Pathogenesis of lymphangioleiomyomatosis: from TSC mutations, metabolic reprogramming, to microenvironmental interactions

Abstract

Lymphangioleiomyomatosis is a rare disease primarily affecting women of reproductive age, characterized by progressive pulmonary cystic destruction and driven by TSC gene loss-induced constitutive mTORC1 activation. Current understanding of the disease extends beyond this primary genetic defect to encompass a multidimensional network involving metabolic reprogramming, tumor microenvironment interactions, and hormonal dependence. This review comprehensively examines the genetic basis and core signaling pathways of LAM, elucidating how dysregulated mTOR signaling orchestrates cellular metabolism and autophagy. We integrate recent advances regarding the origin, migration, and pulmonary colonization of LAM cells. The discussion encompasses the critical roles of the immune microenvironment and lymphangiogenesis in pulmonary tissue remodeling, alongside the regulation of cellular behavior by estrogen. By synthesizing these mechanistic insights, we outline current therapeutic strategies and future directions to provide a strong rationale for developing precision medicine in LAM.