Sulforaphane regulates Nrf2-mediated antioxidant activity and downregulates TGF-β1/Smad pathways to prevent radiation-induced muscle fibrosis.

Aims: This study aimed to examine the efficacy of sulforaphane (SFN) in preventing radiation-induced muscle fibrosis (RIMF) and the potential role in nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidant stress.

Main Methods: The RIMF model was established by a single irradiation of the left thigh of C57BL/6 J mice, and the mice were then randomly divided into control, SFN, irradiation (IR), and IR + SFN (IR/SFN) groups. The serum and skeletal muscle were collected eight weeks after irradiation, and changes in oxidative stress and muscle fibrosis were detected.

Key Findings: The IR group showed a more obvious skeletal muscle fiber atrophy, significantly higher number of collagen fibers, and higher inflammatory cell infiltration compared to control group. Compared to the IR group, the IR/SFN group had orderly arranged muscle fibers, decreased collagen fibers, and infiltration of inflammatory cells. In addition, compared with the control group, the expression of oxidative stress-related indexes was significantly increased, accompanied by activation of the transforming growth factor (TGF-β)/Smad pathway and its downstream fibrogenic molecules in the skeletal muscle of the IR group. After SFN intervention, the above indices were significantly restored. Furthermore, SFN induced the upregulation of Nrf2, activation of AKT, and inhibition of GSK-3β and Fyn accumulation.

Significance: These results revealed that Nrf2 plays a central role in protecting against RIMF. Furthermore, SFN prevents RIMF by activating Nrf2 via the AKT/GSK-3β/Fyn pathway.