INTRODUCTION 🧬
Skin cutaneous melanoma (SKCM) remains one of the most aggressive and treatment-resistant forms of skin cancer, urging the need for innovative therapeutic approaches. Metformin, a well-known antidiabetic drug, has emerged as a promising candidate in cancer therapy due to its antiproliferative and metabolic regulatory properties. This study investigates the effects of metformin on SKCM cells, specifically focusing on its ability to induce ferroptosis—a form of regulated cell death characterized by iron-dependent lipid peroxidation. The research aims to determine whether metformin could suppress melanoma cell proliferation while simultaneously promoting ferroptosis, thereby unveiling a novel pathway for intervention. Additionally, this study delves into the molecular mechanisms underlying metformin’s effects, particularly its impact on the ATF3/NRF2 signaling axis. The findings have the potential to not only deepen our understanding of SKCM biology but also to offer a new theoretical foundation for developing targeted melanoma treatments based on ferroptosis induction.
ANTITUMOR EFFECTS OF METFORMIN ON SKCM CELLS 🧪
The antiproliferative effect of metformin on SKCM cells was assessed using the Cell Counting Kit-8 (CCK-8) assay. Results demonstrated a significant inhibition of cell viability, indicating that metformin effectively impairs melanoma cell proliferation. This observation aligns with prior studies suggesting the anticancer properties of metformin, yet this work contributes by verifying its efficacy specifically in SKCM. By interfering with cellular metabolic processes, metformin disrupts the energy supply essential for cancer cell survival. These findings suggest metformin as a viable repurposed agent capable of suppressing tumor growth in melanoma, laying the groundwork for further clinical research.
METFORMIN AND INDUCTION OF FERROPTOSIS 🔥
To explore whether metformin induces ferroptosis, key biomarkers were evaluated. Treatment led to a reduction in glutathione (GSH) levels and an increase in reactive oxygen species (ROS), lipid peroxides (LPO), and malondialdehyde (MDA), all hallmark indicators of ferroptotic cell death. The disruption of redox balance and lipid metabolism points toward ferroptosis as a major cell death mechanism triggered by metformin. These findings are significant, as targeting ferroptosis offers a non-apoptotic route for killing cancer cells, especially those resistant to traditional therapies. The ability of metformin to modulate ferroptosis highlights a promising therapeutic dimension in combating melanoma.
DIFFERENTIALLY EXPRESSED GENES AND PATHWAY ENRICHMENT 🧫
RNA sequencing (RNA-seq) revealed 2,068 differentially expressed genes (DEGs) in SKCM cells treated with metformin, with 897 genes up-regulated and 1,171 down-regulated. Functional enrichment analysis showed that several biological pathways were affected, notably those related to iron metabolism and ferroptosis. These data provide critical molecular insights into how metformin reprograms cellular responses, promoting cell death and impeding tumor survival. The large number of DEGs also suggests widespread transcriptomic remodeling, reinforcing the potential systemic effects of metformin on melanoma cells. This genomic perspective strengthens the hypothesis that ferroptosis is a metformin-driven process with therapeutic implications.
ROLE OF ATF3 AND NRF2 IN METFORMIN-INDUCED FERROPTOSIS ⚙️
Further molecular investigations revealed that metformin modulates the expression of two critical regulators: ATF3 and NRF2. The mRNA and protein levels of ATF3 were found to increase with metformin treatment in a dose-dependent manner, whereas the expression of NRF2 protein decreased. In SKCM tissues, ATF3 expression was notably lower, but was restored by metformin, suggesting a tumor-suppressive role. NRF2, often associated with antioxidant defenses, was down-regulated, possibly facilitating oxidative stress and ferroptosis. This indicates that metformin may induce ferroptosis through upregulation of ATF3 and suppression of NRF2, establishing the ATF3/NRF2 axis as a key regulatory mechanism in melanoma treatment.
THERAPEUTIC IMPLICATIONS AND FUTURE PERSPECTIVES 💡
The discovery that metformin can trigger ferroptosis in SKCM cells via the ATF3/NRF2 axis opens new avenues for melanoma therapy. This mechanism not only broadens the functional understanding of metformin beyond glucose regulation but also introduces a novel, non-apoptotic strategy to combat melanoma. By targeting ferroptosis, especially in tumors resistant to standard treatments, metformin could be integrated into combination therapies or inspire the development of new ferroptosis-inducing drugs. Future research should focus on validating these findings in vivo, exploring dose optimization, and evaluating clinical outcomes. The repurposing of metformin thus represents a promising, low-cost strategy with high translational potential.
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#MelanomaResearch #SkinCancer #Ferroptosis #Metformin #CancerTherapy #Oncology #ATF3 #NRF2 #RNAseq #CancerBiomarkers #OxidativeStress #TumorSuppression #IronMetabolism #LipidPeroxidation #CellDeath #CancerTreatment #MolecularMechanisms #DrugRepurposing #CancerBiology #TargetedTherapy
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