Berberine as a Multi‐Targeted Therapeutic Agent in Melanoma: Mechanisms, Efficacy, and Combination Therapies

ABSTRACT Melanoma is a type of aggressive cancer distinguished by its high propensity for recurrence, the development of metastases, and an unfavorable outlook for recovery. Treatment modalities for melanoma encompass surgery, immunotherapy, and targeted therapies. In recent decades, berberine has garnered attention for its significant anticancer properties across various cancer types. This review systematically examines the molecular mechanisms of berberine in melanoma, particularly its modulation of critical signaling pathways, including B‐RAF/MEK/ERK, PI3K/AKT, and NF‐κB, which are essential for regulating melanoma cell proliferation and promoting apoptosis. Furthermore, berberine activates AMP‐activated protein kinase, leading to the inhibition of cyclooxygenase‐2, thereby reducing melanoma cell migration and invasion through decreased inflammation and enhanced cellular energy regulation. It also induces mitochondrial dysfunction and oxidative stress, promoting apoptosis while simultaneously inhibiting epithelial‐to‐mesenchymal transition, a key process in metastasis. Additionally, berberine modulates the immune microenvironment through Toll‐like receptors, cytokine networks, and the regulation of various immune cells, thereby enhancing its antitumor effects. Recent studies have shown that the therapeutic effect of berberine is enhanced when used in combination with other therapies, especially immune checkpoint inhibitors, to improve antitumor immune responses. These findings highlight the potential of berberine as a multi‐targeted agent for the treatment of melanoma, providing an avenue for further clinical exploration and integration into therapeutic strategies.