Linking Gut Microbiota, Mitochondrial Redox Dysfunction, and Ferroptosis in Cardiometabolic Diseases: A Narrative Review of Mechanistic Evidence and Redox-Targeted Interventions
5 affiliations
- 1School of Public Health and Health Sciences, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
- 2Clinical Medical School of Acupuncture, Moxibustion and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
- 3Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, VIC 3010, Australia
- 4School of Public Health and Preventive Medicine, Monash University, 553 St Kilda Road, Melbourne, VIC 3004, Australia
- 5School of Sport Science, Beijing Sport University, Beijing 100084, China
Abstract
Cardiometabolic diseases are increasingly understood as disorders involving compartment-specific redox disruption rather than a uniform excess of reactive oxygen species. This narrative review synthesizes evidence for a proposed gut microbiota-mitochondria ferroptosis framework in which dysbiosis-derived lipopolysaccharide, trimethylamine N-oxide, short-chain fatty acids, bile acids, and tryptophan metabolites may modulate mitochondrial reactive species production, antioxidant defenses, iron handling, lipid peroxide detoxification, and inflammatory signaling. The reference set was assembled through searches of PubMed and Web of Science Core Collection, supplemented by targeted Google Scholar searches and citation chaining during manuscript preparation and revision through June 2026 and was organized around microbial metabolites, mitochondrial redox biology, ferroptosis pathways, disease-specific evidence, and redox-targeted interventions. Because this is a narrative synthesis rather than a systematic review, the framework should be interpreted as hypothesis-generating rather than as a systematically validated pathological model. Across atherosclerosis, diabetic cardiomyopathy, metabolic dysfunction-associated steatotic liver disease, obesity-associated insulin resistance, chronic kidney disease, and cardiorenal metabolic injury, the most consistent mechanistic links involve mtROS, impaired mitophagy, glutathione/GPX4 and SLC7A11 dysfunction, ACSL4-dependent lipid peroxidation, Nrf2 signaling, NLRP3 activation, and cGAS-STING-associated inflammation, although human causal evidence remains uneven. Importantly, much of the current literature supports local links within this sequence rather than a fully verified dysbiosis-metabolite-mitochondria ferroptosis-organ dysfunction chain in the same study. We therefore emphasize evidence tiers, terminology discipline, and biomarker requirements when interpreting ferroptosis-sensitive injury. Polyphenols, flavonoids, probiotics, postbiotics, melatonin, CoQ10-related strategies, mitochondria-targeted antioxidants, and ferroptosis-sensitive approaches may be most translatable when paired with microbiome, metabolomic, lipidomic, pharmacokinetic, and redox biomarkers.
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BibTeX
@article{chen2026linking,
title = {{Linking Gut Microbiota, Mitochondrial Redox Dysfunction, and Ferroptosis in Cardiometabolic Diseases: A Narrative Review of Mechanistic Evidence and Redox-Targeted Interventions}},
author = {Yirui Chen and Jingzhi Zhu and Hongxin Gui and Mingyuan Liu and Ye Zhang and Zimu Wu and Chang Liu and Mengyang Wang},
journal = {Antioxidants},
year = {2026},
month = jun,
doi = {10.3390/antiox15070803},
url = {https://doi.org/10.3390/antiox15070803},
note = {CC BY},
}
RIS
TY - JOUR
TI - Linking Gut Microbiota, Mitochondrial Redox Dysfunction, and Ferroptosis in Cardiometabolic Diseases: A Narrative Review of Mechanistic Evidence and Redox-Targeted Interventions
AU - Yirui Chen
AU - Jingzhi Zhu
AU - Hongxin Gui
AU - Mingyuan Liu
AU - Ye Zhang
AU - Zimu Wu
AU - Chang Liu
AU - Mengyang Wang
PY - 2026
DA - 2026/06/27
JO - Antioxidants
DO - 10.3390/antiox15070803
UR - https://doi.org/10.3390/antiox15070803
AB - Cardiometabolic diseases are increasingly understood as disorders involving compartment-specific redox disruption rather than a uniform excess of reactive oxygen species. This narrative review synthesizes evidence for a proposed gut microbiota-mitochondria ferroptosis framework in which dysbiosis-derived lipopolysaccharide, trimethylamine N-oxide, short-chain fatty acids, bile acids, and tryptophan metabolites may modulate mitochondrial reactive species production, antioxidant defenses, iron handling, lipid peroxide detoxification, and inflammatory signaling. The reference set was assembled through searches of PubMed and Web of Science Core Collection, supplemented by targeted Google Scholar searches and citation chaining during manuscript preparation and revision through June 2026 and was organized around microbial metabolites, mitochondrial redox biology, ferroptosis pathways, disease-specific evidence, and redox-targeted interventions. Because this is a narrative synthesis rather than a systematic review, the framework should be interpreted as hypothesis-generating rather than as a systematically validated pathological model. Across atherosclerosis, diabetic cardiomyopathy, metabolic dysfunction-associated steatotic liver disease, obesity-associated insulin resistance, chronic kidney disease, and cardiorenal metabolic injury, the most consistent mechanistic links involve mtROS, impaired mitophagy, glutathione/GPX4 and SLC7A11 dysfunction, ACSL4-dependent lipid peroxidation, Nrf2 signaling, NLRP3 activation, and cGAS-STING-associated inflammation, although human causal evidence remains uneven. Importantly, much of the current literature supports local links within this sequence rather than a fully verified dysbiosis-metabolite-mitochondria ferroptosis-organ dysfunction chain in the same study. We therefore emphasize evidence tiers, terminology discipline, and biomarker requirements when interpreting ferroptosis-sensitive injury. Polyphenols, flavonoids, probiotics, postbiotics, melatonin, CoQ10-related strategies, mitochondria-targeted antioxidants, and ferroptosis-sensitive approaches may be most translatable when paired with microbiome, metabolomic, lipidomic, pharmacokinetic, and redox biomarkers.
SN - 2076-3921
ER -