Gastric Cancer (GC) is a highly prevalent and poorly prognostic gastrointestinal malignancy with low overall treatment efficacy worldwide. Early diagnostic markers and potential therapeutic targets for GC treatment are urgently needed. UFMylation, a novel ubiquitin-like modification is indispensable for numerous fundamental cellular processes. Deficiency in this modification is reported to be associated with several human diseases including cancer. Accumulating evidence suggests that the expression of the key UFMylation components is closely associated with GC cell proliferation, invasion, metastasis, and chemotherapy resistance. Recent clinical studies have further highlighted the prognostic value and therapeutic potential of UFMylation in the clinical management of GC. However, the precise molecular mechanisms through which UFMylation contributes to GC remain largely unclear. This review aims to summarize recent findings on the functional roles of UFMylation in diverse cellular processes, such as endoplasmic reticulum (ER) homeostasis, DNA damage response (DDR), protein translation, and quality control pathways, discuss potential underlying mechanisms in GC development and progression, and to explore potential therapeutic implications targeting the UFMylation pathway in GC.

Met1-linked ubiquitination (Met1-Ub), also known as linear ubiquitination, is a newly identified atypical type of polyubiquitination that is assembled via the N-terminal methionine (Met1) rather than an internal lysine (Lys) residue of ubiquitin. The linear ubiquitin chain assembly complex (LUBAC) composed of HOIP, HOIL-1L and SHARPIN is the sole E3 ubiquitin ligase that specifically generates Met1-linked ubiquitin chains. The physiological role of LUBAC-mediated Met1-Ub has been first described as activating NF-κB signaling through the Met1-Ub modification of NEMO. However, accumulating evidence shows that Met1-Ub is broadly involved in other cellular pathways including MAPK, Wnt/β-Catenin, PI3K/AKT and interferon signaling, and participates in various cellular processes including angiogenesis, protein quality control and autophagy, suggesting that Met1-Ub harbors a potent signaling capacity. Here, we review the formation and cellular functions of Met1-linked ubiquitin chains, with an emphasis on the recent advances in the cellular mechanisms by which Met1-Ub controls signaling transduction.