Ferroptosis, mitochondrial stress and redox imbalance: a pharmacological-toxicological biochemistry framework for precision drug therapeutics
Year: 2026
Type: article
Abstract: Ferroptosis, mitochondrial stress and redox imbalance are increasingly recognised as interconnected determinants of therapeutic efficacy, drug resistance and organ toxicity. Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation and impaired antioxidant defences, with relevance to cancer, cardiovascular disease, inflammatory disorders, ischaemia-reperfusion injury and drug-induced tissue damage. This Perspective reframes the ferroptosis-mitochondrial stress-redox axis as a unified pharmacological-toxicological platform rather than an isolated therapeutic target, resolving its mechanisms to individual electron transport chain complexes, membrane phospholipid species and downstream immunological consequences. Beyond the conventional GPX4-system Xc − NRF2 framework, we incorporate dihydroorotate dehydrogenase (DHODH), GCH1-BH4 signalling, NCOA4-mediated ferritinophagy and p53-dependent regulation of ferroptosis sensitivity. We further define how complex I- and III-derived superoxide, compartmentalised inner-membrane lipid pools and ACSL4/LPCAT3-directed phospholipid remodelling shape organ-specific vulnerability. Because ferroptotic cells release damage-associated molecular patterns whose effects depend on cell death kinetics, immunomodulation is considered a distinct therapeutic opportunity and safety consideration. To consolidate these interacting mechanisms into a single, comprehensible reference, we present an integrated molecular pathway diagram that maps oxidative-stress chemistry, compartment-resolved mitochondrial involvement, lipid-substrate specificity, cell-death execution and kinetics-dependent immunological crosstalk onto their corresponding pharmacological entry points. We propose a tiered biomarker framework, a p53-and biomarker-guided patient stratification strategy, a chemically stratified therapeutic map distinguishing repurposed drugs from experimental compounds, and a conceptual pharmacokinetic-pharmacodynamic framework linking therapeutic and toxic exposure windows. Future research should prioritise biomarker validation, complex-specific mitochondrial functional assays, lipidomic profiling, organ-specific toxicology, tumour-selective delivery systems and pharmacokinetic-pharmacodynamic integration to advance safer, more precise ferroptosis-based therapeutics.
Source: Frontiers in Pharmacology
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,801
OpenAlex ID: W7223185712