Host-defence caerin 1.1 and 1.9 peptides suppress B16 melanoma growth by inducing apoptosis and disrupting lipid metabolism

Caerin peptides, originally isolated from the skin secretions of Australian tree frogs of the genus Litoria, have shown potential as anti-cancer agents in previous studies. This study investigates the impact of caerin 1.1 and 1.9 (F1/F3) peptides on lipid and amino acid metabolism in B16 melanoma cells, assessing their effects on cell proliferation and the tumour microenvironment (TME). F1/F3 significantly inhibited the proliferation of B16 cells in vitro, and metabolomic analysis revealed lipid metabolites, including lysophosphatidylcholines, phosphatidylcholines, phosphatidylethanolamines, and polyunsaturated fatty acids, were significantly downregulated in vivo in a murine model. Pathway enrichment analysis further highlighted suppressed fatty acid biosynthesis and unsaturated fatty acid synthesis, suggesting an impairment in lipid metabolic processes. Additionally, elevated levels of proinflammatory cytokine expression and inflammatory macrophage infiltration were observed in the TME, likely contributing to the enhanced anti-tumour response. Branched-chain amino acid degradation pathways were also less active in the F1/F3 group, suggesting altered acetyl-CoA availability impacting lipid synthesis. Notably, metabolites such as 3-Hydroxyvalproic acid and carnitine derivatives were markedly elevated, indicating potential antiproliferative and anti-inflammatory effects. These findings suggest that caerin peptides exert anti-cancer effects through multifaceted mechanisms, including modulation of lipid metabolism and immune activation, positioning caerin peptides as promising candidates for combination therapy in melanoma and potentially other malignancies.