FLII (Flightless I actin remodeling protein) is a multifunctional actin-binding protein with critical roles in cardiac and cellular homeostasis. Structurally, FLII contains a gelsolin-like actin-binding domain and leucine-rich repeat protein-interaction domains 1, enabling it to regulate actin polymerization and filament organization. Primary cardiac function: FLII associates with tropomodulin-1 to regulate sarcomeric thin filament length 2. The R1243H missense variant impairs this interaction, causing actin thin filament shortening and predisposing to dilated cardiomyopathy 2. Molecular mechanisms: Beyond muscle, FLII acts as a transcriptional coactivator that is sequestered by DGCR8 in naive pluripotent stem cells 3. During differentiation, phosphorylation releases FLII to bind JUN and activate cell migration genes 3. FLII also inhibits the NLRP1 inflammasome in hematopoietic cells, regulating the balance between neutrophil and erythroid differentiation 4. Additionally, FLII suppresses caspase-1 activity on endosomes by interacting with Rubicon in a calcium-dependent manner 5. Clinical significance: FLII elevation impairs wound healing 6, while FLII mutations cause cardiomyopathy, a major cause of heart failure 2. Understanding FLII regulation offers therapeutic targets for cardiac and inflammatory diseases.