescent macrophages directly disrupt hepatocyte lipid homeostasis.Conclusions These findings establish that IgG accumulation promotes fatty liver progression through the induction of macrophage SASP. Consequently, therapeutic modulation of the IgG–macrophage axis holds promise as a novel intervention strategy for age-related metabolic dysfunction in the liver.Abstract IDDF2026-ABS-0121 Figure 1Abstract IDDF2026-ABS-0121 Figure 2