LZTFL1 (leucine zipper transcription factor like 1) is a multifunctional protein with roles in ciliary biology, metabolic regulation, immune function, and tumor suppression. Primary function: LZTFL1 regulates ciliary localization of the BBSome complex and controls SMO ciliary trafficking to modulate sonic hedgehog pathway signaling. Mechanism: The protein functions through multiple pathways—it regulates leptin receptor signaling in hypothalamic neurons by controlling Stat3 phosphorylation 1, modulates T cell activation through NFAT signaling and IL-5 production 2, and destabilizes AKT protein via ZNRF1-mediated ubiquitination in kidney cells 3. Disease relevance: LZTFL1 mutations cause Bardet-Biedl syndrome 17. Genetic variants in LZTFL1 are associated with COVID-19 susceptibility and severity 45, Long COVID development 6, and type 1 diabetes risk 7. Clinical significance: LZTFL1 functions as a tumor suppressor—frequent deletions occur in clear cell renal cell carcinoma, with downregulation correlating to poor prognosis 3. LZTFL1 deficiency causes obesity through leptin resistance 1, establishing links between ciliary dysfunction, metabolic homeostasis, and immune-mediated diseases.