Ferroptosis, mitochondrial stress and redox imbalance: a pharmacological-toxicological biochemistry framework for precision drug therapeutics
- 1Department of Research, Publication and Extension, Kampala International University
- 2Department of Anatomy, Faculty of Biomedical Sciences, Kampala International University
- 3Department of Human Anatomy, State University of Medical and Applied Sciences
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.
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BibTeX
@article{ugwu2026ferroptosis,
title = {{Ferroptosis, mitochondrial stress and redox imbalance: a pharmacological-toxicological biochemistry framework for precision drug therapeutics}},
author = {Okechukwu Paul-Chima Ugwu and Chinyere Nneoma Ugwu and Godson Emeka Anyanwu and Mariam Basajja and Maryann Chiamaka Ebuoh},
journal = {Frontiers in Pharmacology},
year = {2026},
month = oct,
doi = {10.3389/fphar.2026.1890015},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1890015/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Ferroptosis, mitochondrial stress and redox imbalance: a pharmacological-toxicological biochemistry framework for precision drug therapeutics
AU - Okechukwu Paul-Chima Ugwu
AU - Chinyere Nneoma Ugwu
AU - Godson Emeka Anyanwu
AU - Mariam Basajja
AU - Maryann Chiamaka Ebuoh
PY - 2026
DA - 2026/10/22
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.1890015
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.1890015/full
AB - 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.
SN - 1663-9812
ER -