Sis Aghayants,1,* Shengzhi Zhou,1,* Keyu Zhu,1,* Zhixiang Tan,1 Bomin Cheng,2 Song Gong,3 Zhanyong Zhu1 

1Department of Plastic Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, People’s Republic of China; 2Chinese Medicine Health Management Center, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, People’s Republic of China; 3Division of Endocrinology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei 430030, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Bomin Cheng, Email Szhyncbm@163.com Zhanyong Zhu, Email zyzhu@whu.edu.cn

Background: Diabetic foot ulcers (DFUs) are a common and severe complication of diabetes, often resulting in chronic non-healing wounds. This study aims to investigate the role of cyclin-dependent kinase inhibitor 1A (CDKN1A) in diabetic wound healing, focusing on its impact on cell proliferation and differentiation in DFUs.
Methods: We utilized single-cell RNA sequencing (scRNA-seq) to analyze gene expression profiles from DFUs tissues, comparing healing and non-healing groups. Differential gene expression analysis was performed to identify key regulators of wound healing. Mendelian randomization (MR) was employed to explore the causal relationship between CDKN1A expression and metabolic dysfunction in DFUs. Transcription factor analysis was also conducted to identify potential upstream regulators of CDKN1A.
Results: Our study confirmed that CDKN1A played a pivotal role in inhibiting cell proliferation and promoting premature differentiation in DFUs, which contributed to impaired wound healing. FOS was identified as a key transcription factor that upregulates CDKN1A in non-healing DFUs. MR analysis identified CDKN1A as being associated with metabolic changes, including the α-ketobutyrate/pyruvate ratio, leading to the impaired healing process in non-healing DFUs.
Conclusion: These findings shed light on the molecular mechanisms underlying DFU healing, suggesting that targeting FOS and CDKN1A could offer novel therapeutic strategies for enhancing wound healing in diabetic patients.

Keywords: diabetic foot ulcers, mendelian randomization, single-cell RNA sequencing, gene expression, CDKN1A, FOS