MEME KANSERİNDE METABOLİK YENİDEN PROGRAMLAMA, FERROPTOZ VE TEDAVİ DİRENCİ ENZİMATİK HEDEFLERE DAYALI TERAPÖTİK YAKLAŞIMLAR
Özet
Breast cancer is a heterogeneous malignancy in which metabolic plasticity and adaptive stress responses play important roles in tumor progression and treatment resistance. Metabolic reprogramming enables breast cancer cells to modify glucose, glutamine, lipid, and iron metabolism in order to sustain energy production, biosynthesis, redox balance, and survival under therapeutic pressure. These metabolic changes also influence ferroptosis, an iron-dependent form of regulated cell death characterized by excessive lipid peroxidation. The interaction between metabolic reprogramming and ferroptosis therefore represents an important mechanism underlying the survival of treatment-resistant breast cancer cells.
Alterations in glutathione metabolism, NADPH production, membrane lipid composition, and iron homeostasis can determine the susceptibility of tumor cells to ferroptotic death. In particular, the SLC7A11–GSH–GPX4 pathway constitutes one of the major cellular defense mechanisms against ferroptosis by maintaining glutathione availability and limiting lipid peroxide accumulation. In addition, ACSL4, SCD1, glutamine-metabolizing enzymes, and proteins involved in iron transport and storage contribute to the regulation of ferroptotic sensitivity. These mechanisms are especially important in aggressive and treatment-resistant breast cancer subtypes, including triple-negative breast cancer, in which metabolic dependencies may create potential therapeutic vulnerabilities.
This review evaluates the relationship between metabolic reprogramming, ferroptosis, and treatment resistance in breast cancer, with particular emphasis on glucose, glutamine, lipid, and iron metabolism; redox homeostasis; the SLC7A11–GSH–GPX4 pathway; ferroptosis escape mechanisms; and relevant enzymatic targets. Therapeutic strategies combining ferroptosis induction with metabolic targeting, chemotherapy, targeted therapies, or immunotherapy may provide new opportunities for overcoming treatment resistance. However, most ferroptosis-based approaches remain in the preclinical stage, and challenges including tumor heterogeneity, biomarker selection, treatment selectivity, and toxicity to normal tissues require further investigation. A better understanding of tumor-specific metabolic dependencies and ferroptotic vulnerabilities may contribute to the development of more selective and effective therapeutic strategies for resistant breast cancer.
Anahtar Kelimeler: breast cancer; metabolic reprogramming; ferroptosis; treatment resistance; SLC7A11–GSH–GPX4 pathway; lipid metabolism; redox homeostasis; metabolic targeting.
Konu Alanı: Biyoloji -> Biyoloji (diğer) -> Biyokimya
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