FLOT2 (flotillin 2) is a lipid microdomain-associated scaffolding protein that functions as a key regulator of cellular vesicle dynamics and disease progression across multiple pathological contexts. Mechanistically, FLOT2 organizes caveolar membrane microdomains and modulates intraluminal vesicle biogenesis within multivesicular bodies 1. The protein stabilizes critical structural proteins through direct protein-protein interactions; notably, FLOT2 protects synaptopodin from K48-linked polyubiquitination-mediated proteasomal degradation in podocytes 2, and stabilizes EphA2 in gliomas 3. FLOT2 also facilitates autophagosome-lysosome fusion through interaction with LAMP2, a mechanism protective in sepsis-induced cardiac dysfunction 4. Clinically, FLOT2 overexpression is consistently associated with cancer progression and poor prognosis. Elevated FLOT2 correlates with invasion depth, metastasis, and advanced staging in colorectal cancer 56. FLOT2 silencing reduces colorectal cancer cell invasion and migration by suppressing epithelial-mesenchymal transition markers 6. In gliomas, FLOT2 upregulation promotes growth and invasion through EphA2 stabilization 3. HNRNPH1-mediated m6A-dependent stabilization of FLOT2 mRNA drives nasopharyngeal carcinoma progression 7. Conversely, in non-malignant disease, FLOT2 deficiency exacerbates pathology: podocyte-specific FLOT2 knockout worsens diabetic nephropathy 2, while FLOT2 ablation inhibits pathological osteoclastogenesis 8. These findings establish FLOT2 as a multi-functional therapeutic target with context-dependent roles in cancer promotion and disease-protective mechanisms.