酒精相关性肝病（ALD）是世界范围内的一个主要健康问题，但仍然缺乏有效的 ALD 治疗方法。肿瘤坏死因子诱导基因 6 蛋白 (TSG-6) 是一种从间充质干细胞释放的细胞因子，可减少肝脏纤维化并促进肝脏慢性受损小鼠的成功修复。然而，TSG-6 的作用及其在 ALD 中的活性机制仍知之甚少。为了研究其在患有纤维化的 ALD 小鼠中的功能，长期喂食含乙醇 (EtOH) 饮食 9 周的雄性小鼠接受了 TSG-6 治疗。 6 (EtOH  TSG-6) 或 PBS (EtOH  Veh) 再持续 3 周。在喂食 EtOH 的 TSG-6 治疗小鼠中，EtOH 治疗小鼠的严重肝损伤显着减少。 EtOH  TSG-6组的纤维化程度低于EtOH  Veh组。据报道，分化簇 44 (CD44) 的激活可促进 HSC 激活。 CD44 和细胞核 CD44 胞内结构域 (ICD)（一种 CD44 激活剂）在活化的 HSC 中上调，而 ALD 小鼠在饲喂 EtOH 的 TSG-6 暴露小鼠中显着下调。 TSG-6 直接与 MMP14（一种裂解 CD44 的蛋白水解酶）的催化位点相互作用，抑制 CD44 裂解为 CD44ICD，并减少 ALD 小鼠的 HSC 活化和肝纤维化。此外，一种新的肽设计包含与 MMP14 催化位点结合的区域，可抑制 CD44 激活并减轻酒精引起的肝损伤，包括小鼠的纤维化。这些结果表明，TSG-6 可以减轻酒精引起的肝损伤，并减轻酒精引起的肝损伤。通过阻断 CD44 裂解为 CD44ICD 来抑制纤维化，并表明 TSG-6 和 TSG-6 模拟肽可用作治疗伴有纤维化的 ALD。© 2024。作者。

Alcohol-related liver disease (ALD) is a major health concern worldwide, but effective therapeutics for ALD are still lacking. Tumor necrosis factor-inducible gene 6 protein (TSG-6), a cytokine released from mesenchymal stem cells, was shown to reduce liver fibrosis and promote successful liver repair in mice with chronically damaged livers. However, the effect of TSG-6 and the mechanism underlying its activity in ALD remain poorly understood.To investigate its function in ALD mice with fibrosis, male mice chronically fed an ethanol (EtOH)-containing diet for 9 weeks were treated with TSG-6 (EtOH + TSG-6) or PBS (EtOH + Veh) for an additional 3 weeks.Severe hepatic injury in EtOH-treated mice was markedly decreased in TSG-6-treated mice fed EtOH. The EtOH + TSG-6 group had less fibrosis than the EtOH + Veh group. Activation of cluster of differentiation 44 (CD44) was reported to promote HSC activation. CD44 and nuclear CD44 intracellular domain (ICD), a CD44 activator which were upregulated in activated HSCs and ALD mice were significantly downregulated in TSG-6-exposed mice fed EtOH. TSG-6 interacted directly with the catalytic site of MMP14, a proteolytic enzyme that cleaves CD44, inhibited CD44 cleavage to CD44ICD, and reduced HSC activation and liver fibrosis in ALD mice. In addition, a novel peptide designed to include a region that binds to the catalytic site of MMP14 suppressed CD44 activation and attenuated alcohol-induced liver injury, including fibrosis, in mice.These results demonstrate that TSG-6 attenuates alcohol-induced liver damage and fibrosis by blocking CD44 cleavage to CD44ICD and suggest that TSG-6 and TSG-6-mimicking peptide could be used as therapeutics for ALD with fibrosis.© 2024. The Author(s).