{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTMEM97—also known as the sigma‑2 receptor or MAC30—is an endoplasmic reticulum–resident transmembrane protein initially identified through its ligand‐binding properties. Early studies revealed that TMEM97 regulates key aspects of cellular sterol homeostasis by directly interacting with the sterol transporter NPC1, thereby modulating cholesterol trafficking. In Niemann–Pick type C disease models, reducing TMEM97 levels was shown to increase NPC1 abundance and improve cholesterol egress from lysosomes, highlighting its role as a regulator of intracellular lipid transport and a potential therapeutic target in lipid storage disorders."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its function in lipid regulation, TMEM97 has been implicated in the formation of multi‐protein complexes that facilitate receptor‐mediated uptake processes. Gene editing studies demonstrated that loss of TMEM97 disrupts binding of sigma‑2 receptor ligands and impairs the rapid internalization of LDL particles—a process shown to depend on a ternary complex formed with PGRMC1 and the LDL receptor. Such findings indicate a critical involvement of TMEM97 in endocytic pathways and in regulating cholesterol uptake, with potential implications for neurodegenerative diseases such as Alzheimer’s disease where aberrant lipid and amyloid‑β uptake contribute to pathology."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nTMEM97 also plays multifaceted roles in cancer biology. In several tumor types—including glioma, breast, and colorectal cancers—it is frequently upregulated and has been shown to promote cell proliferation, migration, and invasion. Mechanistically, TMEM97 enhances oncogenic signaling by modulating pathways such as Wnt/β‑catenin, via interacting with LRP6 and facilitating its CK1δ/ε‑dependent phosphorylation, and by engaging the Akt/mTOR axis. Transcriptional activation by factors like YY1 further upregulates TMEM97 expression, contributing to chemoresistance (e.g. to 5‑fluorouracil through effects on epithelial–mesenchymal transition and ABC transporter levels) and malignant progression. Moreover, TMEM97’s involvement in modulating store‑operated calcium entry and intracellular cholesterol uptake further supports its role in sustaining the altered metabolic demands of cancer cells."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond these roles, TMEM97 has emerged as a receptor for endogenous ligands. Recent biochemical and cellular studies have demonstrated that histatin‑1—a salivary peptide known for its wound healing and cell‐activating properties—is an endogenous ligand for TMEM97. Its binding mediates the uptake of histatin‑1 via clathrin‑mediated endocytosis and triggers downstream mitochondrial activation. Additionally, TMEM97 has been observed to associate functionally with other receptors such as TSPO, further emphasizing its capacity to integrate diverse signaling pathways that impact cellular metabolism, stress responses, and synaptic function."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "13", "end_ref": "15"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Assaf Alon, Hayden R Schmidt, Michael D Wood, et al. 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