Oxidative stress as a nexus: Integrating mitophagy and ferroptosis in endometrial carcinogenesis (Review)

Endometrial cancer (EC), a malignancy of the uterine lining with rising global incidence that is linked to obesity and metabolic syndrome, is molecularly stratified into four The Cancer Genome Atlas subtypes (DNA polymerase ε ultramutated, microsatellite instability-high, copy-number low and copy-number high), each requiring tailored therapeutic strategies. Despite advancements, drug resistance remains a critical challenge, prompting exploration of regulated cell death pathways such as ferroptosis, an iron-driven process marked by lipid peroxidation and glutathione peroxidase 4 (GPX4) inactivation. Mitochondrial dysfunction, a hallmark of EC, exacerbates oxidative stress by disrupting fission/fusion dynamics (via dynamin-related protein 1/mitofusin 1/2 imbalance) and impairing mitophagy (through PTEN-induced kinase 1/Parkin or FUN14 domain-containing protein 1 pathway defects), thereby promoting iron overload and ferroptotic vulnerability. Reactive oxygen species (ROS), generated via mitochondrial electron transport chains and NADPH oxidases, exhibit dual roles: Moderate levels drive tumorigenesis through DNA damage and immune evasion, while excessive ROS levels induce ferroptosis by depleting antioxidants (such as glutathione) and amplifying lipid peroxidation. The present review systematically integrates evidence on mitophagy and ferroptosis in EC pathogenesis; it highlights oxidative stress as a central nexus linking mitochondrial surveillance failure (such as cristae collapse and BCL2/adenovirus E1B 19 kDa protein-interacting protein 3-like-mediated mitophagy in TP53-mutant tumors) to iron-dependent membrane damage (via acyl-CoA synthetase long-chain family member 4 and ferroptosis suppressor protein 1-coenzyme Q10 dysregulation). Emerging therapeutic strategies targeting redox-sensitive nodes, including GPX4 degraders, mitophagy inducers (urolithin A) and chronotherapy, have the potential to overcome resistance. By elucidating the crosstalk between mitochondrial quality control and ferroptotic signaling, the present review provides a mechanistic framework for precision oncology in EC, emphasizing subtype-specific vulnerabilities and spatiotemporal redox profiling.