Abstract <p>Ovarian cancer remains one of the most aggressive cancers, and resistance to Poly (ADP-ribose) Polymerase inhibitors (PARPi) poses a major therapeutic challenge. SIRT5, a NAD + -dependent desuccinylase, plays a crucial role in regulating fatty acid metabolism, which is often reprogrammed in cancer cells to promote drug resistance. This study aimed to investigate the potential of polydopamine (PDA)-polymerized antioxidant nanozyme-loaded SIRT5-modified human umbilical cord mesenchymal stem cells (hUCMSCs) to overcome PARPi resistance in ovarian cancer. We employed multi-omics approaches, including transcriptomics, metabolomics, and proteomics, to identify key molecular pathways associated with resistance mechanisms. High-throughput sequencing and metabolic profiling revealed that SIRT5 modifies fatty acid β-oxidation and regulates the desuccinylation of Enoyl-CoA Hydratase (ECHA), a key enzyme involved in this process. In vitro and in vivo experiments demonstrated that nanozyme-engineered hUCMSCs effectively enhanced PARPi resistance by promoting fatty acid metabolism and desuccinylation. These findings suggest that SIRT5-modified hUCMSCs loaded with antioxidant nanozymes offer a promising therapeutic strategy to combat PARPi resistance in ovarian cancer. The study provides new insights into overcoming drug resistance through metabolic reprogramming and enhances the potential of engineered stem cells in cancer therapy.</p> Graphical Abstract <p></p>