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Background <p>Ischemia-reperfusion acute kidney injury (IRI-AKI) is a common critical clinical condition characterized by high morbidity and mortality. Renal tubular epithelial cells (TECs) ferroptosis plays a key role in the pathogenesis of IRI-AKI. We observed that olfactomedin 4 (OLFM4) expressed in TECs and was downregulated in the kidney of AKI patients. And the downregulation of OLFM4 was correlated with TECs ferroptosis. Therefore, our present study intended to clarify the role and mechanism of OLFM4 in TEC ferroptosis and IRI-AKI.</p> Methods <p>OLFM4-deficient HK-2 cell lines and OLFM4<sup>−/−</sup> mice were generated. In vitro hypoxia/reoxygenation (H/R) TECs model and IRI-AKI mouse models, were employed. Renal injury and ferroptosis-related markers were evaluated by immunofluorescence, Western blotting, and biochemical assays to evaluate the role of OLFM4 in TECs ferroptosis. Molecular docking, co-immunoprecipitation (Co-IP), and yeast two-hybrid assays were performed to identify the mechanism of OLFM4 on ferroptosis pathway.</p> Results <p>OLFM4 was markedly downregulated in renal tissues of IRI-AKI mice and HK-2 cells subjected to H/R. OLFM4 deficiency aggravated renal function impairment of the IRI-AKI mice (Cr, BUN), accompanied by elevated ferroptosis markers (Fe<sup>²⁺</sup>, ROS, and MDA) and reduced GSH, whereas OLFM4 overexpression ameliorated IRI-AKI and suppressed TECs ferroptosis. Additionally, we demonstrated that OLFM4 stabilizes GPX4 by inhibiting its ubiquitination, and GPX4 is a key molecule in the occurrence of ferroptosis. The overexpression of OLFM4 upregulating GPX4 expression, enhancing antioxidant defenses, and attenuating TECs ferroptosis in H/R HK-2 cell model and IRI-AKI mice.</p> Conclusions <p>Our present study demonstrates that OLFM4 reduction play an important role in IRI-AKI occurrence. Overexpression could protect IRI-AKI by reducing TEC ferroptosis via GPX4. For the first time, OLFM4 is identified as a ferroptosis suppressor, expanding our understanding of AKI pathogenesis, and highlighting OLFM4 as a potential therapeutic target.</p>

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OLFM4 mediating ischemia/reperfusion-induced kidney injury by regulating renal tubular epithelial cells ferroptosis via GPX4

  • 期刊论文

  • 发表日期：

    2026年4月25日

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  • Zehao Zhang,
  • Yaqi Wang,
  • Zhiqiang Mu,
  • Sheng Zhao,
  • Tingting Zhang,
  • Ziqi Zhang,
  • Shiren Sun,
  • Ming Bai

摘要

Background

Ischemia-reperfusion acute kidney injury (IRI-AKI) is a common critical clinical condition characterized by high morbidity and mortality. Renal tubular epithelial cells (TECs) ferroptosis plays a key role in the pathogenesis of IRI-AKI. We observed that olfactomedin 4 (OLFM4) expressed in TECs and was downregulated in the kidney of AKI patients. And the downregulation of OLFM4 was correlated with TECs ferroptosis. Therefore, our present study intended to clarify the role and mechanism of OLFM4 in TEC ferroptosis and IRI-AKI.

Methods

OLFM4-deficient HK-2 cell lines and OLFM4−/− mice were generated. In vitro hypoxia/reoxygenation (H/R) TECs model and IRI-AKI mouse models, were employed. Renal injury and ferroptosis-related markers were evaluated by immunofluorescence, Western blotting, and biochemical assays to evaluate the role of OLFM4 in TECs ferroptosis. Molecular docking, co-immunoprecipitation (Co-IP), and yeast two-hybrid assays were performed to identify the mechanism of OLFM4 on ferroptosis pathway.

Results

OLFM4 was markedly downregulated in renal tissues of IRI-AKI mice and HK-2 cells subjected to H/R. OLFM4 deficiency aggravated renal function impairment of the IRI-AKI mice (Cr, BUN), accompanied by elevated ferroptosis markers (Fe²⁺, ROS, and MDA) and reduced GSH, whereas OLFM4 overexpression ameliorated IRI-AKI and suppressed TECs ferroptosis. Additionally, we demonstrated that OLFM4 stabilizes GPX4 by inhibiting its ubiquitination, and GPX4 is a key molecule in the occurrence of ferroptosis. The overexpression of OLFM4 upregulating GPX4 expression, enhancing antioxidant defenses, and attenuating TECs ferroptosis in H/R HK-2 cell model and IRI-AKI mice.

Conclusions

Our present study demonstrates that OLFM4 reduction play an important role in IRI-AKI occurrence. Overexpression could protect IRI-AKI by reducing TEC ferroptosis via GPX4. For the first time, OLFM4 is identified as a ferroptosis suppressor, expanding our understanding of AKI pathogenesis, and highlighting OLFM4 as a potential therapeutic target.