Farouk Baboni,1 Kingsley Miyanda Tembo,2,3 Xi Zhou,1 Qingwen Li,1 Chen Dai,1 Yuanyuan Zhao,1 Samiratou Batoko,4 Peixiang Lan,1 Zhishui Chen1 

1Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, People’s Republic of China; 2The Center for Biomedical Research, Department of Respiratory and Critical Care Medicine, Key Laboratory of Pulmonary Diseases of Health Ministry, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, People’s Republic of China; 3Healit Research International and TRACE Research and Innovation, Untold Global Healit Zambia, Lusaka, Zambia; 4School of Economics, Zhongnan University of Economics and Law, Wuhan, 430073, People’s Republic of China

Correspondence: Zhishui Chen, Email zschen@tjh.tjmu.edu.cn Peixiang Lan, Email lansong9783@126.com

Abstract: SET domain-containing lysine methyltransferase 7 (SETD7) is a critical enzyme that methylates lysine residues on both histone and non-histone proteins, thereby regulating gene expression and protein function. This methyltransferase plays a versatile and context-dependent role in a wide range of physiological processes, including cell differentiation, reactive oxygen species (ROS) signaling, oxidative stress regulation, and energy metabolism. SETD7’s dual nature is highlighted by its paradoxical involvement in various diseases such as cancer, asthma, and Alzheimer’s disease, where it can either promote or suppress pathological progression depending on the cellular environment and molecular context. The multifaceted functions of SETD7 underscore its importance in maintaining cellular homeostasis but also present significant challenges for therapeutic targeting. Although selective inhibitors like Cyproheptadine and (R)-PFI-2 have recently been identified, the development of highly specific and effective therapies remains complex due to SETD7’s broad regulatory roles and the potential for unintended effects on normal physiological processes. These challenges necessitate nuanced therapeutic strategies, including the exploration of combination treatments and context-specific modulation to maximize efficacy while minimizing adverse outcomes. This review comprehensively explores SETD7’s structure, subcellular localization, and diverse biological functions in both normal and disease states. By elucidating the dual and context-dependent nature of SETD7, it aims to provide a framework for future research focused on unraveling its molecular mechanisms and advancing targeted therapeutic approaches that leverage its unique regulatory capabilities.

Keywords: lysine methyltransferase, gene expression, cancer, oxidative stress, inflammation, transcription factors