Lhpp, or phospholysine phosphohistidine inorganic pyrophosphate phosphatase, is a phosphatase with diverse functions. It can dephosphorylate residues of histidine, serine, threonine, and tyrosine. LHPP is involved in various biological pathways and has significant importance in both normal physiological processes and disease states. Genetic models, such as KO mouse models, have been crucial in studying its functions [2,3,5,7].

In cancer, LHPP acts as a tumor suppressor. Low LHPP expression in tumor tissues and cells is associated with a poorer prognosis. Functional studies show it can inhibit tumor cell proliferation, metastasis, and apoptosis by affecting different target genes. For example, in prostate cancer, LHPP interacts with AKT, inhibiting ACSL4 phosphorylation and promoting ferroptosis [1,4]. In gastric cancer, it suppresses progression via the PI3K/AKT/mTOR signaling pathway [6]. In hepatocellular carcinoma, overexpression of LHPP inhibits cell growth and metastasis [8]. In glioblastoma, LHPP impedes energy metabolism by inducing ubiquitin-mediated degradation of PKM2 [9].

In the context of depression, LHPP in the medial prefrontal cortex and glutamatergic neurons of the ventral hippocampus is involved in regulating stress-induced depression-like behaviors. Genetic deletion of LHPP in relevant regions can affect behaviors in mice under chronic social defeat stress [2,5].

In liver fibrosis, LHPP deficiency aggravates fibrosis through the TGF-β/Smad3 pathway [7].

In conclusion, LHPP has essential biological functions in regulating tumor progression, stress-related depression-like behaviors, and liver fibrosis. The use of KO/CKO mouse models has significantly contributed to understanding its role in these disease areas, providing potential therapeutic targets for cancer, major depressive disorder, and liver fibrosis.