Pkp3, short for plakophilin 3, is a member of the armadillo protein family. It is a component of desmosomes, playing a role in cell-cell adhesion by binding to desmosomal proteins like desmoglein, desmocollin, plakoglobin, and desmoplakin [4,6]. Pkp3 also participates in signal transduction pathways, responding to components of the canonical-Wnt pathway [5]. It has significant importance in maintaining tissue integrity and is involved in various cellular processes such as proliferation, invasion, and autophagy, which are crucial for normal development and disease-related processes [1,4,7].

In cancer research, studies have shown that Pkp3 is highly expressed in many cancers including ovarian, pancreatic, and non-small cell lung cancers. In ovarian cancer, Pkp3 modulates cellular proliferation and invasion, and activates the mTOR pathway to regulate autophagy through its interaction with the upstream of the MAPK pathway [1]. In pancreatic cancer, it promotes cancer cell progression, migration, and invasion, and is associated with the regulation of the PI3K-Akt and MAPK signaling pathways. Also, it impedes CD8+ T-cell infiltration and immune cytokine expression in the tumor microenvironment [3]. In non-small cell lung cancer, circIGF2BP3 upregulates Pkp3 expression by sponging specific microRNAs, and Pkp3 then engages with FXR1 to stabilize OTUB1 mRNA, which elevates PD-L1 abundance through deubiquitination, facilitating tumor immune evasion [2]. Loss of Pkp3 in tumor cells leads to increased autophagy and radio-resistance, suggesting autophagy inhibitors could target Pkp3-deficient tumors [7].

In conclusion, Pkp3 is essential for desmosome-mediated cell adhesion and participates in key signaling pathways. Model-based research, especially in cancer studies, has revealed its oncogenic potential in multiple cancer types. It affects cancer cell behavior, immune cell infiltration, and responses to treatment, highlighting its importance as a potential biomarker and therapeutic target in cancer.