Catestatin peptide impedes melanoma progression and drug resistance by reprogramming oncogenic signaling pathways

Melanoma remains one of the most aggressive and therapy-resistant cancers, underscoring the need for innovative therapeutic strategies. In our current study we report a peptide-based approach as potential therapeutic. Here we report for the first time the involvement of Catestatin (CST) peptide in carcinogenesis, with melanoma identified as unexplored and therapeutically relevant context. The expression and role of CST, a Chromogranin A (CgA)-derived peptide with immunomodulatory and reparative properties in skin injury, led us to examine its connection to melanoma. Analysis of human melanoma tissues revealed that CST expression decreases with advancing disease stage, suggesting a potential tumor-suppressive function. Restoration of CST in patient-derived melanoma cells and established melanoma cell lines (A375, B16F10, and SKMEL28) induced apoptosis and suppressed proliferation and migratory capacity, while normal skin fibroblasts remained unaffected, indicating tumor-selective activity. In vivo, CST administration significantly reduced tumor growth and tumor weight in the B16F10 melanoma mouse model, with no detectable systemic toxicity. Transcriptomic profiling of CST-treated melanoma cells and tumors revealed downregulation of pathways involved in hypoxia signaling, extracellular-matrix remodeling, epithelial-to-mesenchymal transition (EMT), and stress-adaptive responses, key drivers of melanoma invasion and progression. Consistent with these findings, CST suppressed several mediators of tumor progression. CST also reduced the viability and migration of Vemurafenib-resistant A375 cells, accompanied by the downregulation of multiple resistance-associated genes. Together, these findings establish catestatin as a novel regulator of melanoma growth and therapeutic resistance and provide a mechanistic rationale for the development of CST-based peptide therapeutics targeting both treatment-naive and drug-resistant melanoma. Catestatin Suppresses Tumor Progression and Metastasis by Inducing Apoptosis and Inhibiting Pro-tumorigenic Signaling. Catestatin (CST), a Chromogranin A-derived peptide, exhibits potent anti-tumor activity by suppressing cancer progression across multiple stages. CST levels decline with advancing tumor stage, suggesting a loss of endogenous tumor restraint during progression to metastasis. In patient-derived melanoma cells and tumor models (A375 and B16F10), CST treatment induces apoptotic cell death. Mechanistically, CST downregulates key pro-tumorigenic and pro-fibrotic signaling molecules, including LOXL2, PDGFRB, CCN2, and DDIT4, which are associated with extracellular-matrix remodeling, growth factor signaling, and cellular stress adaptation. These findings identify CST as a novel regulator of tumor survival and metastatic potential, supporting its therapeutic potential as a peptide-based anti-cancer agent.