Thymosin β4 increases hepatic susceptibility to repeated irradiation and enhances cellular senescence and fibrosis.

Radiation-induced liver injury limits the efficacy of hepatic radiotherapy; however, the factors influencing hepatic susceptibility to repeated irradiation are poorly understood. Thymosin β4 (Tβ4) has been implicated in hepatic stellate cell (HSC) activation and fibrosis, but its role in radiation-induced liver injury remains unclear. Therefore, this study aims to investigate the effects of sustained Tβ4 overexpression on the hepatic response to repeated irradiation in Tβ4-overexpressing transgenic (Tβ4-Tg) mice. Wild-type and Tβ4-Tg mice were exposed to 6 Gy irradiation once weekly for 5 consecutive weeks. Following repeated irradiation, Tβ4-Tg mice exhibited markedly reduced survival, substantial decreases in body and liver weight, and increased hepatic triglyceride accumulation. Despite this increased susceptibility, irradiated Tβ4-Tg mice did not exhibit higher serum AST or ALT levels or cleaved CASPASE-3 staining than irradiated wild-type mice. However, irradiated Tβ4-Tg mice showed upregulated expression of the senescence-associated proteins p21, p53, and p16, along with increased HSC activation and collagen deposition. These findings demonstrate that elevated Tβ4 may promote hepatic senescence and fibrosis, and increased susceptibility to repeated irradiation, suggesting that Tβ4 may be an important determinant of hepatic vulnerability to repeated irradiation.