{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTMEM100 acts as a critical tumor‐suppressor factor in several cancers. In lung adenocarcinoma, hepatocellular carcinoma, gastric cancer, and non–small cell lung cancer, TMEM100 expression is markedly downregulated, and its experimental overexpression leads to reduced cell proliferation, migration, invasion, and colony formation while enhancing apoptosis and autophagy. These tumor‐suppressive effects are mediated through multiple signaling cascades, including TGF‑β/ALK1, PI3K/AKT, Wnt/β‑catenin, and MAPK pathways, and may involve epigenetic regulation mechanisms that repress TMEM100 transcription."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its role in tumor suppression, TMEM100 is intricately regulated by key developmental and stress‐response signals. Its transcriptional control involves bone morphogenetic protein (BMP)/ALK1/TGF‑β signaling, and modulatory effects mediated by ER stress and calcium signaling—mechanisms that not only underlie its participation in arterial differentiation and angiogenesis but also influence inflammatory responses. For example, TMEM100 overexpression can reduce the secretion of inflammatory cytokines through modulation of MAPK (ERK and JNK) phosphorylation in fibrotic liver cells."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nTMEM100 also plays versatile roles in the nervous system and sensory perception. Initially identified as a marker for enteric neurons, it is expressed in the gastrointestinal tract as well as in other neural structures such as the dorsal root ganglia and dental pulp cells. In these sensory neurons, TMEM100 forms functional complexes with TRPA1 and TRPV1 channels, where it modulates pain transmission and itch. Notably, inflammation‐induced upregulation of TMEM100 in silent nociceptors is both required and sufficient to “un‐silence” these neurons, thereby triggering secondary mechanical hypersensitivity and contributing to chronic itch."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Elisa Frullanti, Francesca Colombo, Felicia S Falvella, et al. 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