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Background Non alcoholic fatty liver disease (NAFLD) has emerged as a major global public health issue, while its etiology is complex and molecular mechanisms are unclear. The abnormal expression and function of RNA binding proteins are important driving factors for the occurrence and development of NAFLD. T cell intracellular antigen 1 (TIA1), an RNA binding protein involved in the post transcriptional regulation of gene expression, is also a key molecule involved in the assembly of stress granules (SGs) under cell stress. However, the function and mechanism of TIA1 and SGs in the context of NAFLD are poorly understood. This research aims to systematically elucidate the roles and molecular mechanisms of TIA1 and SGs in the occurrence and development of NAFLD from clinical samples, animal models, and cell experiments, providing new biomarkers for early diagnosis of NAFLD and potential intervention targets for clinical treatment.Method We generated hepatocyte-specific TIA1 knockout (TIA1LKO) mice to study in vivo effects of TIA1 on lipid metabolism under high-fat diet (HFD), HFD containing high cholesterol and high fructose (HFHC; also known as Gubra Amylin NASH (GAN) diet) and methionine- and choline deficient diet (MCD). Lipid deposition and metabolic homeostasis were analyzed in AML12 cells with multiple loss- and gain-of function studies. Additionally, the relationship of TIA1 with SREBP1 was explored via RNA immunoprecipitation and third-generation sequencing. The regulatory role of TIA1 in modulating SREBP1 translation was further elucidated using luciferase reporter assays and chromatin immunoprecipitation.Abstract P14 Figure 1Results Through RNA sequencing of clinical samples and GEO database analysis, we have found that TIA1 expression is upregulated in NAFLD liver and is associated with clinical indicators and poor prognosis of NAFLD/NASH. Hepatocyte-specific knockdown of TIA1 in mice significantly exacerbate liver steatosis and fibrosis in multiple mouse models of metabolic dysfunction-associated steatohepatitis and liver fibrosis. Additionally, multiple loss- and gain-of function studies in vitro, we demonstrate that TIA1 expression and TIA1-assmbled SGs are elevated in palmitic acid (PA)-simulated AML12 cells and essential to maintain lipid homeostasis. Both the upregulation of TIA1 and the stimulation of SGs contribute to the alleviation of hepatocellular steatosis. Mechanistically, TIA1 can specifically bind to the mRNA 3’UTR region of SREBP1, isolating it in SGs to inhibit its expression. Based on the above, we propose a scientific hypothesis that TIA1 may inhibit the activity of SREBP1 by mediating the formation of stress granules, thereby reducing liver lipid deposition and delaying the progression of NAFLD.