Podocytopathies, characterized by podocyte injury and proteinuria, are leading causes of end-stage renal disease (ESRD). The coordinated cytoskeleton is crucial for maintaining the structure and function of podocytes. Cytoskeleton rearrangement in podocytopathies involves significant alterations in slit diaphragm (SD) proteins, such as nephrin, calcium influx via transient receptor potential channel 6 (TRPC6), and regulation of the Rho family, leading to disorganized cytoskeletal architecture. This review discusses the molecular mechanisms of cytoskeleton rearrangement in podocytopathies, including focal segmental glomerulosclerosis (FSGS), minimal change disease (MCD), membranous nephropathy (MN), and diabetic kidney disease (DKD). It also summarizes the effects of current drugs on regulating the podocyte cytoskeleton, highlighting potential therapeutic approaches. Key proteins and signaling pathways involved in cytoskeleton rearrangement, such as nephrin, TRPC6, RhoA, Rac1, and dynamin, are discussed, along with their roles in podocyte injury and disease progression. The review emphasizes the importance of targeting the podocyte cytoskeleton for therapeutic interventions in podocytopathies.Podocytopathies, characterized by podocyte injury and proteinuria, are leading causes of end-stage renal disease (ESRD). The coordinated cytoskeleton is crucial for maintaining the structure and function of podocytes. Cytoskeleton rearrangement in podocytopathies involves significant alterations in slit diaphragm (SD) proteins, such as nephrin, calcium influx via transient receptor potential channel 6 (TRPC6), and regulation of the Rho family, leading to disorganized cytoskeletal architecture. This review discusses the molecular mechanisms of cytoskeleton rearrangement in podocytopathies, including focal segmental glomerulosclerosis (FSGS), minimal change disease (MCD), membranous nephropathy (MN), and diabetic kidney disease (DKD). It also summarizes the effects of current drugs on regulating the podocyte cytoskeleton, highlighting potential therapeutic approaches. Key proteins and signaling pathways involved in cytoskeleton rearrangement, such as nephrin, TRPC6, RhoA, Rac1, and dynamin, are discussed, along with their roles in podocyte injury and disease progression. The review emphasizes the importance of targeting the podocyte cytoskeleton for therapeutic interventions in podocytopathies.