Defensins are a class of small antimicrobial peptides that play a crucial role against pathogens. However, recent research has highlighted defensins exhibit the ability to influence cell cycle checkpoints, promoting or inhibiting specific phases such as G1 arrest or S/M transition. By regulating the cell cycle, defensins impact the proliferation of normal and cancerous cells, with implications for cancer development and progression. Dysregulation of defensin expression can disrupt the delicate balance of cell cycle regulation, leading to uncontrolled cell growth and an increased risk of tumor formation. Defensins contribute to the resolution of inflammation, stimulate angiogenesis, and enhance the migration and proliferation of cells involved in tissue repair. Furthermore, The ability of defensins to respond to microenvironmental changes further demonstrates the significance of these peptides in host defense mechanisms and immune function. By adjusting their expression, defensins continue to combat pathogens effectively and maintain homeostasis within the body. This review highlights the multifaceted role of defensins in regulating the cell cycle and their broader implications in cancer progression, tissue repair, and microenvironmental response.Copyright © 2024. Published by Elsevier Inc.