Current insight into the molecular mechanisms of lymphangioleiomyomatosis

Abstract Lymphangioleiomyomatosis (LAM) is a rare, progressive lung disease that predominantly affects women, particularly during their reproductive years. It is characterized by the proliferation of abnormal smooth muscle-like cells that infiltrate the lungs, leading to cystic destruction of lung tissue and a decline in respiratory function. The pathogenic defect in LAM occurs due to mutations in the tuberous sclerosis complex genes, resulting in failure to suppress the mTOR pathway activation, which drives abnormal cell proliferation and lymphangiogenesis. Although mTOR inhibitors, such as sirolimus, have improved clinical management by slowing disease progression, they are not curative and do not reverse existing lung damage. Recent research has expanded our understanding of LAM pathogenesis by revealing substantial genetic and cellular heterogeneity within LAM lesions. Beyond mTOR dysregulation, pathways involving estrogen signaling, metabolic adaptation, and immune evasion contribute to disease development. These insights open new avenues for treatment. A better understanding of these pathways will pave the way for more durable and individualized treatments for LAM.