Tert‐butylhydroquinone promotes skin flap survival by inhibiting oxidative stress mediated by the Nrf2/HO‐1 signalling pathway

• Published in: British journal of pharmacology 2024-12, Vol.181 (23), p.4845-4858
• Main Authors: Wang, Kaitao, Wang, An, Deng, Jiapeng, Yang, Jialong, Chen, Guodong, Chen, Qingyu, Ye, Minle, Lin, Dingsheng
• Format: Article
• Language: English
• Subjects: Angiogenesis; Animal models; Animals; Antioxidants - pharmacology; Apoptosis; Apoptosis - drug effects; Autophagy; Autophagy - drug effects; BAX protein; Blood flow; Cytokines; Dose-Response Relationship, Drug; Food additives; Heme Oxygenase (Decyclizing); Heme Oxygenase-1 - metabolism; Hydroquinones - administration & dosage; Hydroquinones - pharmacology; Inflammation; Interleukin 6; Male; NF-E2-Related Factor 2 - metabolism; Nrf2/HO‐1; Oxidative stress; Oxidative Stress - drug effects; Patients; Rats; Rats, Sprague-Dawley; Signal transduction; Signal Transduction - drug effects; Skin; Skin - drug effects; Skin - metabolism; Skin - pathology; Surgical Flaps; Survival; t-Butylhydroquinone; tert‐butylhydroquinone; Vascular endothelial growth factor; Western blotting; Wound healing
• ISSN: 0007-1188; 1476-5381; 1476-5381
• DOI: 10.1111/bph.17321

Background and Purpose Skin flaps are among the most important means of wound repair in clinical settings. However, partial or even total distal necrosis may occur after a flap operation, with severe consequences for both patients and doctors. This study investigated whether tert‐butylhydroquinone (TBHQ), a known agonist of the transcription factor nuclear factor erythroid 2‐related factor 2 (Nrf2), and an antioxidant, could promote skin flap survival. Experimental Approach McFarlane skin flap models were established in male Sprague–Dawley rats and then randomly divided into control, low‐dose TBHQ, and high‐dose TBHQ treatment groups. On postoperative day 7, the survival and blood flow of the skin flaps were assessed. Using flap tissue samples, angiogenesis, inflammation, apoptosis, autophagy, and Nrf2/haem oxygenase 1 (HO‐1) signalling pathway activity were measured with immunohistochemical techniques and western blotting. Key Results TBHQ dose‐dependently stimulated the Nrf2/HO‐1 signalling pathway, inducing autophagy through the up‐regulation of LC3B and beclin 1 and concurrently suppressing p62 expression. Additionally, TBHQ hindered apoptosis by enhancing Bcl‐2 expression while inhibiting the expression of Bax. It suppressed inflammation by inhibiting the expression of interleukin 1β, interleukin 6, and tumour necrosis factor‐α and enhanced angiogenesis by promoting the expression of vascular endothelial growth factor. Conclusion and Implications In summary, TBHQ promoted flap survival in rats by up‐regulating the Nrf2/HO‐1 signalling pathway. As TBHQ is already widely used as a food additive, it could offer an acceptable means of improving clinical outcomes following skin flap surgery in patients.