Post-translational modifications of integrins: molecular mechanisms and pathological implications

Integrins are cell-surface adhesion receptors that mediate bidirectional signaling governing migration, proliferation, and survival. Emerging evidence reveals that integrin function is finely controlled by an interconnected network of post-translational modifications (PTMs), spanning classical modifications such as glycosylation and phosphorylation, as well as novel metabolite-driven alterations including carbamoylation and cysteine carboxyethylation. These PTMs collectively orchestrate integrin stability, conformation, trafficking, and downstream signaling, with profound implications for tumor progression, metastasis, fibrosis, and therapy resistance. We further highlight critical cross‑talk among distinct modification types and demonstrate how environmental cues (e.g., metabolic byproducts, gut microbiota metabolites) directly modify integrins. Finally, we explore emerging therapeutic strategies inspired by these insights, including targeted enzyme inhibitors, proteolysis targeting chimeras (PROTACs), deubiquitinase-targeting chimeras (DUBTACs), and PTM-editing tools such as dCasRx-based m6A editors. Deciphering the integrin PTM code transforms our understanding of cell adhesion biology and opens new frontiers for diagnostic biomarkers and precision therapy.