{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nUSP8 is emerging as a critical deubiquitinating enzyme whose dysregulation—often through gain‐of‐function mutations—plays a central role in endocrine disorders. In corticotroph adenomas that cause Cushing’s disease, mutations clustered in the 14–3–3 binding motif enhance USP8’s catalytic activity to deubiquitinate targets such as the epidermal growth factor receptor (EGFR), thereby impeding its lysosomal degradation and amplifying downstream pro‐hormone (ACTH) production. These genetic alterations are common in both adult and pediatric patients, underscoring USP8’s pathogenic significance in endocrine tumorigenesis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "8"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role in endocrine tumors, USP8 regulates the trafficking and signaling of multiple cell surface receptors. By removing ubiquitin modifications, USP8 stabilizes crucial receptors—including EGFR, Smoothened in Hedgehog signaling, the chemokine receptor CXCR4, PAR2, the epithelial Na⁺ channel (ENaC), the β‐secretase BACE1, and the Met receptor among others—thereby influencing their endocytic sorting, recycling, and lysosomal degradation. Such regulation not only modulates downstream mitogen‐activated protein kinase (MAPK) signals and other pathways but also affects cytokine receptor abundance and the overall cellular responsiveness to growth factors."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "18"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nUSP8 additionally plays an essential role in mitochondrial quality control. In the context of mitophagy, USP8 selectively removes non‐canonical K6-linked ubiquitin chains from parkin, the E3 ligase that tags damaged mitochondria, thereby fostering its recruitment to depolarized mitochondria and promoting efficient elimination of dysfunctional organelles. This function extends to β-cell biology, where USP8 forms part of a multiprotein complex that safeguards mitochondrial integrity under metabolic stress."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "19", "end_ref": "21"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nStructural and mechanistic studies have illuminated the multifaceted nature of USP8 function. Its architecture—comprising coiled‐coil, rhodanese, MIT, and catalytic domains—underpins substrate recognition and endosomal localization through interactions with ESCRT components and CHMP proteins. USP8 also deubiquitinates key regulators of autophagy such as SQSTM1/p62 and controls the ubiquitination status of endosomal proteins like Eps15, thereby influencing endosome morphology and apoptotic pathways (for example, via stabilization of FLIP). These regulatory events impact ciliogenesis, where USP8 modulates the degradation of components that would otherwise trigger cilia disassembly, and further contribute to the processing of neurodegenerative substrates including α‐synuclein and TDP-43."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "22", "end_ref": "34"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the nervous system, USP8 contributes to synaptic development and neuronal signaling. By deubiquitinating the long form of the leptin receptor (LepRb) and synaptic scaffolding proteins such as SHANK3, USP8 enhances receptor surface availability, thereby promoting leptin-mediated synaptogenesis and dendritic spine formation. This modulation of synaptic protein turnover is likely to be relevant to neurodevelopmental as well as neurodegenerative disorders."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "35", "end_ref": "37"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nUSP8’s oncogenic potential is further highlighted in studies of solid tumors. In non-small cell lung and cervical cancers, elevated USP8 activity contributes to tumor growth and resistance to therapy by stabilizing receptor tyrosine kinases and other oncogenic substrates. In these settings, targeting USP8 emerges as a promising strategy to overcome drug resistance and impede tumor progression."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "38", "end_ref": "40"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Martin Reincke, Silviu Sbiera, Akira Hayakawa, et al. 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