An Anionic Cathelicidin Exerts Antimelanoma Effects in Mice by Promoting Pyroptosis

While cationic antimicrobial peptides (AMPs) are extensively studied for antitumor effects, anionic AMPs remain underexplored. Notably, no amphibian-derived anionic cathelicidins with antitumor activity have been reported. This study identifies Boma-CATH, a novel anionic cathelicidin (net charge–3) from Bombina maxima skin, which suppresses melanoma growth in mice and triggers pyroptosis-like morphological changes in A375 cells via the NLRP3/Caspase-1/GSDMD pathway. Further investigation revealed that ROS played a crucial role in promoting pyroptosis, as NAC (ROS scavenger) and Ac-YVAD-cmk (Caspase-1 inhibitor) reversed cell death and reduced LDH/IL-1β release in vitro and in vivo. GSDMD knockdown further validated its role. Additionally, Boma-CATH inhibited A375 cell proliferation, migration, and invasion, demonstrating dual antitumor mechanisms: pyroptosis induction and metastasis suppression. Importantly, Boma-CATH caused no adverse effects in mice, highlighting its therapeutic safety. These findings position Boma-CATH as a promising melanoma treatment and expand the mechanistic understanding of anionic AMPs in oncology.