{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPAQR3 is a Golgi‐resident transmembrane protein that functions as a spatial regulator of key signaling pathways. It sequesters Raf kinases—including Raf‐1 and oncogenic B‐Raf—to the Golgi apparatus, thereby limiting their association with Ras and tempering downstream MEK/ERK activation (see, for example."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Structural analyses have revealed that specialized domains in PAQR3 are critical for its Golgi targeting and protein–protein interactions, with studies even implicating adiponectin as an agonist for PAQR3 (e.g.."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " In addition, PAQR3 modulates G protein–coupled receptor (GPCR) signaling by binding and redistributing Gβγ subunits to the Golgi—altering receptor desensitization and downstream effector engagement"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "—and it promotes the degradation of Nrf2 by tethering it together with Keap1, thus influencing the cellular antioxidant response."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the realm of cancer biology, PAQR3 predominantly acts as a tumor suppressor. Multiple studies have documented its downregulation or epigenetic silencing in diverse cancers—including colorectal"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": ", gastric"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "and"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": ", osteosarcoma"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": ", laryngeal"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": ", breast"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": "and"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": ", esophageal"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": "and"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": ", prostate"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": ", glioma"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": ", papillary thyroid"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": "and acute lymphoblastic leukemia"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "20"}]}, {"type": "t", "text": "—and its loss correlates with enhanced cell proliferation, migration, epithelial‐mesenchymal transition (EMT) and metastasis. Mechanistic investigations indicate that PAQR3 facilitates the degradation of oncogenic drivers such as Twist1"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": ", and its levels are further controlled by posttranslational modifiers like DDB2"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "21"}]}, {"type": "t", "text": "as well as by alterations in histone methylation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "22"}]}, {"type": "t", "text": " In several cancers, aberrant promoter hypermethylation and microRNA‐mediated suppression of PAQR3 have been implicated"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}, {"type": "fg_f", "ref": "23"}]}, {"type": "t", "text": ", and emerging studies—including comprehensive pan‐cancer analyses—underscore its potential as a prognostic marker."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "24"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nPAQR3 also plays pivotal roles in metabolic regulation and autophagy. It anchors the Scap/SREBP complex to the Golgi apparatus, thereby promoting SREBP processing and cholesterol biosynthesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "26"}]}, {"type": "t", "text": " In hepatic cells, PAQR3 facilitates the ubiquitination and degradation of PPARα via the E3 ubiquitin ligase HUWE1, modulating fatty acid oxidation and lipid homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "27"}]}, {"type": "t", "text": " Moreover, by regulating FoxO1 phosphorylation through the NF‐κB pathway, PAQR3 influences insulin signaling and glucose–lipid metabolism."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "28"}]}, {"type": "t", "text": " PAQR3 further modulates cellular anabolic responses by negatively impacting amino acid–induced mTOR complex 1 activity, thereby affecting autophagy."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "29"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Lin Feng, Xiaoduo Xie, Qiurong Ding, et al. 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