Ferroptosis and Innate Immunity in a Vicious Cycle: Emerging Therapeutic Target for Diabetic Kidney Disease
Background
Diabetic kidney disease (DKD) is a major cause of end-stage renal disease worldwide. Despite aggressive management of blood glucose and blood pressure and the use of renoprotective medications, some patients continue to experience declining kidney function, indicating the presence of residual risk that cannot be explained by metabolic disturbances and glomerular pressure alone.
A recently emerging pathological mechanism is ferroptosis, a regulated form of cell death caused by iron-dependent lipid peroxidation. When polyunsaturated fatty acids in cell membranes are oxidized and antioxidant defenses are compromised, cells suffer irreversible damage. The kidney, with its high oxygen consumption and lipid metabolic activity, is particularly vulnerable to such oxidative injury. Evidence from animal and cell models has accumulated showing that ferroptosis contributes to tubular and glomerular injury, but its stage of operation in human DKD and predictive biomarkers of therapeutic response remain unclear.
This review shifts the perspective from viewing ferroptosis as an isolated cell death phenomenon to framing it as a pathological axis that interacts and amplifies with innate immune responses. Rather than reporting new clinical trial results, it connects preclinical and molecular biological evidence to propose therapeutic targets and validation challenges.
Key Findings
The central concept proposed by the researchers is the 'ferroptosis-immunity feedback loop.' In a diabetic environment, disrupted iron homeostasis and increased reactive oxygen species lead to lipid peroxidation. When the protective capacity of glutathione peroxidase 4 (GPX4) declines or the activity of acyl-CoA synthetase long-chain family member 4 (ACSL4)—which incorporates oxidation-prone fatty acids into membrane phospholipids—increases, renal cells become more susceptible to ferroptosis.
Ferroptotic cells release damage-associated molecular patterns (DAMPs), including high-mobility group box 1 (HMGB1), which stimulate toll-like receptor 4 (TLR4) signaling and NLRP3 inflammasome activation, promoting M1 macrophage polarization, neutrophil infiltration, and dendritic cell maturation. Inflammatory signals such as interleukin-18 (IL-18) following NLRP3 activation further increase oxidative stress and disrupt iron metabolism, creating a self-amplifying circuit between cell death and inflammation.
The authors suggest that five categories of candidate biomarkers—GPX4 depletion, ACSL4 expression, lipid peroxidation products, IL-18, and NLRP3 activation—could be used for early risk assessment and patient stratification. Potential therapeutic candidates include ferroptosis inhibitors, iron chelators, GPX4 modulation strategies, TLR4/NLRP3 immunomodulators, kidney-targeted nanoparticles, and CRISPR-based regulation. The key proposal is a combination strategy that simultaneously reduces both ferroptosis and inflammation, rather than targeting only one aspect.
Implications and Outlook
This perspective broadens the therapeutic goals for DKD from glucose and blood pressure control to the disruption of injury-amplifying circuits. Combining multi-omics data with artificial intelligence (AI) could allow for the molecular classification of patients into ferroptosis-dominant or inflammation-dominant subtypes, enabling the design of rational combination therapies. If biomarkers measurable through repeated urine or blood tests are established, it may become possible to identify high-risk individuals before significant kidney function decline occurs.
However, much of the current evidence comes from cultured cells, animal models, and association analyses. Whether changes in GPX4 or ACSL4 are causal or a result of disease progression still needs to be confirmed in humans. Standardized measurement methods and criteria for candidate biomarkers are lacking, and long-term follow-up data are insufficient. Systemic ferroptosis inhibition or immune suppression may interfere with normal infection defense and iron metabolism, so renal-cell-specific targeting and long-term safety evaluations are essential. Clinical value can only be assessed when confirmed in prospective patient cohorts and randomized clinical trials.
SIGNIFICANCE: Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease worldwide. Its burden continues to increase despite advances in glycemic and blood pressure control. This persistent risk highlights the need for therapeutic strategies that address injury-amplifying mechanisms beyond conventional metabolic and hemodynamic pathways. Ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation, has emerged as a contributor to renal injury in DKD. However, its precise role in human disease is incompletely defined. RECENT ADVANCES: Ferroptosis is closely linked to lipid peroxidation-derived danger signals that promote innate immune activation, including M1 macrophage polarization, neutrophil infiltration, dendritic-cell maturation, TLR4 signaling, and NLRP3 inflammasome activation. Ferroptotic cells release damage-associated molecular patterns, including HMGB1, which activate inflammatory cascades. In turn, inflammatory cytokines disrupt iron homeostasis, increase oxidative stress, and further sensitize renal cells to ferroptosis, forming a self-amplifying ferroptosis-immunity feedback loop. CRITICAL ISSUES: Candidate biomarkers, including GPX4 depletion, ACSL4 expression, lipid peroxidation products, interleukin-18, and NLRP3 activation, may support earlier risk assessment and patient stratification. However, clinical validation is limited, and standardized biomarker thresholds, longitudinal human data, renal-cell-specific targeting, and long-term safety data are still lacking. FUTURE DIRECTIONS: Therapeutic strategies under investigation include ferroptosis inhibitors, iron chelators, GPX4-directed approaches, TLR4/NLRP3-targeted immunomodulators, kidney-targeted nanoparticles, and CRISPR-based modulation of ferroptosis regulators. Multiomics profiling and artificial intelligence may further support rational combination therapies. Targeting the ferroptosis-immunity axis alongside optimal glycemic control may provide a
Clinically, urine lipid peroxidation products and serum IL-18 could be considered alongside existing albuminuria and estimated glomerular filtration rate tests to identify patients at high risk of kidney function decline. For patients who have undergone kidney biopsy, GPX4, ACSL4, and NLRP3 activity could be measured together to determine whether they have ferroptosis-inflammation dominant DKD, which could be used as criteria for clinical trial enrollment.
Industrial applications are likely to focus on nanoparticles that selectively accumulate in the kidney and carry ferroptosis inhibitors or NLRP3 modulators. However, candidate biomarkers have not yet been clinically validated, and the proposed therapies are not standard treatments. In early development stages, it is essential to evaluate not only target tissue delivery but also infection risk, iron accumulation, and long-term disruption of antioxidant defenses.