Catestatin suppresses melanoma progression and drug resistance through multitargeted modulation of signaling pathways.

Background: Despite advances in targeted and immune-based therapies, melanoma remains one of the most aggressive and treatment-resistant cancers. Resistance to small-molecule inhibitors and immune checkpoint blockade highlights the need for new mechanistically distinct interventions. Catestatin (CST), a Chromogranin A (CgA)-derived peptide with immunomodulatory and reparative properties, has been implicated in tissue protection, but its role in melanoma remains unknown. Methods: CST expression was analyzed across melanoma stages and correlated with disease progression. Functional effects of CST were assessed in patient-derived and established melanoma cell lines, as well as in B16-F10 melanoma-bearing mice. RNA sequencing and pathway analyses were performed to delineate CST-regulated molecular networks. Vemurafenib-resistant A375 cells were used to examine CST's effects on drug resistance mechanisms. Results: CST expression declined with advancing tumor stage. CST treatment inhibited proliferation, migration, and invasion, while inducing apoptosis in melanoma cells but not in normal fibroblasts. In vivo, systemic CST administration significantly reduced tumor volume and mass. Transcriptomic profiling revealed coordinated downregulation of hypoxia-inducible, epithelial-mesenchymal transition (EMT), and collagen-remodeling pathways, alongside suppression of oxidative stress-adaptive signaling. In Vemurafenib-resistant A375 cells, CST restored apoptotic sensitivity and repressed multiple MAPK and PI3K-AKT-linked resistance genes. Conclusions: CST acts as a mechanistically distinct peptide modulator that reprograms oncogenic signaling through inhibition of hypoxia, EMT, and survival pathways. These findings identify CST as a promising therapeutic prototype for mitigating melanoma progression and overcoming resistance to targeted therapy.