{"doi":"10.1101/2025.10.22.684062","title":"Catestatin suppresses melanoma progression and drug resistance through multitargeted modulation of signaling pathways","abstract":"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: , 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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":578996,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9535,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":948269,"name":"Suborno Jati","orcid":"0000-0003-1397-8318","position":1,"is_corresponding":false},{"id":562346,"name":"Kechun Tang","orcid":null,"position":2,"is_corresponding":false},{"id":294553,"name":"Nicholas J. G. Webster","orcid":"0000-0002-3827-5750","position":3,"is_corresponding":false},{"id":1488822,"name":"Angelo Corti","orcid":"0000-0002-0893-6191","position":4,"is_corresponding":false},{"id":548362,"name":"Sushil K. Mahata","orcid":"0000-0002-8300-9873","position":5,"is_corresponding":false},{"id":1088744,"name":"Satadeepa Kal","orcid":"0000-0002-1858-3959","position":0,"is_corresponding":true}],"reference_count":73,"raw_metadata":null,"created_at":"2026-07-19T02:58:24.957414Z","pmid":"41279995","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}