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Review
. 2025 Jun 6;18(6):853.
doi: 10.3390/ph18060853.

Metabolic Reprogramming in Melanoma: An Epigenetic Point of View

Stefano Giuliani  1 , Celeste Accetta  2 , Simona di Martino  2 , Claudia De Vitis  3 , Elena Messina  3 , Edoardo Pescarmona  2 , Maurizio Fanciulli  1 , Gennaro Ciliberto  4 , Rita Mancini  3 , Italia Falcone  1
Affiliations
Review

Metabolic Reprogramming in Melanoma: An Epigenetic Point of View

Stefano Giuliani et al. Pharmaceuticals (Basel). .

Abstract

Metabolic reprogramming and epigenetic alterations are fundamental hallmarks of cancer cells, contributing to adaptation, progression, and resistance. In melanoma, high metabolic-epigenetic plasticity enables the rapid modulation of cell states in response to environmental and therapeutic pressures. Recent studies have highlighted a bidirectional crosstalk between cellular metabolism and epigenetic regulation. Epigenetic modifications influence the transcriptional control of metabolic genes, thereby shaping metabolic phenotypes. Conversely, specific metabolites are essential cofactors or substrates for epigenetic enzymes, directly modulating the epigenome. Understanding the intricate mechanisms of this interaction offers opportunities for the development of innovative tumor management that combines epigenetic, metabolic, and therapy interventions. In this review, we summarize the latest evidence on the role of the metabolism-epigenetics axis in melanoma and discuss its potential clinical implications, aiming to provide a comprehensive overview of metabolic/epigenetic interconnections.

Keywords: drug resistance; epigenetics; immunotherapy; melanoma; metabolism; target therapy.

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Conflict of interest statement

Author Prof. Gennaro Ciliberto was employed by the company Takis s.r.l. The authors declare that this study no received funding from Takis s.r.l. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest.

Figures

Figure 1
Figure 1
(A,B) Schematic representation of epigenetic mechanisms involved in melanoma metabolic reprogramming: DNA methylation; histone modifications. Created in BioRender. Giuliani, S. (2025) https://app.biorender.com/illustrations/680f7fb6830216ca4c9e5fdc.
Figure 2
Figure 2
Overview of principal metabolites acting as cofactors and substrates for epigenetic enzymes in melanoma. Acetyl-CoA, α-KG, and lactate dynamically modulate chromatin states through histone acetylation, DNA/histone demethylation, and histone lactylation, respectively. Acetyl-CoA promotes H3K27 acetylation via p300 at the PD-L1 promoter; α-KG activates TET2/3 and histone demethylases, enhancing immune visibility; lactate induces H3K18 lactylation, promoting immune evasion or quiescence. Created in BioRender. Giuliani, S. (2025) https://app.biorender.com/illustrations/680f4315e7e7d75d587258ed.
See this image and copyright information in PMC

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