Ferroptosis-related proteins ALOX15 and HMOX1 are upregulated and associated with inflammation in patients with diabetic nephropathy: a prospective cross-sectional study.

PURPOSE: To delineate the renal expression of ferroptosis-driving proteins ALOX15 and HMOX1 in DN and to determine their relationship with intra-renal inflammatory activity.

METHODS

In this prospective, single-centre cross-sectional study, 150 consecutive biopsy-proven DN patients and 150 age- and sex-matched type 2 diabetes mellitus (T2DM) controls without nephropathy were enrolled between April 2021 and April 2025. After identifying the intersection of ferroptosis- and DN-related transcriptomic signatures by integrative bioinformatics, Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway enrichment was performed. Demographics, routine biochemistry and concurrent inflammatory indices were captured. Serum concentrations of ALOX15, HMOX1, IL-1β, IL-6 and TNF-α were quantified in duplicate by validated high-sensitivity ELISA.

RESULTS

Compared with T2DM controls, DN patients exhibited a longer diabetes duration, higher fasting plasma glucose (FBG), glycated haemoglobin (HbA1c), serum creatinine (Scr), blood urea nitrogen (BUN) and urine albumin-to-creatinine ratio (UACR), and a markedly lower estimated glomerular filtration rate (eGFR) (all P < 0.05). Circulating ALOX15 and HMOX1 were significantly elevated in DN (both P < 0.05). Multivariable logistic regression identified increased Scr, UACR, ALOX15 and HMOX1, together with reduced eGFR, as independent risk factors for DN (all P < 0.05). ROC analysis revealed AUCs of 0.750, 0.726 and 0.881 for ALOX15 alone, HMOX1 alone and their combination, respectively, in predicting DN. Both ferroptosis markers correlated positively with IL-1β, IL-6 and TNF-α (all P < 0.001).

CONCLUSION

ALOX15 and HMOX1 are markedly up-regulated in DN and tightly linked to systemic inflammation. Their combined quantification offers robust diagnostic performance and positions these ferroptosis executors as candidate therapeutic targets for early interception of DN.