GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE299nnn/GSE299307/primaryOK200GenomicsMus musculusGenome binding/occupancy profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE299307GEOGSEfalseMetabolically and epigenetically reprogrammed splenic TRNP1hiCD8+ T cells exacerbate liver fibrosisMASLD, especially its severe form MASH, progresses to liver fibrosis, leading to cirrhosis and liver cancer. The cross-talk between spleen and liver in MASLD/MASH progression remains poorly understood. Here, we find the enlarged spleens in MASLD patients, and the induced TRNP1hiCD8+ T cells in the spleens of MASLD/MASH mouse models and confirmed in MASLD patients, with pro-fibrotic property by secreting INSR-α. Mechanistically, demethylated DNA and H3K27me3, increased H3K27ac, together with bolstered enhancer-promoter contact, synergistically reorganized chromatin topologically associating domains spatially to initiate the expression of transcription factor TRNP1 in splenic CD8+ T cells. TRNP1 then transcriptionally activates the expression of FURIN and CTSD, promoting the maturation and ectodomain shedding of INSR-α thereby facilitating its secretion to activate hepatic stellate cells. In vivo blockade of INSR-α using neutralizing antibodies amelioratesalleviates MASLD/MASH-induced liver fibrosis. Therefore, this study reveals splenic TRNP1hiCD8+ T cells with pro-fibrotic property and suggests a potential anti-fibrotic strategy.2026/04/30GSE299307GSM9036934GSM9036939GSM9036935GSM9036936GSM9036937GSM903693834290299307Mus musculus