Acyl-CoA Synthetase Long Chain Family Member 4 (ACSL4): A Novel Prognostic Marker in Cutaneous Melanoma

Soumya Subhra Paria¹Rebecca Lapides^2,3Babak Saravi⁴Anjali Rajagopal⁵Alina Müller⁶Peter Kölblinger⁷Michael Wang-Evers³Dieter Manstein³Alexander A Navarini⁶Péter Lázár⁸Lajos V. Kemeny⁹Kaustubh Adhikari^1*Istvan Balazs Nemeth^10*Elisabeth Roider^3,6*

• ¹School of Mathematics and Statistics, The Open University (United Kingdom), Milton Keynes, England, United Kingdom
• ²Larner College of Medicine, University of Vermont, Burlington, Vermont, United States
• ³Department of Dermatology, Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Boston, Massachusetts, United States
• ⁴Department of Orthopedics and Trauma Surgery, University of Freiburg, Freiburg, Baden-Wurttemberg, Germany
• ⁵Department of Internal Medicine, University of Connecticut, Storrs, Connecticut, United States
• ⁶Department of Dermatology, University Hospital of Basel, Basel, Basel-Stadt, Switzerland
• ⁷Department of Dermatology and Allergology, Paracelsus Medical University, Salzburg, Salzburg, Austria
• ⁸Department of Oral and Maxillofacial Surgery, University of Szeged, Szeged, Hungary
• ⁹Department of Dermatology, Venereology and Dermatooncology; HCEMM-SU Translational Dermatology Research Group; Department of Physiology, Semmelweis University, Budapest, Hungary
• ¹⁰Department of Dermatology and Allergology, University of Szeged, Szeged, Hungary

Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation. Acyl-CoA synthetase long-chain family member 4 (ACSL4) promotes ferroptosis by enriching cellular membranes with polyunsaturated fatty acids, yet its prognostic relevance in melanoma remains unclear. We conducted a retrospective analysis of 63 patients with melanoma to evaluate associations between ACSL4 expression and overall survival (OS), metastasis-free survival (MFS), and disease-free survival (DFS). Correlation analyses and Cox proportional hazards models were used to identify prognostic factors, and immune cell infiltration was assessed in tumor samples. Higher ACSL4 expression was consistently associated with improved OS, MFS, and DFS in cutaneous melanoma. ACSL4 levels also correlated with greater immune cell infiltration within the tumor microenvironment. Notably, metastatic melanoma cases exhibited higher ACSL4 expression than non-metastatic cases; however, within cutaneous melanoma, elevated ACSL4 remained linked to more favorable survival outcomes. Together, these findings position ACSL4 as a promising prognostic biomarker in melanoma and suggest a potential connection between ferroptosis biology and antitumor immunity. While the study is retrospective and correlative, it provides a strong rationale for prospective validation and mechanistic studies to test whether modulating ACSL4-driven ferroptosis can improve clinical outcomes.