{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n EDA2R (also known as XEDAR) is a member of the tumor necrosis factor receptor superfamily that mediates signals initiated by its ligand EDA‐A2. In several developmental and pathological contexts, EDA2R activation triggers intracellular signaling cascades that regulate cell fate. For example, in ectoderm‐derived tissues such as hair follicles, binding of EDA‐A2 to EDA2R activates both canonical and non‐canonical NF‐κB as well as MAP kinase pathways through adapter proteins including TRAF3 and TRAF6, ultimately inducing apoptosis via a caspase‐8 and FADD–dependent mechanism. This activity is critical for promoting a timely transition of the hair cycle (premature entry into the catagen phase) and has been implicated in the etiology of androgenetic alopecia and female pattern hair loss, as genetic association studies have identified risk variants within or near the EDA2R locus"}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "and."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition to its developmental role, EDA2R functions as a mediator of cell stress responses. p53 can transcriptionally induce EDA2R, and upon activation, the receptor contributes to tumor‐suppressive activities by inhibiting focal adhesion kinase and promoting apoptosis in colorectal cancer cells"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "and."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " In renal epithelial cells, high glucose conditions induce EDA2R expression, leading to elevated reactive oxygen species and podocyte apoptosis, thereby contributing to diabetic kidney injury."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Moreover, aberrant activation of the EDA‐A2/EDA2R pathway is observed in salivary gland epithelial cells from Sjögren’s syndrome patients, where it also elicits apoptosis"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": ", and in the context of colonic inflammation, EDA2R signaling suppresses stem cell properties and epithelial repair."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, genetic studies also suggest that variations in EDA2R or its associated pathway components may contribute to dental anomalies such as crowding"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "and modulate additional aspects of ectodermal organogenesis. Together with emerging evidence detailing its ability to engage both canonical and non‐canonical NF‐κB signaling"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": ", these findings underscore the multifunctional nature of EDA2R as a regulator of apoptosis, differentiation, and tissue homeostasis in both normal developmental and disease settings.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Dionigio Antonio Prodi, Nicola Pirastu, Giuseppe Maninchedda, et al. 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