MCOLN1 encodes a nonselective cationic channel localized to late endosomes and lysosomes that mediates release of divalent cations—including calcium, zinc, and iron—from lysosomes to the cytosol. This channel plays a central role in regulating autophagy and lysosomal biogenesis by controlling lysosomal ionic homeostasis and membrane dynamics. MCOLN1 is transcriptionally upregulated during autophagy induction; for example, trehalose promotes autophagy in models of neurodegeneration partly through TFEB-dependent upregulation of MCOLN1 1. MCOLN1 also governs calcium-dependent lysosomal exocytosis and intramitochondrial quality control through a reactive oxygen species-activated calcium signaling pathway 2. In cancer, MCOLN1 has emerged as a druggable target. Activation of MCOLN1 by agonists such as ML-SA5 or MK6-83 arrests autophagy in pancreatic cancer, breast cancer, gastric cancer, malignant melanoma, and glioma by disrupting autophagosome-lysosome fusion through zinc-mediated inhibition of SNARE proteins; this autophagic arrest triggers apoptosis and suppresses tumor growth in xenograft models 3. Conversely, TRPML1-mediated lysosomal exocytosis promotes ferroptosis resistance in AKT-hyperactivated cancer cells, and TRPML1 blockade or inactivation enhances ferroptosis sensitivity and radiotherapy response 4. MCOLN1 dysfunction is also implicated in neuropsychiatric disease; astrocyte-specific loss of TRPML1 impairs lysosomal ATP release and induces depressive-like behaviors, whereas TRPML1 overexpression reverses this phenotype 5. At the population level, gnomAD v4.1 classifies MCOLN1 as loss-of-function tolerant (LOEUF=0.90), yet ClinVar documents 131 pathogenic or likely pathogenic variants, indicating clinical relevance in disease contexts distinct from population-level constraint. Mutations in MCOLN1 cause Lisch epithelial corneal dystrophy, an autosomal dominant condition characterized by corneal opacity 6.