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. 2025 Dec 11.
doi: 10.1007/s11255-025-04949-6. Online ahead of print.

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

Wei Zhao  1 , Yuxin Liu  2 , Chao Zhang  1 , Kaifa Luo  1 , Panpan Liu  1 , Jinghua Wang  1 , Xudong Huang  1 , Yunshuang Chen  1 , Guangli Wu  1 , Xinjun Yang  3 , Lihui Wang  4
Affiliations

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

Wei Zhao et al. Int Urol Nephrol. .

Abstract

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.

Keywords: ALOX15; Diabetic nephropathy; HMOX1; Inflammatory cytokines; Type 2 diabetes mellitus.

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Conflict of interest statement

Declarations. Conflict of interest: The authors declare no competing interests. Ethical approval: This study involving human participants was conducted in accordance with the Declaration of Helsinki and received ethical approval from the Bethune International Peace Hospital (Approval Number: 2021-KY-16). Written informed consent was obtained from all participants, ensuring their confidentiality and anonymity throughout the research process.

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