TNFRSF1A encodes tumor necrosis factor receptor 1 (TNFR1), a cell surface receptor that binds TNF-alpha to initiate critical inflammatory and cell death pathways 1. Upon TNF-alpha binding, TNFR1 activates multiple signaling cascades including NF-κB and MAPK pathways, which regulate inflammation, immune responses, and cell survival 2. The receptor's expression is regulated by alternative splicing, producing different isoforms that can modulate cellular responses to TNF-alpha stimulation 3. TNFRSF1A translation is enhanced through m6A RNA modifications mediated by ATXN2, particularly in cancer contexts 2. Beyond inflammation, TNFR1 has emerged as having neuromodulatory functions, with TNF signaling through Tnfrsf1a-expressing neurons in the thalamus regulating sleep patterns after cardiac injury 4. Clinically, TNFRSF1A mutations cause TNF-receptor-associated periodic syndrome (TRAPS), an autoinflammatory disorder characterized by recurrent fever and inflammation due to impaired receptor cleavage 5. The gene shows polymorphisms associated with inflammatory myopathy conditions 6. Given its central role in inflammatory diseases, TNFR1 represents an important therapeutic target, with small molecule inhibitors like balinatunfib showing promise in clinical development 7.