Palmitoyl protein thioesterase 1, is a lysosomal enzyme that catalyzes protein depalmitoylation. It is crucial in regulating lysosomes, mitochondria, lipid metabolism, and Ca2+转运, and is involved in multiple biological pathways. Dysregulation of PPT1 has been linked to various diseases, including neurological disorders and cancers [3].

In hepatocellular carcinoma (HCC), PPT1 is predominantly expressed in macrophages. High intratumoral PPT1+ macrophages abundance is associated with inferior patient survival and is an independent risk factor for prognosis. PPT1+ macrophages promote immunosuppressive transformation of the tumor microenvironment, and targeting PPT1 may enhance immunotherapy efficacy [1].

In an angiogenesis study, PPT1 -regulated depalmitoylation negatively impacts Gpx1 protein stability. Inhibiting PPT1 enhances Gpx1 palmitoylation, which suppresses angiogenesis [2].

In oral squamous cell carcinoma (OSCC), increased PPT1 expression correlates with poor prognosis, and PPT1 promotes cell proliferation, migration, invasion, and inhibits ferroptosis [4].

In a mouse model mimicking CLN1 disease (caused by inactivating mutations in PPT1), Ppt1 -deficiency dysregulates lysosomal Ca++ homeostasis, impairs lysosomal degradative function, and autophagy [5].

In melanoma, inhibiting PPT1 enhances the antitumor activity of anti -PD -1 antibody, and Ppt1 inhibition leads to M2 to M1 phenotype switching in macrophages [6].

In summary, PPT1 plays essential roles in various biological processes such as lipid metabolism, cellular homeostasis, and immune regulation. Studies using gene knockout (KO) or conditional knockout (CKO) mouse models, like in the CLN1 disease-mimicking mouse model, have been instrumental in revealing its functions in disease conditions. PPT1's involvement in diseases like HCC, OSCC, and melanoma suggests its potential as a therapeutic target for these malignancies, while its role in neurological disorders like CLN1 disease indicates its significance in understanding neurodegenerative mechanisms.