{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n ARRDC4, a member of the α‐arrestin family, plays multifaceted roles in regulating cellular metabolism, receptor trafficking, innate immune responses, and extracellular vesicle biogenesis. Several studies have demonstrated that ARRDC4—similar to its paralog TXNIP—acts as a negative regulator of glucose uptake in multiple cell types including adipocytes, muscle cells, and pancreatic β‐cells, thereby linking nutrient sensing to insulin signaling and cellular energy homeostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": " In conditions of lactic acidosis, ARRDC4 is transcriptionally induced via the MondoA–Mlx pathway, contributing to the “anti‐Warburg” effect observed in tumor cells, whereas its suppression by small molecules can enhance insulin responsiveness."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " Beyond metabolic regulation, ARRDC4 functions as an adaptor that links substrates to ubiquitin ligases, thereby facilitating receptor ubiquitination and lysosomal trafficking; this role is also implicated in PPXY‐dependent viral egress."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " In the context of innate immunity, ARRDC4 is upregulated upon enterovirus 71 infection, where it interacts with the viral sensor MDA5 and recruits the E3 ligase TRIM65 to enhance K63‐linked ubiquitination, ultimately activating downstream proinflammatory signaling and cytokine production."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Moreover, ARRDC4 has been identified as a direct target of METTL14‐mediated m6A modification in colorectal cancer, with increased ARRDC4 mRNA stability linked to suppression of metastatic signaling via an ARRDC4–ZEB1 axis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " Finally, ARRDC4 is essential for extracellular vesicle biogenesis, a process that is critical for proper sperm function."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " Sequence analyses further suggest that the genetic variability and haplotype structure of ARRDC4 may influence its regulatory functions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Parth Patwari, William A Chutkow, Kiersten Cummings, et al. 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