VSTM2L is a mitochondria-localized, transmembrane protein with multifaceted roles in cancer progression and neurological disease. Primary function: VSTM2L regulates ferroptosis resistance and cell survival through protein-protein interactions. Mechanism: VSTM2L binds to voltage-dependent anion channel 1 (VDAC1) and hexokinase 2 (HK2), preventing VDAC1 oligomerization and maintaining mitochondrial homeostasis 1. In ovarian cancer, VSTM2L promotes anoikis resistance via epithelial-mesenchymal transition (EMT) signaling through TGF-β and NF-κB pathways 2. VSTM2L also modulates IL-4 signaling, affecting immune cell infiltration and tumor microenvironment composition 3. Disease relevance: VSTM2L expression shows cancer-type-specific prognostic significance: upregulation associates with poor outcomes in stomach adenocarcinoma and favorable outcomes in kidney renal papillary cell carcinoma 3. In cholangiocarcinoma, VSTM2L silencing reduces cell viability and promotes favorable prognosis; soluble VSTM2L functions as a blood-based biomarker 4. VSTM2L variants (rs6021854) are associated with restless legs syndrome in migraineurs, with functional studies showing involvement in dopaminergic system development 5. VSTM2L downregulation impairs antioxidant defense in intermittent hypoxia models 6. Clinical significance: VSTM2L represents a therapeutic target for ferroptosis-inducing cancer treatment and a prognostic biomarker across multiple malignancies.