Paroxysmal Nocturnal Hemoglobinuria: Unraveling Its Molecular Pathogenesis and Advancing Targeted Therapeutic Strategies

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired clonal hematologic disorder caused by somatic mutations in the PIGA gene of hematopoietic stem cells, leading to the absence of GPI-anchored proteins, including the complement regulators CD55 and CD59. This deficiency results in uncontrolled complement activation, causing intravascular and extravascular hemolysis, thrombosis, and bone marrow failure. His-torically associated with substantial morbidity, PNH management has been transformed by the advent of complement inhibitors. Eculizumab, the first approved C5 inhibitor, significantly reduced thrombotic risk and improved survival but did not eliminate anemia due to extravascular hemolysis. Newer agents now target proximal complement components, offering broader control and improved convenience. This review summa-rizes the pathophysiology of PNH, evaluates established and emerging complement inhibitors, and discusses ongoing therapeutic challenges and future directions.