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<p>The soluble form of T-cell immunoglobulin and mucin-domain containing-3 (Tim-3) has been reported to be associated with various liver diseases and to serve as a prognostic marker for disease progression. Nevertheless, its role in drug-induced liver injury is not defined. In this work, we initially measured the level of serum soluble Tim-3 (sTim-3) in acetaminophen (APAP) -administered mice and found that it increased in a dose-dependent manner. An increase in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and liver damage were observed in anti-Tim-3 antibody-treated mice. Therefore, we speculated that sTim-3 could protect against liver injury. To prove this hypothesis, the exogenous extracellular region of sTim-3 protein was injected into mice, leading to a significant decline in ALT and AST levels, coagulative necrosis of liver tissue, and ratio of mouse survival. Single-nucleus RNA sequencing (snRNA-seq) showed a decreased immune infiltration and a downregulation of inflammatory cytokines in sTim-3-treated liver. SnRNA-seq and immunohistochemical staining also showed that, besides immune cells, hepatocytes contribute to the expression of Tim-3. This finding was further demonstrated in hepatocyte-specific Tim-3 gene knockout mice, in which liver injury was more serious after APAP administration. Moreover, Galectin-3 and 9 were shown to act as ligands for sTim-3. Importantly, analysis of clinical serum samples confirmed these findings. Taken together, this study reveals an autocrine feedback loop in which hepatocyte-derived sTim-3 protein participates in protecting the liver from injury, and suggests that supplementation with exogenous sTim-3 could benefit the treatment of drug-induced liver injury.</p>

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Hepatocyte-derived soluble Tim-3 contributes to alleviating acetaminophen-induced liver injury

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月9日

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  • Chenlu Huang,
  • Jin Li,
  • Shiqi Chen,
  • Cong Wang,
  • Xuhua Jiang,
  • Qiang Li,
  • Liangjun Shen,
  • Kuangjie Zhao,
  • Hong Gao,
  • Yuxian Huang,
  • Liang Chen,
  • Li Zhu,
  • Zhenghong Yuan,
  • Zhong Fang

摘要

The soluble form of T-cell immunoglobulin and mucin-domain containing-3 (Tim-3) has been reported to be associated with various liver diseases and to serve as a prognostic marker for disease progression. Nevertheless, its role in drug-induced liver injury is not defined. In this work, we initially measured the level of serum soluble Tim-3 (sTim-3) in acetaminophen (APAP) -administered mice and found that it increased in a dose-dependent manner. An increase in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and liver damage were observed in anti-Tim-3 antibody-treated mice. Therefore, we speculated that sTim-3 could protect against liver injury. To prove this hypothesis, the exogenous extracellular region of sTim-3 protein was injected into mice, leading to a significant decline in ALT and AST levels, coagulative necrosis of liver tissue, and ratio of mouse survival. Single-nucleus RNA sequencing (snRNA-seq) showed a decreased immune infiltration and a downregulation of inflammatory cytokines in sTim-3-treated liver. SnRNA-seq and immunohistochemical staining also showed that, besides immune cells, hepatocytes contribute to the expression of Tim-3. This finding was further demonstrated in hepatocyte-specific Tim-3 gene knockout mice, in which liver injury was more serious after APAP administration. Moreover, Galectin-3 and 9 were shown to act as ligands for sTim-3. Importantly, analysis of clinical serum samples confirmed these findings. Taken together, this study reveals an autocrine feedback loop in which hepatocyte-derived sTim-3 protein participates in protecting the liver from injury, and suggests that supplementation with exogenous sTim-3 could benefit the treatment of drug-induced liver injury.