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Protein phosphorylation is involved in the regulation of a variety of biological processes. Histidine phosphatase dephosphorylates proteins containing histidine phosphorylation. Therefore, histidine phosphatase dysfunction can lead to the occurrence of a variety of clinical diseases, such as tumors, metabolic diseases, etc. This review summarizes the composition of histidine phosphatase, the relationship between histidine phosphatase and clinical diseases in orer to provide a new pathway for the clinical treatment of diseases.