LHPP (phospholysine phosphohistidine inorganic pyrophosphate phosphatase) is a phosphatase with broad substrate specificity that hydrolyzes phosphohistidine, phospholysine, and inorganic pyrophosphate 1. Operating primarily in the cytosol and nucleus, LHPP functions as a tumor suppressor by dephosphorylating signaling proteins including CaMKIIα, ERK, AKT, and TYK2, thereby regulating multiple cellular pathways 234. In cancer contexts, low LHPP expression correlates with poor prognosis across gastric, prostate, and nasopharyngeal cancers 534. LHPP suppresses tumor stemness and chemotherapy resistance in gastric cancer by inhibiting GSK-3β phosphorylation and promoting antitumor immune infiltration 5. In prostate cancer, LHPP activates ferroptosis by preventing AKT-SKP2-mediated ACSL4 degradation 3. Genetically, LHPP variants (rs35936514) associate with major depressive disorder, modulating brain regional activity in the prefrontal cortex and temporal regions 67. In depression pathophysiology, LHPP upregulation in ventral hippocampal glutamatergic neurons promotes depression-like behavior via CaMKIIα and ERK dephosphorylation, reducing BDNF and dendritic spine density 2. LHPP represents a promising therapeutic target, with HDAC inhibitors potentially enhancing LHPP stability in cancer treatment 34.