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<p>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<sup>hi</sup>CD8<sup>+</sup> 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<sup>+</sup> 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<sup>hi</sup>CD8<sup>+</sup> T cells with pro-fibrotic properties and suggests a potential anti-fibrotic strategy.</p>

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Metabolically and epigenetically reprogrammed splenic TRNP1hiCD8+ T cells exacerbate liver fibrosis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月8日

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  • 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

摘要

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 TRNP1hiCD8+ 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 TRNP1hiCD8+ T cells with pro-fibrotic properties and suggests a potential anti-fibrotic strategy.