{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nUbiquitin‐specific protease 2 (USP2) is a multifunctional deubiquitinase whose various isoforms—most notably USP2a—play pivotal roles in regulating the stability of key oncogenic proteins, thereby promoting cell cycle progression and tumor cell survival. In several cancers, USP2a removes degradative polyubiquitin chains from targets such as fatty acid synthase (FAS) and cyclins. For example, USP2a interacts with FAS to stabilize its levels in prostate tumors and gliomas, and it specifically deubiquitinates cyclin D1 and cyclin A1 to prevent their proteasomal degradation, thereby sustaining proliferation and contributing to chemoresistance. USP2 also regulates the stability of other cell cycle regulators such as Aurora‐A and SKP2, modulating mitotic progression and affecting the maintenance of cancer stem cell populations and receptor recycling (e.g., ErbB2). These findings underscore the oncogenic potential of USP2 through its ability to maintain elevated levels of prosurvival and cell cycle–promoting proteins."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to promoting proliferation, USP2 exerts critical control over the p53 tumor suppressor pathway and apoptotic responses. USP2a directly interacts with the E3 ligases Mdm2 and MdmX, deubiquitinating them to sustain their protein levels and, consequently, facilitating p53 degradation. Such regulation not only blunts p53‐dependent apoptosis in several tumor types but also correlates with differential USP2 expression in certain cancers. Moreover, USP2 has been implicated in pathways governing caspase‐independent cell death by stabilizing factors such as the truncated form of apoptosis‐inducing factor (tAIF). These activities highlight a dual role for USP2 in modulating both survival and death signals within malignant cells."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "21"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nUSP2 also dynamically modulates multiple signaling pathways involved in immune responses, inflammation, and even circadian regulation. It acts as a positive regulator of TNF‐α–induced NF‐κB signaling by modifying ubiquitin chains on components of the TNFR1 complex, yet under certain circumstances its deubiquitinating activity toward TRAF proteins can attenuate NF‐κB activation. In T cell receptor signaling, USP2 associates with the adaptor MALT1, facilitating the interaction with TRAF6 and modulating downstream cytokine responses. In antiviral defense, USP2 (particularly the USP2b isoform) removes K63‐linked ubiquitins from TBK1 to inhibit its activation, while USP2-dependent deubiquitination of phosphorylated STAT1 bolsters type I interferon signaling. Furthermore, USP2a stabilizes the clock protein CRY1 by counteracting FBXL3‐mediated ubiquitination, and alternate splicing events regulated by several factors further diversify USP2 function. Together, these studies reveal USP2 as a central modulator of ubiquitin‐dependent signaling cascades that balance inflammatory, immune, and circadian outputs."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "22", "end_ref": "32"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in cell proliferation and immune signaling, aberrant USP2 expression is associated with tumor pathogenesis in several malignancies and with alterations in metabolic homeostasis. In lung cancer, upper tract urothelial carcinoma, and hepatocellular or renal carcinoma, dysregulated USP2 expression correlates with disease progression, metastasis, and poor clinical outcomes. Moreover, in the central nervous system, USP2 in the ventromedial hypothalamus has been shown to modulate circulating glucose levels via a reactive oxygen species–AMPK–sympathetic nerve axis. These diverse roles indicate that USP2 not only orchestrates key oncogenic and apoptotic pathways but also integrates metabolic and tumorigenic signals, making it a promising target for therapeutic intervention in a broad range of diseases."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "33", "end_ref": "36"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Edgard Graner, Dan Tang, Sabrina Rossi, et al. 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