{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nOTUD1 acts as a pivotal deubiquitinase in oncogenic signaling by directly stabilizing key tumor‐suppressive and pro‐apoptotic proteins. For instance, OTUD1 deubiquitinates and stabilizes p53, thereby enhancing its transcriptional output and downstream cell cycle arrest and apoptosis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Moreover, OTUD1 removes ubiquitin modifications from SMAD7, facilitating proper turnover of TGF‑β receptors and repressing metastatic traits"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ", while non–proteolytic K63‑linked ubiquitination of YAP is reversed by OTUD1 to restrict its nuclear localization and growth‐promoting activity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " In addition, melatonin‐induced upregulation of OTUD1 leads to deubiquitination and stabilization of the pro‐apoptotic factor Bim, thus triggering apoptosis in cancer cells"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ", and OTUD1’s protection of peroxiredoxin 4 (PRDX4) from degradation contributes to enhanced immunoglobulin synthesis and proteasome inhibitor sensitivity in multiple myeloma."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Furthermore, an interaction between OTUD1 and the pleckstrin homology domain of Akt—mediated by an intrinsic N‑terminal peptide—disrupts Akt membrane recruitment and phosphorylation, thereby limiting Akt‑dependent tumor cell proliferation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn parallel, OTUD1 modulates innate immune responses and programmed cell death pathways through its precise deubiquitination activities. OTUD1 removes ubiquitin chains from IRF3 in two independent studies: one demonstrating that its deubiquitination of IRF3 attenuates the transcription of type I interferons, and another showing that loss‐of‐function mutations in OTUD1 promote IRF3 nuclear translocation and aberrant interferon production implicated in autoimmunity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " In addition, by deubiquitinating iron‐responsive element‑binding protein 2 (IREB2), OTUD1 facilitates transferrin receptor–mediated iron uptake, thereby promoting reactive oxygen species generation and ferroptotic cell death to bolster antitumor immunity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " OTUD1 also targets apoptosis‑inducing factor (AIF), modulating its ubiquitination status to influence both caspase‑independent (parthanatos) and caspase‑dependent apoptotic signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " Beyond these functions, OTUD1 suppresses canonical NF‑κB activation—contributing to the regulation of inflammatory and antiviral responses—and in sepsis it deubiquitinates TIPE2, thereby inhibiting TAK1‑mediated MAPK and NF‑κB signaling to protect against inflammatory lung injury."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nOTUD1 further exerts control over immune cell function and protein trafficking. In neutrophils, OTUD1 deubiquitinates SEC23B—specifically removing K63‑linked ubiquitin chains—to restrict coat protein complex II–mediated ER‐to‐Golgi trafficking and modulate the surface expression of integrin‑associated proteins, thereby limiting excessive cytokine secretion and cell migration."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": " Complementary studies establishing OTUD1‑specific monoclonal antibodies have revealed its predominantly cytosolic distribution, underscoring its involvement in multiple signaling circuits."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Shudong Piao, Han Zhong Pei, Bin Huang, et al. 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