Hepatocyte TIA1 constrains metabolic steatohepatitis by translationally suppressing Srebf1 mRNA in stress granules

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its inflammatory sequel, metabolic dysfunction-associated steatohepatitis (MASH), pose escalating global health burdens, underscoring the urgent need to elucidate their molecular mechanisms and identify novel therapeutic targets. T-cell intracellular antigen 1 (TIA1), an RNA-binding protein and core organizer of stress granules (SGs), regulates post-transcriptional gene expression during cellular stress. However, its functional role in MASLD pathogenesis remains poorly understood. Hepatocyte-specific TIA1-knockout (TIA1-HKO) and wild-type control mice were subjected to three distinct diet-induced MASLD models. Parallel gain- and loss-of-function studies were conducted in PA-treated AML12 hepatocytes. RNA immunoprecipitation sequencing (RIP-seq), RIP-qPCR, fluorescence in situ hybridization (FISH), dual-luciferase reporter assays, and mRNA stability measurements were employed to map TIA1-sterol regulatory element binding transcription factor 1 (Srebf1) mRNA interactions and quantify translational repression. Pharmacological and genetic rescue experiments confirmed mechanistic findings. Integrated transcriptomic analysis of clinical specimens and murine models revealed significant TIA1 upregulation during MASLD progression. Hepatocyte-specific TIA1 deletion exacerbated dietary-induced steatosis, inflammation, and fibrosis. In vitro, TIA1 was essential for SGs assembly and maintenance of lipid homeostasis under lipotoxic stress. Mechanistically, TIA1 directly binds the 3' UTR of Srebf1 mRNA, sequestering it within SGs and repressing the translation of sterol regulatory element binding protein 1 (SREBP1)-a master transcriptional regulator of lipogenesis. Inhibition of SREBP1 activity rescued the metabolic perturbations induced by TIA1 ablation. This study identifies TIA1 as a crucial hepatoprotective factor that attenuates MASLD progression by orchestrating SGs-dependent translational control of Srebf1 mRNA. Impairment of the TIA1-SGs-SREBP1 axis accelerates steatohepatitis, highlighting its potential as a therapeutic target for metabolic liver diseases.TIA1 Constrains MASH Progression by Assembling Stress Granules to Suppress SREBP1-Driven Lipogenesis. This study delineates a hepatoprotective pathway centered on the RNA-binding protein TIA1. In response to metabolic stress. TIA1 nucleates SGs assembly and sequesters Srebf1 mRNA, leading to translational repression of the master lipogenic transcription factor SREBP1 and its downstream lipogenic program, thereby mitigating steatosis and subsequent inflammatory and fibrotic response.