TNFSF12 (TNF superfamily member 12) is a cytokine ligand that binds to the FN14 receptor to regulate multiple physiological and pathological processes. Mechanistically, TNFSF12/FN14 signaling activates NF-κB pathways and modulates endothelial cell function, promoting angiogenesis and endothelial cell proliferation 1. The ligand also induces inflammatory cytokine secretion and can weakly induce apoptosis in select cell types. Disease relevance spans multiple conditions. In retinal disease, TNFSF12 upregulation contributes to pathological angiogenesis in diabetic retinopathy through AGGF1-dependent mechanisms 1. Elevated TNFSF12 associates with increased risk of intracranial aneurysms (OR: 1.24) and aneurysmal subarachnoid hemorrhage, with enrichment in microglial and astrocyte populations 2. In amyotrophic lateral sclerosis, TNFSF12 represents a druggable target (OR: 1.36) for neuroinflammatory mechanisms 3. TNFSF12 is upregulated in endometriosis as a programmed cell death-related biomarker 4 and implicated in psoriasis where it synergizes with TNF and IL-17 in keratinocytes 5. Clinical significance includes potential therapeutic targeting: anti-TWEAK antibodies showed efficacy comparable to IL-17 or TNF inhibitors in psoriasis models 5. TWEAK/Fn14 blockade may attenuate cholangiocarcinoma niche development 6 and protect against pulmonary fibrosis by inhibiting fibroblast activation 7.