SCARA5 Induces Ferroptosis to Inhibit the Proliferation and Migration of Skin Melanoma Cells and Regulates the GPX4/ACSL4 Signaling Pathway

Skin cutaneous melanoma (SKCM) is a highly aggressive skin cancer with poor prognosis in advanced stages, despite recent advances in immunotherapy and targeted treatments. Novel therapeutic targets are urgently needed to improve the patient outcomes. Scavenger receptor class A member 5 (SCARA5), a scavenger receptor widely expressed in various human tissues, has been reported to act as a tumor suppressor in multiple cancers. The expression level of SCARA5 in SKCM tissues and cell lines was analyzed using the Gene Expression Profiling Interactive Analysis (GEPIA) database and validated by Western blotting. SKCM cells were transfected with SCARA5 overexpression plasmids, and cell proliferation, migration, and apoptosis were assessed using Cell Counting Kit-8 (CCK-8), colony formation, flow cytometry, and Transwell assays. Ferroptosis-related changes were examined by detecting intracellular Fe², lipid Reactive Oxygen Species (ROS), and malondialdehyde (MDA) levels. Additionally, the expression of ferroptosis-associated proteins glutathione peroxidase 4 (GPX4), acyl-CoA synthetase long-chain family member 4 (ACSL4), and SLC7A11 was analyzed by Western blotting. SCARA5 expression was markedly downregulated in SKCM cells compared with normal skin cells. Restoration of SCARA5 expression significantly suppressed the proliferation and migration of SKCM cells. Further analysis revealed that SCARA5 overexpression induced ferroptosis, as evidenced by increased levels of Fe², lipid ROS, and MDA. Mechanistically, SCARA5 regulated the ferroptosis process through modulation of the GPX4/ACSL4 pathway. CARA5 inhibits SKCM progression by promoting ferroptosis and disrupting the GPX4/ACSL4 axis.