Lhpp, or phospholysine phosphohistidine inorganic pyrophosphate phosphatase, is a histidine phosphatase. It has phosphatase activity and can dephosphorylate residues of histidine, serine, threonine, and tyrosine [1,3]. LHPP is involved in multiple biological pathways and has significant importance in both normal biological processes and disease conditions. Genetic models, such as knockout (KO) mouse models, have been crucial in studying its functions.

In cancer, LHPP is often expressed at low levels in tumor tissues and cells, and patients with low LHPP expression have a poorer prognosis. Functional studies show that it can inhibit tumor cell proliferation, metastasis, and apoptosis by affecting different target genes. For example, in prostate cancer, LHPP interacts with AKT, dampening AKT phosphorylation and promoting ferroptosis by modulating the AKT-SKP2-ACSL4 pathway [2]. In gastric cancer, LHPP inhibits cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) by regulating the PI3K/AKT/mTOR pathway [4]. In liver-related diseases, LHPP deficiency aggravates liver fibrosis through the TGF-β/Smad3 signaling pathway [5], while in hepatocellular carcinoma, overexpression of LHPP inhibits cell growth and metastasis [6]. In the context of depression, LHPP levels are upregulated in glutamatergic neurons of the ventral hippocampus in mice with stress-induced depression-like behaviors. KO of LHPP in glutamatergic neurons of the brain improves the spontaneous activity of mice, and knockdown of LHPP in the ventral hippocampus enhances resistance against chronic social defeat stress [1].

In summary, LHPP plays essential roles in tumor suppression, as well as in the pathogenesis of depression and liver fibrosis as revealed through KO mouse models. Its functions in these disease areas provide potential therapeutic targets. Understanding LHPP's functions through these research models helps in uncovering new strategies for treating related diseases.

References:

1. Zhuang, Lvping, Gao, Weijie, Chen, Yanbing, Chen, Xiaochun, Zhang, Jing. 2023. LHPP in Glutamatergic Neurons of the Ventral Hippocampus Mediates Depression-like Behavior by Dephosphorylating CaMKIIα and ERK. In Biological psychiatry, 95, 389-402. doi:10.1016/j.biopsych.2023.08.026. https://pubmed.ncbi.nlm.nih.gov/37678540/

2. Xie, Guoqing, Li, Ningyang, Li, Keqiang, Jia, Zhankui, Huang, Zhenlin. 2024. Phosphatase LHPP confers prostate cancer ferroptosis activation by modulating the AKT-SKP2-ACSL4 pathway. In Cell death & disease, 15, 665. doi:10.1038/s41419-024-07007-8. https://pubmed.ncbi.nlm.nih.gov/39261475/

3. Lin, Dong, Li, Luhui, Chen, Wen-Bing, Pan, Bing-Xing, Fei, Erkang. 2022. LHPP, a risk factor for major depressive disorder, regulates stress-induced depression-like behaviors through its histidine phosphatase activity. In Molecular psychiatry, 28, 908-918. doi:10.1038/s41380-022-01893-0. https://pubmed.ncbi.nlm.nih.gov/36460727/

4. Wang, Danfang, Li, Jianhui, Li, Wenhan. 2022. LHPP suppresses gastric cancer progression via the PI3K/AKT/mTOR signaling pathway. In Journal of Cancer, 13, 3584-3592. doi:10.7150/jca.78098. https://pubmed.ncbi.nlm.nih.gov/36484014/

5. Zhang, Yue, Li, Bi-Min, Zhang, Wang, Huang, Chenkai, Zhu, Xuan. . LHPP deficiency aggravates liver fibrosis through TGF-β/Smad3 signaling. In FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 38, e70053. doi:10.1096/fj.202400117RR. https://pubmed.ncbi.nlm.nih.gov/39373847/

6. Liao, Lijuan, Duan, Deyu, Liu, Yanfeng, Chen, Liang. 2020. LHPP inhibits hepatocellular carcinoma cell growth and metastasis. In Cell cycle (Georgetown, Tex.), 19, 1846-1854. doi:10.1080/15384101.2020.1783472. https://pubmed.ncbi.nlm.nih.gov/32578511/