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. 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.