Metabolically and epigenetically reprogrammed splenic TRNP1^hiCD8⁺ T cells exacerbate liver fibrosis.

Authors

Liyuan Zhang, Yahui Wang, Kai Wei, Wen Nie, Yayuan Feng, Zhiwen Shi, Hongmei Xiao, Weifen Xie, Yong Lin, Xin Zeng, Yongquan Shi, Wei Tang, Tuo Li, Fu Yang, Ye Zhou, Minjun Wang, Yanfang Liu, Shanrong Liu, Jin Hou

Published in

Nature genetics. Jul 08, 2026. Epub Jul 08, 2026.

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD), especially its severe form, metabolic dysfunction-associated steatohepatitis (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 found enlarged spleens in patients with MASLD and identified induced TRNP1^hiCD8⁺ T cells in spleens of MASLD/MASH mouse models and patients. These cells exhibited pro-fibrotic properties through secretion of INSR-α. Mechanistically, demethylated DNA and H3K27me3, increased H3K27ac and 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 activated the expression of FURIN and CTSD, promoting the maturation and ectodomain shedding of INSR-α and facilitating its secretion to activate hepatic stellate cells. In vivo blockade of INSR-α using neutralizing antibodies alleviated MASLD/MASH-induced liver fibrosis. This study reveals splenic TRNP1^hiCD8⁺ T cells with pro-fibrotic properties and suggests a potential anti-fibrotic strategy.

PMID:
42420523
Bibliographic data and abstract were imported from PubMed on 09 Jul 2026.

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