{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Inositol polyphosphate 4‐phosphatase type II (INPP4B) is a lipid phosphatase that modulates phosphoinositide signaling by converting phosphatidylinositol‐(3,4)‐bisphosphate [PI(3,4)P₂] to PI(3)P, thus influencing the activity of downstream effectors such as AKT and SGK3. In several cancer types—in particular, subsets of breast cancer, thyroid cancer, and hepatocellular carcinoma—INPP4B functions as a tumor suppressor by limiting AKT activation, which in turn restrains cell proliferation and promotes controlled survival (see."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": " In these contexts, loss or reduced expression of INPP4B is associated with more aggressive tumor phenotypes and poorer clinical outcomes. Conversely, other studies, particularly in PIK3CA‐mutated breast cancers and colon cancer, have implicated INPP4B in an oncogenic role where its expression promotes activation of SGK3 while concurrently suppressing AKT phosphorylation, thereby fostering three‐dimensional proliferation, invasive migration, and tumorigenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " In acute myeloid leukemia, INPP4B is frequently overexpressed and confers chemoresistance, highlighting a gain‐of‐function role that supports leukemic cell survival."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Moreover, INPP4B is essential for fundamental cellular processes such as macropinocytosis by participating in the ordered dephosphorylation of phosphoinositides."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " Its expression is also subject to regulation by noncoding RNAs; for example, mesenchymal stem cell–derived exosomes carrying miR‑222‑3p can reduce INPP4B levels, thereby altering signaling pathways that govern cell proliferation and apoptosis in leukemic cells."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these studies reveal that INPP4B plays a context‑dependent dual role in cancer biology. It can function as a tumor suppressor by attenuating oncogenic PI3K–AKT signaling in certain settings, while in other contexts its activity promotes oncogenesis via SGK3 activation or by conferring chemoresistance. Understanding the mechanisms that dictate these divergent functions of INPP4B is critical for informing the development of targeted therapeutic strategies.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Christina Gewinner, Zhigang C Wang, Andrea Richardson, et al. 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