The lipotoxicity–ferroptosis axis in the transition from insulin resistance to type 2 diabetes: mechanistic integration and therapeutic opportunities
- 1Changchun University of Chinese Medicine , , ,
- 2The Third Affiliated Hospital of Changchun University of Chinese Medicine , , ,
Abstract
Insulin resistance is an early feature of type 2 diabetes mellitus (T2DM), but progression to persistent hyperglycemia requires failure of pancreatic β-cell compensation. Lipotoxicity develops when adipose storage and oxidative capacity are exceeded, increasing fatty-acid flux and accumulation of ceramides, diacylglycerols, and oxidizable phospholipids in liver, skeletal muscle, and pancreatic islets. Ferroptosis is an iron-dependent form of regulated cell death driven by uncontrolled phospholipid peroxidation. Lipotoxicity can increase ferroptosis susceptibility by enriching polyunsaturated fatty acid-containing membrane phospholipids, increasing organelle-derived reactive oxygen species, and weakening system Xc−–glutathione–glutathione peroxidase 4 defense; however, expansion of a redox-active iron pool is a distinct, cell- and context-dependent requirement. We organize these processes into a four-state working model spanning metabolic compensation, systemic lipid overflow and insulin resistance, ferroptosis sensitization, and β-cell decompensation. This is a non-obligate conceptual trajectory rather than a universally recognized clinical sequence. Evidence is strongest in pancreatic β-cell and liver models; direct skeletal-muscle causality is limited, and a causal role in human T2DM has not been established. Ferroptosis also has cell-specific effects: protecting β cells may be beneficial, whereas ferroptotic removal of selected inflammatory or lipid-storing cell populations can improve metabolic outcomes in some models. Upstream lipid unloading through weight loss and established metabolic treatments has the greatest clinical maturity. ACSL4/LPCAT3-dependent membrane remodeling, GPX4-centered defense, ferritinophagy, labile iron, parallel suppressor systems, and targeted delivery remain predominantly preclinical or candidate approaches. Multidimensional biomarker panels may support future mechanistic studies, but no individual marker or composite panel is currently validated to diagnose ferroptosis or a ferroptosis-susceptible phenotype in T2DM. The lipotoxicity–ferroptosis axis should therefore be viewed as a testable, tissue-specific amplifier rather than a universal or solitary cause of T2DM.
Related
- Redox Dysregulation in the Abdominal Aortic Aneurysm Wall: Ferroptosis and Experimental Therapeutic Opportunities
- The cGAS-STING pathway in metabolic dysfunction-associated steatotic liver disease: mechanistic insights and therapeutic opportunities
- Targeting Ferroptosis in Neurodegenerative Diseases: Therapeutic Potential and Mechanistic Insights of Traditional Chinese Medicine.
- The SLC7A11–ferroptosis axis in BRCA1-mutant breast cancer: current mechanistic evidence, potential therapeutic vulnerabilities, and translational perspectives
- Chronic Inflammation, Fibrotic Remodeling, and Regenerative Failure in Duchenne Muscular Dystrophy: Mechanisms and Therapeutic Opportunities
BibTeX
@article{cui2026lipotoxicityferroptosis,
title = {{The lipotoxicity–ferroptosis axis in the transition from insulin resistance to type 2 diabetes: mechanistic integration and therapeutic opportunities}},
author = {Jianzhong Cui and Hongguang Li and Junying Liu and Mingjun Liu and Jinying Zhao},
journal = {Frontiers in endocrinology},
year = {2026},
month = oct,
doi = {10.3389/fendo.2026.1952532},
url = {https://europepmc.org/article/PMC/PMC13669671},
note = {CC BY},
}
RIS
TY - JOUR
TI - The lipotoxicity–ferroptosis axis in the transition from insulin resistance to type 2 diabetes: mechanistic integration and therapeutic opportunities
AU - Jianzhong Cui
AU - Hongguang Li
AU - Junying Liu
AU - Mingjun Liu
AU - Jinying Zhao
PY - 2026
DA - 2026/10/01
JO - Frontiers in endocrinology
DO - 10.3389/fendo.2026.1952532
UR - https://europepmc.org/article/PMC/PMC13669671
AB - Insulin resistance is an early feature of type 2 diabetes mellitus (T2DM), but progression to persistent hyperglycemia requires failure of pancreatic β-cell compensation. Lipotoxicity develops when adipose storage and oxidative capacity are exceeded, increasing fatty-acid flux and accumulation of ceramides, diacylglycerols, and oxidizable phospholipids in liver, skeletal muscle, and pancreatic islets. Ferroptosis is an iron-dependent form of regulated cell death driven by uncontrolled phospholipid peroxidation. Lipotoxicity can increase ferroptosis susceptibility by enriching polyunsaturated fatty acid-containing membrane phospholipids, increasing organelle-derived reactive oxygen species, and weakening system Xc−–glutathione–glutathione peroxidase 4 defense; however, expansion of a redox-active iron pool is a distinct, cell- and context-dependent requirement. We organize these processes into a four-state working model spanning metabolic compensation, systemic lipid overflow and insulin resistance, ferroptosis sensitization, and β-cell decompensation. This is a non-obligate conceptual trajectory rather than a universally recognized clinical sequence. Evidence is strongest in pancreatic β-cell and liver models; direct skeletal-muscle causality is limited, and a causal role in human T2DM has not been established. Ferroptosis also has cell-specific effects: protecting β cells may be beneficial, whereas ferroptotic removal of selected inflammatory or lipid-storing cell populations can improve metabolic outcomes in some models. Upstream lipid unloading through weight loss and established metabolic treatments has the greatest clinical maturity. ACSL4/LPCAT3-dependent membrane remodeling, GPX4-centered defense, ferritinophagy, labile iron, parallel suppressor systems, and targeted delivery remain predominantly preclinical or candidate approaches. Multidimensional biomarker panels may support future mechanistic studies, but no individual marker or composite panel is currently validated to diagnose ferroptosis or a ferroptosis-susceptible phenotype in T2DM. The lipotoxicity–ferroptosis axis should therefore be viewed as a testable, tissue-specific amplifier rather than a universal or solitary cause of T2DM.
SN - 1664-2392
ER -