Metabolomic and Proteomic Analyses Unveil That Polyethylene Glycol–Polycaprolactone-Loaded Curcumin Nanoparticles Induce Mitochondrial Dysfunction and Metabolic Reprogramming to Suppress Melanoma Growth

作者：Yixun Zhang, Xin Zhou, Wenlian Zheng, Jianwei Chen, Qianfeng Xu, Zhenguo Liang, Hongli Zhang, Jundong Lin, Wenjie Xie, Yangjia Zhuo, Muqi Chen, Fen Zou, Biyan Wen, Zeheng Tan, Weide Zhong, Huikang Yang, Ronghua Yang · 发表于：ACS Applied Materials & Interfaces · 年份：2025 · DOI：10.1021/acsami.5c02854 · 被引用次数：7 · 研究领域：Curcumin's Biomedical Applications、Retinoids in leukemia and cellular processes、Genomics, phytochemicals, and oxidative stress

Melanoma is highly dependent on cellular metabolism, but current treatments show limited effectiveness. Despite the promising antitumor properties of curcumin, its clinical utility is limited by its poor bioavailability and potential systemic toxicity. To address these challenges, we formulated curcumin-loaded polyethylene glycol-polycaprolactone (PEG-PCL) nanoparticles, denoted as PEG-PCL@Cur. We employed omics technologies to investigate their impact on melanoma at the molecular level. In vitro studies revealed that PEG-PCL@Cur notably suppressed the growth, movement, and invasiveness of A375 melanoma cells in a dose-dependent manner. Untargeted metabolomics identified 347 metabolites that were significantly altered. A decrease in fumaric acid levels indicated the suppression of oxidative phosphorylation and a shift in metabolism. Proteomics further confirmed the downregulation of key mitochondrial proteins, such as SDHA, pointing to mitochondrial dysfunction. Mechanistically, PEG-PCL@Cur increased reactive oxygen species (ROS) production by raising NADH levels and inhibiting SDHA expression. This led to a reduction in the level of fumaric acid production and a disruption of the tricarboxylic acid (TCA) cycle. Additionally, PEG-PCL@Cur hindered the generation of inorganic phosphate (Pi), resulting in a decreased level of ATP production. These metabolic changes promoted apoptosis and enhanced melanoma cell death. In vivo, PEG-PCL@Cur significantly curtailed tumor growth in a...