Pdpk1, also known as 3-phosphoinositide dependent protein kinase 1, is a phosphorylation-regulated kinase. It plays a central role in activating multiple signaling pathways, such as the AKT1-MTOR pathway, and is involved in various cellular processes like autophagy, cell proliferation, and metabolism [1,2,3,4,5,6,7,8,9,10]. Genetic models, especially KO/CKO mouse models, are valuable for studying its functions.

In autophagy, SUMOylated Pdpk1 regulates its phosphorylation and AKT1-MTOR activation, while non-SUMOylated Pdpk1 tethers LC3 to the endoplasmic reticulum to initiate autophagy [1]. In hepatocellular carcinoma cells, downregulation of FBXW5 leads to AQP3-induced Pdpk1 degradation, inactivating the AKT-MTOR axis and promoting autophagic death [2]. Pdpk1 also directs the switch from virophagy to mitophagy in coronavirus infection by phosphorylating SQSTM1 at T138 [3]. In tumor-related processes, macrophage-associated Pdpk1-mediated PGK1 phosphorylation promotes aerobic glycolysis and tumorigenesis [4]. In alcoholic steatohepatitis, downregulating Pdpk1 or its phosphorylation protects hepatocytes by promoting autophagy [5]. In CD4 T-cell homeostasis, SUMOylation of Pdpk1 is required to maintain glycolysis-dependent proliferation [6]. In ischemic stroke, the FasL-Pdpk1 pathway promotes the cytotoxicity of CD8+ T cells [7]. In prostate cancer, CPT1A-mediated succinylation of SP5 activates Pdpk1 transcription to promote cell viability and glycolysis [8]. In hepatocellular carcinoma, the non-N-terminal fragment of GSDME in macrophages binds to Pdpk1, activating the PI3K-AKT pathway and facilitating M2-like polarization [9]. In epithelial ovarian cancer, estrogen up-regulates Pdpk1 expression, and Pdpk1 acts as an oncogene promoting cell proliferation [10].

In conclusion, Pdpk1 is crucial for multiple biological functions including autophagy, cell metabolism, and immune-related processes. Studies using KO/CKO mouse models and other loss-of-function experiments have revealed its significant roles in various disease conditions such as cancer, liver diseases, and virus-induced diseases, providing insights into potential therapeutic targets.