The lipotoxicity–ferroptosis axis in the transition from insulin resistance to type 2 diabetes: mechanistic integration and therapeutic opportunities

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.