Current insight into molecular mechanisms of Lymphangioleiomyomatosis

Abstract Lymphangioleiomyomatosis (LAM) is a rare, progressive lung disease that predominantly affects women, particularly during their reproductive years. It is characterised 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 (TSC) genes, resulting in failure to suppress the mechanistic target of rapamycin (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 signalling, 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 individualised treatments for LAM.