Hepatic injury is one of the most challenging diseases in clinical medicine. Hepatic injury is accompanied by hepatocyte apoptosis and leads to hepatic fibrosis and cirrhosis, which may cause liver cancer and increased mortality. Therefore, it is essential to investigate the regulation mechanism and therapeutic strategies for hepatic injury. In the study, the effects of Thymosin β4 (Tβ4) on Long intergenic noncoding RNA-p21 (lincRNA-p21)-mediated liver injury were investigated. Results showed that lincRNA-p21 overexpression promoted hepatocytes apoptosis, which was blocked by Tβ4. Besides, Tβ4 reversed the levels of cleaved caspase-3 and caspase-9 induced by lincRNA-p21. LincRNA-p21 overexpression also caused the pathological injury and fibrosis in hepatic tissues and increased the levels of fibrosis-related proteins (Collagen I, α-SMA and TIMP-1), and induced hydroxyproline and ALT production. However, Tβ4 reversed the effects of overexpression of lincRNA-p21 on hepatic injury and fibrosis. In vitro experiments, after lincRNA-p21 was overexpressed in hepatic stellate cells (HSCs), the proliferation ability and the levels of HSCs markers α-SMA and Desmin were increased. However, Tβ4 reversed the effects of lincRNA-p21 on HSCs. Furthermore, the PI3K-AKT-NF-κB pathway was activated by lincRNA-p21, which was then reversed by the Tβ4 administration. After the mice treated by insulin-like growth factor-1 (IGF-1) (the activator of PI3K-AKT), the inhibitory effect of Tβ4 on activated the PI3K-AKT-NF-κB pathway was abrogated. Besides, IGF-1 abolished the protective effects of Tβ4 on hepatic apoptosis and fibrosis induced by lincRNA-p21. Therefore, Tβ4 reversed.

lincRNA-p21-mediated liver injury through inhibiting PI3K-AKT-NF-κB pathway. Tβ4 may be a promising drug for fibrosis therapy.

肝损伤是临床医学中最具挑战性的疾病之一。肝损伤伴有肝细胞凋亡，并导致肝纤维化和肝硬化，可能导致肝癌并增加死亡率。因此，研究肝损伤的调控机制和治疗策略至关重要。在这项研究中，研究了胸腺素β4（Tβ4）对长基因间非编码RNA-p21（lincRNA-p21）介导的肝损伤的影响。结果表明，lncRNA-p21的过度表达促进了肝细胞的凋亡，而Tβ4阻止了它的凋亡。此外，Tβ4逆转了lincRNA-p21诱导的切割的caspase-3和caspase-9的水平。LincRNA-p21的过表达也引起了肝组织的病理损伤和纤维化，并增加了纤维化相关蛋白（胶原I，α-SMA和TIMP-1）的水平，并诱导羟脯氨酸和ALT产生。然而，Tβ4逆转了lincRNA-p21过表达对肝损伤和纤维化的影响。体外实验中，在肝星状细胞（HSC）中过表达lincRNA-p21后，其增殖能力以及HSCs标记α-SMA和Desmin的水平均升高。然而，Tβ4逆转了lincRNA-p21对HSC的作用。此外，PI3K-AKT-NF-κB途径被lincRNA-p21激活，然后通过Tβ4给予逆转。用胰岛素样生长因子-1（IGF-1）（PI3K-AKT的激活剂）治疗小鼠后，Tβ4抑制了PI3K-AKT-NF-κB通路的激活作用。此外，IGF-1取消了Tβ4对lincRNA-p21诱导的肝细胞凋亡和肝纤维化的保护作用。因此，Tβ4反转。

lincRNA-p21通过抑制PI3K-AKT-NF-κB途径介导的肝损伤。Tβ4可能是用于纤维化治疗的有前途的药物。