Biao Huang,1,* Gong Chen,2,* Tao Yan,1,* Xiaolan Ou,1 Long Yang,2 Tinghao He,2 Fenghao Geng,3 Zehua Zhou,1 Guozhong Lyu,4 Shuyu Zhang,3 Daojiang Yu1,4 

1Department of Plastic and Burn Surgery, The Second Affiliated Hospital of Chengdu Medical College, Nuclear Industry 416 Hospital, Chengdu, 610051, People’s Republic of China; 2Department of Medicine, Chengdu Medical College, Chengdu, 610051, People’s Republic of China; 3Laboratory of Radiation Medicine, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, 610041, People’s Republic of China; 4Department of Burn and Plastic Surgery, Affiliated Hospital of Jiangnan University, Wuxi, 214122, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Shuyu Zhang, Laboratory of Radiation Medicine, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, 610041, People’s Republic of China, Email zhangshuyu@scu.edu.cn Daojiang Yu, Department of Plastic and Burn Surgery, The Second Affiliated Hospital of Chengdu Medical College, Nuclear Industry 416 Hospital, Chengdu, 610051, People’s Republic of China, Email ydj51087@163.com

Background: Radiation-induced skin injury (RISI) is a common complication of radiotherapy, affecting up to 95% of cancer patients. It manifests as acute erythema and ulceration or chronic fibrosis and telangiectasia, severely compromising patients’ quality of life. The pathogenesis of RISI involves oxidative stress, inflammation, DNA damage, and cellular senescence. However, current treatments are largely supportive and fail to address underlying mechanisms. Berberine (BBR), a natural isoquinoline alkaloid, exhibits anti-inflammatory, antioxidant, and wound-healing properties, making it a promising candidate for managing RISI.
Methods: Single-cell RNA sequencing and proteomic analyses were employed to characterize the molecular and cellular changes in patient, rats and cells exposed to ionizing radiation. Differentially expressed genes (DEGs) and proteins were identified, and functional enrichment analyses were performed. Key senescence markers were validated using molecular docking and in vitro assays. The therapeutic effect of BBR was validated in skin cells and in mouse models of radiation-induced skin injury, focusing on wound healing and systemic health.
Results: Transcriptomic analysis identified 217 DEGs in RISI, highlighting pathways such as TNF, p53, and NF-kappa B signaling. Key senescence markers, including CDKN1A, IGFBP7, and CTSL, were overexpressed, correlating with impaired wound healing. Proteomic analysis revealed that BBR modulated 684 proteins, enhancing keratinocyte migration and reducing oxidative damage. BBR treatment promoted the proliferation and migration of skin cells, alleviated radiation-induced cellular senescence, and downregulated inflammatory pathways including p53, ROS, and JAK-STAT. BBR-treated mice exhibited significantly reduced skin injury scores, improved body weight retention, and enhanced wound healing.
Conclusion: Radiation injury leads to persistent senescence, inflammation, and impaired wound healing in skin tissues. CDKN1A, IGFBP7, and CTSL are core senescence markers in RISI. By downregulating the expression of senescence markers and suppressing inflammatory pathways (including p53, ROS, and JAK-STAT), BBR accelerates radiation-induced wound healing, offering a novel therapeutic strategy for managing RISI.

Keywords: radiation-induced skin injury, berberine, cellular senescence, proteomics, single-cell RNA sequencing, wound healing