Enhancing Gpx1 palmitoylation to inhibit angiogenesis by targeting PPT1

The role of protein S-palmitoylation in angiogenesis has been largely overlooked, leaving key areas unexplored. Recent findings identifying Gpx1 as a palmitoylated protein have sparked interest in its potential involvement in novel angiogenic mechanisms. In this study, we show that Gpx1 undergoes palmitoylation at cysteine residues 76 and 113, with PPT1 playing a key role in regulating its depalmitoylation. Notably, PPT1-mediated depalmitoylation destabilizes the Gpx1 protein. Inhibiting Gpx1 palmitoylation—either by expressing a non-palmitoylated Gpx1 mutant or increasing PPT1 expression—significantly promotes neovascular angiogenesis. In contrast, angiogenesis is markedly reduced in PPT1-deficient mice compared to wild-type mice in the Oxygen-Induced Retinopathy (OIR) model, which replicates pathological angiogenesis. Under hypoxic conditions, Gpx1 palmitoylation levels are sharply reduced, suggesting that maintaining its palmitoylation could offer therapeutic benefits. Supporting this, enhancing Gpx1 palmitoylation by inhibiting PPT1 with DC661 effectively suppresses retinal angiogenesis in the OIR model. These findings underscore the importance of protein palmitoylation in regulating angiogenesis and reveal a novel mechanism through which the PPT1-Gpx1 axis modulates angiogenesis, offering a promising therapeutic strategy for targeting PPT1 in angiogenic diseases.