LGSN (lengsin, lens protein with glutamine synthetase domain) is a cytoplasmic protein implicated in cell fate determination and stemness maintenance across multiple cancer types. While originally characterized as a lens protein component potentially involved in intermediate filament reorganization during terminal differentiation, recent evidence reveals its critical role in cancer stem cell biology. In gastric cancer stem cells, LGSN is significantly overexpressed and maintains stemness through interaction with vimentin, promoting epithelial-to-mesenchymal transition 1. Similarly, in breast cancer, the transcription factor SIX2 directly activates LGSN expression to promote cancer stemness and metastatic potential, with both SIX2 and LGSN elevation correlating with poor prognosis 2. LGSN knockdown in gastric cancer triggers gasdermin-D-mediated pyroptosis via vimentin degradation and NLRP3 signaling, restoring chemosensitivity when combined with 5-fluorouracil and oxaliplatin 1. Genetically, the LGSN rs12663017 polymorphism independently predicts cutaneous melanoma-specific survival, with the A allele associated with increased mRNA expression 3. These findings establish LGSN as a key regulator of cancer stemness and a promising therapeutic target, though its precise biochemical function remains incompletely characterized.