Evernic and Diffractaic Acids Disrupt Redox Homeostasis, Inducing Distinct Cytotoxic Mechanisms in MCF-7 Breast Cancer Cells

Oxidative stress is a critical driver of tumor development and cancer cell survival, yet the precise impact of natural compounds like lichen secondary metabolites on antioxidant defense systems remains underexplored. Cancer cells frequently upregulate key oxidoreductase enzymes such as thioredoxin reductase 1 (TrxR1) to maintain cellular redox balance. Previous work showed evernic acid (EA) and diffractaic acid (DA) inhibit TrxR1, exerting cytotoxic and anti-migratory effects in MCF-7 breast cancer cells. This study aimed to comprehensively investigate how EA and DA modulate oxidative stress and the antioxidant system.

Researchers investigated the effects of evernic acid (EA) and diffractaic acid (DA) on MCF-7 breast cancer cells. They measured intracellular glutathione (GSH), reactive oxygen species (ROS), and malondialdehyde (MDA) levels. Additionally, they assessed the activities of various antioxidant enzymes, including superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), glutathione peroxidase (GPX), and glutathione S-transferase (GST). Gene and protein expression of these enzymes were also evaluated to understand the molecular mechanisms underlying the observed redox changes. No specific doses or treatment durations were detailed in the abstract.

Both evernic acid (EA) and diffractaic acid (DA) significantly disrupted cellular redox homeostasis in MCF-7 cells. They consistently decreased intracellular GSH levels and increased ROS accumulation. EA further elevated MDA levels, indicating increased lipid peroxidation, and caused a profound redox imbalance by suppressing the activity of multiple antioxidant enzymes: SOD, CAT, GR, GPX, and GST. In contrast, DA exhibited a more selective and balanced redox modulation, primarily inhibiting SOD, CAT, and GST activity while promoting apoptosis. The study concluded that EA specifically triggered ferroptosis-associated molecular alterations, primarily by disrupting the GSH-GPX4 axis. This suggests distinct mechanisms of cytotoxicity for the two compounds.

Evernic acid (EA) triggered ferroptosis-associated molecular alterations by disrupting the GSH-GPX4 axis, while diffractaic acid (DA) selectively inhibited SOD, CAT, and GST activity, promoting apoptosis.