Pdcd6, also known as Programmed cell death protein 6, is an evolutionarily conserved Ca2+-binding protein. It is involved in regulating diverse cellular processes in different cellular compartments, such as apoptosis, alternative splicing, endoplasmic reticulum-to-Golgi apparatus vesicular transport, cytoskeletal dynamics, innate immune responses, and membrane repair [1]. Abnormal expression of PDCD6 is closely associated with many diseases, especially cancer [1].

PDCD6 deficiency in mice and macrophages leads to enhanced bactericidal activity and LC3-associated phagocytosis (LAP) formation. Mechanistically, PDCD6 interacts with lactate dehydrogenase A (LDHA) to downregulate lactate metabolism, affecting RUBCN lactylation and subsequent LAP-related protein interactions and LAP formation [2]. In various cancers, different PDCD6 polymorphisms show associations with cancer risk. For example, PDCD6 rs3756712 T>G polymorphism was associated with decreased cancer risk in a meta-analysis [3]. In hepatocellular carcinoma, overexpression of PDCD6 promotes cell proliferation, migration, and invasion through the AKT/GSK3β/β-catenin pathway [4]. In colorectal cancer, PDCD6 interacts with c-Raf, activating the c-Raf/MEK/ERK pathway and promoting cancer progression [5]. In cervical cancer, MAT2A facilitates PDCD6 methylation and promotes cell growth under glucose deprivation [6]. In glioblastoma, elevated PDCD6 expression is found in classical tumor tissues, and its overexpression is associated with poor overall survival, and knockdown attenuates tumor size in glioblastoma stem cells [7].

In conclusion, Pdcd6 is a multifaceted protein with essential functions in various cellular processes and is significantly associated with many diseases, especially cancer. Studies using gene knockout models, such as PDCD6-deficient mice, have revealed its roles in innate immune responses and antibacterial defense, as well as its oncogenic or protective roles in different cancers. These findings provide insights into the biological functions of Pdcd6 and potential therapeutic targets for related diseases.