Fibroblasts are stromal cells found in nearly every organ tissue, previously considered "passive" in maintaining the extracellular matrix (ECM). Recent studies reveal their dynamic role in tissue homeostasis, inflammation, and wound healing. Dysregulation of fibroblasts contributes to chronic diseases, including diabetes mellitus (DM), which is a major cause of morbidity and mortality. Diabetic foot ulcers (DFUs), a severe complication of DM, affect 40–60 million people, leading to infections, gangrene, and amputation. Current treatments for DFUs, such as debridement, wound dressings, and glucose control, are often ineffective, leading to high failure rates and significant healthcare costs. Innovative therapies are needed to address this public health issue. Fibroblasts are highly plastic and heterogeneous, capable of trans-differentiation into myofibroblasts and adipocytes. They play a central role in wound healing, with myofibroblasts driving contraction and ECM remodeling. However, in DFUs, fibroblasts are impaired by hyperglycemia, reactive oxygen species (ROS), and advanced glycation end products (AGEs), leading to chronic inflammation and delayed healing. Fibroblasts in DFUs exhibit premature senescence, reduced migratory and proliferative abilities, and impaired trans-differentiation into myofibroblasts. Fibroblasts are regulated by signaling pathways such as TGF-β, Notch, and Wnt, which influence their phenotypic switch and function. Dysregulation of these pathways in DFUs disrupts the balance between fibroblast proliferation and differentiation, impairing ECM synthesis and wound healing. Epigenetic modifications, including DNA methylation and histone modifications, also play a role in fibroblast plasticity and function. In DFUs, chronic inflammation and fibroblast dysfunction contribute to persistent tissue damage and impaired healing. The interplay between fibroblasts, immune cells, and the extracellular matrix is crucial for wound repair. Understanding fibroblast biology and their dysregulation in DFUs is essential for developing novel therapeutic strategies to improve outcomes for patients with this severe complication of diabetes.Fibroblasts are stromal cells found in nearly every organ tissue, previously considered "passive" in maintaining the extracellular matrix (ECM). Recent studies reveal their dynamic role in tissue homeostasis, inflammation, and wound healing. Dysregulation of fibroblasts contributes to chronic diseases, including diabetes mellitus (DM), which is a major cause of morbidity and mortality. Diabetic foot ulcers (DFUs), a severe complication of DM, affect 40–60 million people, leading to infections, gangrene, and amputation. Current treatments for DFUs, such as debridement, wound dressings, and glucose control, are often ineffective, leading to high failure rates and significant healthcare costs. Innovative therapies are needed to address this public health issue. Fibroblasts are highly plastic and heterogeneous, capable of trans-differentiation into myofibroblasts and adipocytes. They play a central role in wound healing, with myofibroblasts driving contraction and ECM remodeling. However, in DFUs, fibroblasts are impaired by hyperglycemia, reactive oxygen species (ROS), and advanced glycation end products (AGEs), leading to chronic inflammation and delayed healing. Fibroblasts in DFUs exhibit premature senescence, reduced migratory and proliferative abilities, and impaired trans-differentiation into myofibroblasts. Fibroblasts are regulated by signaling pathways such as TGF-β, Notch, and Wnt, which influence their phenotypic switch and function. Dysregulation of these pathways in DFUs disrupts the balance between fibroblast proliferation and differentiation, impairing ECM synthesis and wound healing. Epigenetic modifications, including DNA methylation and histone modifications, also play a role in fibroblast plasticity and function. In DFUs, chronic inflammation and fibroblast dysfunction contribute to persistent tissue damage and impaired healing. The interplay between fibroblasts, immune cells, and the extracellular matrix is crucial for wound repair. Understanding fibroblast biology and their dysregulation in DFUs is essential for developing novel therapeutic strategies to improve outcomes for patients with this severe complication of diabetes.