Establishment and comparative analysis of radiation-induced liver disease in normal and fibrotic rat models

Abstract

Purpose: Hepatocellular carcinoma (HCC) is a lethal malignancy in which stereotactic body radiotherapy (SBRT) is used for inoperable cases. However, radiation-induced liver disease (RILD) remains a major risk, particularly in fibrotic livers. This study established rat models of RILD with and without preexisting fibrosis to evaluate the effects of radiation-fibrosis on liver damage.

Experimental design: Male Sprague-Dawley rats were divided into radiation therapy (RT) (n = 41; 25 Gy right liver irradiation) and thioacetamide (TAA)+RT (n = 46; 6-week TAA-induced fibrosis + 20 Gy RT) groups. Pathological assessments (Hematoxylin and Eosin, Masson's Trichrome, Picro-Sirius Red, and TGF-β/α-SMA immunohistochemistry) were performed at 2, 4, 8, and 12 weeks post-RT to quantify fibrosis, collagen, inflammation, and ballooning degeneration. Statistical analyses included independent sample t-tests, Mann-Whitney U tests, and one-way ANOVA, with p < 0.05 considered significant.

Results: The RT group exhibited mild edema (2–12 weeks), mild ballooning degeneration (4–12 weeks), and minimal inflammation (2–12 weeks). Collagen deposition and TGF-β expression increased significantly at 8–12 weeks (p < 0.05), whereas α-SMA remained mildly elevated at 4–12 weeks (p > 0.05). The TAA+RT group showed mild/severe ballooning degeneration, moderate inflammation, and markedly higher collagen/fibrosis compared with the RT group (p < 0.05). Both TGF-β and α-SMA increased progressively in the TAA+RT group, peaking at 12 weeks (p < 0.05).

Conclusions: Radiation combined with preexisting fibrosis exacerbates hepatic damage and stellate cell activation. This study provides validated RILD models for translational research and highlights the need for cautious radiation dose selection in patients with fibrosis to mitigate the risk of liver injury.

Keywords

hepatic stellate cells / Hepatocellular carcinoma / liver fibrosis / thioacetamide / stereotactic body radiotherapy / radiation-induced liver disease

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2026 The Author(s). Precision Radiation Oncology published by John Wiley & Sons Australia, Ltd on behalf of Shandong Cancer Hospital & Institute.