Succinylated D-Type Neuropeptide Integrated with Iron-Based Probes for Regulating Mitochondrial Function and Homeostasis in Breast Cancer.

Despite the critical role of succinylation as a posttranslational modification in regulating cellular homeostasis and metabolic pathways, achieving precise control over mitochondrial function and homeostasis to induce apoptosis in breast cancer remains a significant challenge. In this study, we designed a succinylated D-type neuropeptide integrated with an iron-based probe aimed at regulating mitochondrial function and homeostasis through SIRT5-mediated desuccinylation. The probe is selectively delivered to breast cancer cells via Y1 receptor-mediated endocytosis, where it undergoes SIRT5-catalyzed desuccinylation within the mitochondria. This enzymatic modification induces substantial changes in the secondary structure of the D-type neuropeptide, transforming the probe into aggregates that disrupt the mitochondrial membrane potential and electron transport. By interacting competitively with cellular desuccinylation pathways, this probe further disturbs cellular homeostasis, ultimately leading to apoptosis in tumor cells. Additionally, we observe the upregulation of key genes associated with inflammation and ferroptosis, which may contribute to the establishment of an inflammatory microenvironment, thereby enhancing the antitumor effect. Notably, the aggregation process shifts the magnetic resonance imaging (MRI) contrast from T1 to T2, enabling the real-time visualization of mitochondrial perturbations. This work establishes a versatile platform for designing neuropeptide-based nanoprobes with diagnostic and therapeutic potential for the treatment of breast cancer.