TNFRSF21 (TNF receptor superfamily member 21) is a death receptor that regulates cell survival and immune responses through multiple pathways. The protein promotes apoptosis via NF-kappa-B activation and mitochondrial cytochrome c release, while also serving as a regulator of pyroptosis by recruiting CASP8 in response to oxidative stress 1. TNFRSF21 negatively regulates T-cell responses, inhibiting cytokine production (IL4, IL5, IL10, IL13, IFNG) and antibody production, while also suppressing oligodendrocyte survival and myelination. In disease contexts, TNFRSF21 shows significant pathological relevance. Variants in TNFRSF21 cause non-syndromic high myopia in Chinese populations, with the P146A variant significantly increasing retinal pigment epithelial cell apoptosis 2. The gene is upregulated in lung adenocarcinoma and contributes to cisplatin resistance by modulating cancer stem cell characteristics through ROS regulation 3. In inflammatory diseases, TNFRSF21+ fibroblasts are enriched in periodontitis and express high levels of chemokines 45. Additionally, epithelial cells can induce necroptosis of FOLR2+ macrophages via the APP-TNFRSF21 axis during early gastric cancer progression 6. TNFRSF21 represents a potential biomarker for psoriasis and atherosclerosis 7, highlighting its clinical significance across multiple disease contexts.