{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n HACE1 (HECT domain and Ankyrin repeat Containing E3 ubiquitin‐protein ligase 1) is a multifunctional enzyme that plays critical roles in diverse cellular processes by catalyzing the ubiquitination of specific substrates. Numerous studies have demonstrated that HACE1 acts as a potent tumor suppressor by targeting activated Rac1 for proteasomal degradation, thereby limiting Rac1‐dependent reactive oxygen species (ROS) generation, cell migration, and proliferation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "12"}]}, {"type": "t", "text": " In several cancer types, including osteosarcoma, hepatocellular carcinoma, and B‐cell lymphomas, HACE1 expression is downregulated—often via epigenetic mechanisms—and its loss is associated with enhanced metastatic potential, defective autophagic turnover, and increased oxidative stress."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}, {"type": "fg_f", "ref": "10"}, {"type": "fg_fs", "start_ref": "13", "end_ref": "15"}]}, {"type": "t", "text": " Beyond its tumor‐suppressive functions, HACE1 modulates immune signaling by negatively regulating virus‐triggered type I interferon responses through disruption of key adaptor complexes"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": ", and it plays an important role in neuroinflammation where its regulation of Rac1 activity confers neuronal protection in Parkinson’s disease models."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": " In addition, a circular RNA derived from the HACE1 locus (circ‐HACE1) has been implicated in mediating cellular injury in models of chronic obstructive pulmonary disease by acting as a sponge for microRNAs"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": ", while HACE1 also ubiquitinates cyclin C, promoting mitochondrial fission and influencing chemosensitivity in gastric cancer."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": " Developmentally, loss‐of‐function mutations in HACE1 underlie a neurodevelopmental disorder characterized by learning disabilities, spasticity, and abnormal gait, indicating its role in regulating Rac1 and Rab GTPases during neural morphogenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}, {"type": "fg_f", "ref": "20"}]}, {"type": "t", "text": " Its importance is further underscored in cardiac biology, where HACE1 helps maintain proteostasis and supports normal heart development and function by modulating autophagic turnover of key contractile regulators"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "21"}]}, {"type": "t", "text": ", and its deficiency can lead to structural and functional heart defects. Finally, emerging evidence suggests that alterations in HACE1 may influence synaptic integrity in the brain"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "23"}]}, {"type": "t", "text": "as well as contribute to neurodegenerative risk, for instance, in Alzheimer’s disease."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "24"}]}, {"type": "t", "text": " Together, these findings position HACE1 as a central regulator of ubiquitin‐dependent proteolysis, redox homeostasis, autophagy, and signaling pathways that govern tumor suppression, neurodevelopment, cardiac function, and immune responses"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "–."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "24"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Moreover, integrative bioinformatics analyses have identified HACE1 as a key hub gene in networks underlying disorders such as slow‐transit constipation, further highlighting its systemic relevance"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "25"}]}, {"type": "t", "text": ", and pharmacological studies suggest that modulators like propofol influence HACE1 expression to exert antitumor effects."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "26"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Michael S Anglesio, Valentina Evdokimova, Nataliya Melnyk, et al. 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