The significance of protein S-palmitoylation in angiogenesis has been largely overlooked, leaving various aspects unexplored. Recent identification of Gpx1 as a palmitoylated protein has generated interest in exploring its potential involvement in novel pathological mechanisms related to angiogenesis. In this study, we demonstrate that Gpx1 undergoes palmitoylation at cysteine-76 and -113, with PPT1 playing a crucial role in modulating the depalmitoylation of Gpx1. Furthermore, we find that PPT1-regulated depalmitoylation negatively impacts Gpx1 protein stability. Interestingly, inhibiting Gpx1 palmitoylation, either through expression of a non-palmitoylated Gpx1 mutant or by expressing PPT1, significantly enhances neovascular angiogenesis. Conversely, in PPT1-deficient mice, angiogenesis is notably attenuated compared to wild-type mice in an Oxygen-Induced Retinopathy (OIR) model, which mimics pathological angiogenesis. Physiologically, under hypoxic conditions, Gpx1 palmitoylation levels are drastically reduced, suggesting that increasing Gpx1 palmitoylation may have beneficial effects. Indeed, enhancing Gpx1 palmitoylation by inhibiting PPT1 with DC661 effectively suppresses retinal angiogenesis in the OIR disease model. Overall, our findings highlight the pivotal role of protein palmitoylation in angiogenesis and propose a novel mechanism whereby the PPT1-Gpx1 axis modulates angiogenesis, thereby providing a potential therapeutic strategy for targeting PPT1 to combat angiogenesis.
With an increasing global cancer burden, the regulatory function of the human microbiome and its metabolites in tumor epigenetics has garnered significant interest. Microbial metabolites are not merely passive byproducts but serve as signaling molecules and epigenetic modulators, contributing to tumor progression through multiple overlapping pathways. Short-chain fatty acids (SCFAs) such as butyrate directly inhibit histone deacetylases to reactivate tumor suppressor genes, while secondary bile acids (BAs) induce gene silencing via DNA methylation remodeling by altering the FXR/TGR5 signaling pathway. Folate and vitamin B12 serve as substrates for DNA and histone methylation through one-carbon metabolism. A complex bidirectional feedback loop exists between microbial metabolism and tumor epigenetics: reprogramming driven by hypoxia or oncogenes alters metabolite flux, generating molecules such as lactate and succinate that not only remodel chromatin and the tumor microenvironment (TME) but also selectively promote the growth of metabolically adapted microbial species, thereby reinforcing epigenetic dysregulation. Despite growing mechanistic insights, establishing causality and correlating spatiotemporal dynamics and dose responses within the highly heterogeneous TME remain major challenges. Data integration across multi-omics remains limited by methodological and computational constraints. Resolving these issues will be critical for understanding the microbe-metabolite-epigenetic axis and advancing personalized precision oncology.