Fibroblasts, stromal cells widely distributed in the body, have recently been recognized for their versatility and dynamic role in maintaining tissue homeostasis and integrity. Their ability to switch phenotypes in response to tissue injury and their multifaceted functions, including angiogenesis and inflammation, make them central to wound healing. However, dysregulation of fibroblasts underlies many chronic conditions, including diabetes mellitus (DM), which is a major cause of morbidity and mortality. Diabetic foot ulcers (DFUs) are severe complications of DM, affecting 40 to 60 million people, and can lead to infections, gangrene, amputation, and death. Current treatments for DFUs are limited, and innovative therapies are urgently needed. This review aims to provide an understanding of fibroblast function and the mechanisms involved in DFU pathophysiology, highlighting potential targets for novel therapeutics. Fibroblasts are mesenchymal stem cell-like cells found in the stroma of most organ tissues. They were previously considered "passive" cells maintaining the extracellular matrix (ECM) but are now recognized for their dynamic and central role in tissue homeostasis and integrity. Recent studies have revealed the high plasticity and heterogeneity of fibroblasts, with different lineages and phenotypes. Single-cell analysis has enabled the identification of distinct fibroblast subtypes, such as myofibroblasts and adipocytes, and their involvement in various physiological and pathological processes. Fibroblasts can undergo trans-differentiation and dedifferentiation, responding to diverse stimuli and environmental cues. The TGF-β signaling pathway plays a central role in driving the phenotypic switch of fibroblasts into myofibroblasts, which are crucial for wound closure and tissue repair. Chronic inflammation, a key feature of DFUs, impairs wound healing by overstimulating the immune system and preventing the trans-differentiation of fibroblasts into myofibroblasts. Epigenetic modifications, such as DNA methylation, also regulate fibroblast plasticity and function. Fibroblasts play a multifaceted role in wound healing, modulating immune responses and contributing to tissue regeneration. However, dysregulation of fibroblasts in DFUs leads to impaired wound healing, characterized by excessive scar formation or chronic ulceration. Understanding the molecular and cellular mechanisms underlying fibroblast dysregulation in DFUs is crucial for developing effective therapeutic strategies.Fibroblasts, stromal cells widely distributed in the body, have recently been recognized for their versatility and dynamic role in maintaining tissue homeostasis and integrity. Their ability to switch phenotypes in response to tissue injury and their multifaceted functions, including angiogenesis and inflammation, make them central to wound healing. However, dysregulation of fibroblasts underlies many chronic conditions, including diabetes mellitus (DM), which is a major cause of morbidity and mortality. Diabetic foot ulcers (DFUs) are severe complications of DM, affecting 40 to 60 million people, and can lead to infections, gangrene, amputation, and death. Current treatments for DFUs are limited, and innovative therapies are urgently needed. This review aims to provide an understanding of fibroblast function and the mechanisms involved in DFU pathophysiology, highlighting potential targets for novel therapeutics. Fibroblasts are mesenchymal stem cell-like cells found in the stroma of most organ tissues. They were previously considered "passive" cells maintaining the extracellular matrix (ECM) but are now recognized for their dynamic and central role in tissue homeostasis and integrity. Recent studies have revealed the high plasticity and heterogeneity of fibroblasts, with different lineages and phenotypes. Single-cell analysis has enabled the identification of distinct fibroblast subtypes, such as myofibroblasts and adipocytes, and their involvement in various physiological and pathological processes. Fibroblasts can undergo trans-differentiation and dedifferentiation, responding to diverse stimuli and environmental cues. The TGF-β signaling pathway plays a central role in driving the phenotypic switch of fibroblasts into myofibroblasts, which are crucial for wound closure and tissue repair. Chronic inflammation, a key feature of DFUs, impairs wound healing by overstimulating the immune system and preventing the trans-differentiation of fibroblasts into myofibroblasts. Epigenetic modifications, such as DNA methylation, also regulate fibroblast plasticity and function. Fibroblasts play a multifaceted role in wound healing, modulating immune responses and contributing to tissue regeneration. However, dysregulation of fibroblasts in DFUs leads to impaired wound healing, characterized by excessive scar formation or chronic ulceration. Understanding the molecular and cellular mechanisms underlying fibroblast dysregulation in DFUs is crucial for developing effective therapeutic strategies.