{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n LHPP (phospholysine phosphohistidine inorganic pyrophosphate phosphatase) has emerged as a multifunctional protein with evolutionarily conserved phosphatase activity that plays key roles in regulating cellular homeostasis. In mammals, LHPP functions predominantly as a tumor suppressor – its expression is frequently downregulated in a variety of human cancers, including hepatocellular carcinoma, cervical cancer, bladder cancer, colorectal cancer, papillary thyroid carcinoma, pancreatic cancer, oral and laryngeal squamous cell carcinoma, prostate cancer, renal cell carcinoma, intrahepatic cholangiocarcinoma, and glioblastoma."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "13"}]}, {"type": "t", "text": " Its tumor‐suppressive effects are mediated through multiple mechanisms, including the inactivation of oncogenic signaling cascades such as the PI3K/AKT, TGF‑β/Smad, and Wnt/β‑catenin pathways, modulation of cell cycle regulators (for example, p53) and the inhibition of epithelial‐to‐mesenchymal transition, thereby restraining cell proliferation, invasion, and metastasis while promoting apoptosis.\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the nervous system, genetic variations in the LHPP gene have been associated with major depressive disorder. Polymorphisms of LHPP are linked to alterations in the structure and function of key limbic and prefrontal regions – notably within the hippocampal-corticolimbic circuitry – thereby influencing neural connectivity and contributing to the pathophysiology of depression."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "14", "end_ref": "18"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond its roles in mammalian disease, LHPP is also represented in photosynthetic organisms. In plants, homologous complexes containing LHPP-like proteins have been proposed to participate in light-harvesting and chlorophyll biosynthesis during etiolation and greening."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": " Biochemical studies further demonstrate that LHPP catalyzes the removal of phosphate groups from phospho-histidine and phospho-lysine residues, thereby contributing to the regulation of protein post-translational modifications."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "21", "end_ref": "23"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Sravanth K Hindupur, Marco Colombi, Stephen R Fuhs, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The protein histidine phosphatase LHPP is a tumour suppressor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nature26140"}], "href": "https://doi.org/10.1038/nature26140"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29562234"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29562234"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Jiangli Zheng, Xue Dai, Hailin Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Down-regulation of LHPP in cervical cancer influences cell proliferation, metastasis and apoptosis by modulating AKT."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2018.06.127"}], "href": "https://doi.org/10.1016/j.bbrc.2018.06.127"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29944886"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29944886"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Yansheng Li, Xin Zhang, Xiaoguang Zhou, et al. "}, {"type": "b", "children": [{"type": "t", "text": "LHPP suppresses bladder cancer cell proliferation and growth via inactivating AKT/p65 signaling pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biosci Rep (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1042/BSR20182270"}], "href": "https://doi.org/10.1042/BSR20182270"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31262971"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31262971"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Bin Hou, Wenhan Li, Jianhui Li, et al. 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