Melanoma, originating from the malignant transformation of melanocytes, is the deadliest form of skin cancer. The incidence of primary cutaneous melanoma is increasing, with about 132,000 new cases annually. While early-stage melanoma can often be treated successfully with surgery, advanced melanoma remains challenging, necessitating new therapeutic targets. The MAPK pathway, particularly involving MEK and ERK, is critical in melanoma progression. PLEKHA4, a protein involved in cancer biology, has been identified as a key factor in melanoma cell proliferation and progression. Our study investigated the role of PLEKHA4 in regulating MAPK signaling and its impact on drug sensitivity in melanoma. Proteomic analysis, cell culture experiments, and various molecular techniques, including immunoblotting and quantitative proteomics, were employed to elucidate PLEKHA4’s function. Results indicates that PLEKHA4 is overexpressed in melanoma, promoting cell proliferation. PLEKHA4 knockdown induces apoptosis through the MAPK and cMyc pathway. enhances cMyc ubiquitination and degradation, suggesting a potential mechanism for its role in melanoma. These findings highlight PLEKHA4 as a significant player in melanoma progression and a potential target for therapeutic intervention.