AbstractMelanoma is the most invasive skin cancer, with a high mortality rate. However, existing therapeutic drugs have side effects, low reactivity, and lead to drug resistance. As the power source in cells, mitochondria play an important role in the survival of cancer cells and are an important target for tumor therapy. This study aimed to develop a new anti‐melanoma compound that targets mitochondria, evaluate its effect on the proliferation and metastasis of melanoma cells, and explore its mechanism of action. The novel mitochondria‐targeting compound, SCZ0148, was synthesized by modifying the structure of cyanine. Then, A375 and B16 cells were incubated with different concentrations of SCZ0148, and different doses of SCZ0148 were administered to A375 and B16 xenograft zebrafish. The results showed that SCZ0148 targeted mitochondria, had dose‐ and time‐dependent effects on the proliferation of melanoma cell lines, and had no obvious side effects on normal cells. In addition, SCZ0148 induced melanoma cell apoptosis through the reactive oxygen species‐mediated mitochondrial pathway of apoptosis and promoted autophagy. SCZ0148 significantly inhibited the migration of melanoma cells via a matrix metalloprotein 9‐mediated pathway. Similarly, SCZ0148 inhibited melanoma cell proliferation in a concentration‐dependent manner in vivo. In summary, SCZ0148 may be a novel anti‐melanoma compound that targets mitochondria.

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