Summary: This review discusses the critical transition from the inflammatory to the proliferative phase during wound healing, which is essential for effective healing and scar reduction. The inflammatory phase is crucial for initial immune response and tissue clearance, while the proliferative phase involves tissue repair and regeneration. Understanding the mechanisms regulating this transition is vital for developing more effective therapies for chronic wounds and excessive scarring. Key factors influencing the transition include macrophage polarization, which shifts from a pro-inflammatory M1 phenotype to a reparative M2 phenotype. Macrophages play a central role in clearing neutrophils and promoting tissue repair. Stromal cells, such as fibroblasts, also contribute by regulating inflammation and supporting tissue regeneration. Bioactive lipid mediators, including eicosanoids, endocannabinoids, and sphingolipids, regulate inflammation and proliferation. For example, PGE2 promotes keratinocyte proliferation and migration, facilitating the transition to the proliferative phase. Endocannabinoids like anandamide and 2-AG have anti-inflammatory effects and support wound healing. Redox signals, particularly reactive oxygen species (ROS), are crucial for wound healing. Low levels of ROS support cell proliferation and migration, while excessive ROS cause oxidative stress and impair healing. Negative regulation of TLR signaling is also important for resolving inflammation and transitioning to proliferation. Transcription factors, such as NF-κB, AP-1, E2F, and Smad proteins, regulate gene expression during wound healing. Their dysregulation can lead to impaired healing. Glucocorticoids, androgens, and estrogens also influence wound healing through their effects on inflammation and cell proliferation. The balance between estrogen and androgen signaling may impact wound healing outcomes. Peroxisome proliferator-activated receptors (PPARs) and homeobox genes also play roles in regulating wound healing processes. Epigenetic mechanisms, including DNA methylation and histone modification, influence gene expression and the transition from inflammation to proliferation. Overall, understanding the complex interplay of these factors is essential for developing targeted therapies to improve wound healing and reduce scarring.Summary: This review discusses the critical transition from the inflammatory to the proliferative phase during wound healing, which is essential for effective healing and scar reduction. The inflammatory phase is crucial for initial immune response and tissue clearance, while the proliferative phase involves tissue repair and regeneration. Understanding the mechanisms regulating this transition is vital for developing more effective therapies for chronic wounds and excessive scarring. Key factors influencing the transition include macrophage polarization, which shifts from a pro-inflammatory M1 phenotype to a reparative M2 phenotype. Macrophages play a central role in clearing neutrophils and promoting tissue repair. Stromal cells, such as fibroblasts, also contribute by regulating inflammation and supporting tissue regeneration. Bioactive lipid mediators, including eicosanoids, endocannabinoids, and sphingolipids, regulate inflammation and proliferation. For example, PGE2 promotes keratinocyte proliferation and migration, facilitating the transition to the proliferative phase. Endocannabinoids like anandamide and 2-AG have anti-inflammatory effects and support wound healing. Redox signals, particularly reactive oxygen species (ROS), are crucial for wound healing. Low levels of ROS support cell proliferation and migration, while excessive ROS cause oxidative stress and impair healing. Negative regulation of TLR signaling is also important for resolving inflammation and transitioning to proliferation. Transcription factors, such as NF-κB, AP-1, E2F, and Smad proteins, regulate gene expression during wound healing. Their dysregulation can lead to impaired healing. Glucocorticoids, androgens, and estrogens also influence wound healing through their effects on inflammation and cell proliferation. The balance between estrogen and androgen signaling may impact wound healing outcomes. Peroxisome proliferator-activated receptors (PPARs) and homeobox genes also play roles in regulating wound healing processes. Epigenetic mechanisms, including DNA methylation and histone modification, influence gene expression and the transition from inflammation to proliferation. Overall, understanding the complex interplay of these factors is essential for developing targeted therapies to improve wound healing and reduce scarring.