Glutathione peroxidase 4 and Matrix metalloproteinases (GPX4/MMPs)

Glutathione peroxidase 4 (GPX4) is a selenium-dependent enzyme that plays a critical role in protecting cells from oxidative damage by reducing lipid hydroperoxides to non-toxic lipid alcohols (Yang et al., 2014, Cell). It is the primary regulator of ferroptosis, a form of regulated cell death characterized by iron-dependent lipid peroxidation (Conrad & Pratt, 2019, Nature Chemical Biology). Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases responsible for the degradation and remodeling of extracellular matrix components (Jabłońska-Trypuć et al., 2016, J Enzyme Inhib Med Chem). While GPX4 maintains cellular redox homeostasis, MMPs facilitate tissue remodeling, cell migration, and tissue repair. In pathological states such as cancer and chronic inflammation, the dysregulation of both GPX4 (often upregulated to resist ferroptosis) and MMPs (upregulated to promote invasion) contributes to disease progression and metastasis. Therapeutic strategies often target GPX4 to induce cell death in resistant tumors or inhibit MMPs to prevent tissue destruction and metastatic spread (Vandenbroucke & Libert, 2014, Nature Reviews Drug Discovery). However, broad inhibition of these enzymes can lead to significant side effects, including musculoskeletal syndrome for MMP inhibitors and potential systemic toxicity for GPX4 inhibitors.

Other names

Phospholipid-hydroperoxide glutathione peroxidaseMatrixinsGSHPx-4Matrix metalloproteinase family

GPX4 inhibitors induce ferroptosis by blocking the reduction of lipid hydroperoxides; MMP inhibitors block the proteolytic activity of matrix metalloproteinases to prevent ECM degradation.