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TNF-\u03b1 signaling dysregulation is linked to chronic inflammatory diseases, multiorgan dysfunction, and tissue destruction through activation of TNF receptor 1 (TNFR1)-mediated inflammatory, apoptotic, and necroptotic pathways, while TNF receptor 2 (TNFR2) stimulation promotes immune regulation and tissue repair. Understanding these divergent signaling mechanisms is crucial for augmenting therapeutic interventions. The present review summarizes the molecular structure of TNF-\u03b1, compares TNFR1 and TNFR2 signaling cascades, and describes the cytokine\u2019s role in diseases such as rheumatoid arthritis, inflammatory bowel disease, ankylosing spondylitis, multiple sclerosis, diabetes mellitus, atherosclerosis, heart failure, systemic lupus erythematosus, and cancer. We further evaluate clinically approved TNF inhibitors and emergent investigational agents, prominent advances in receptor-selective modulation, and small-molecule TNF suppression. 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