Roles of ACSL4/GPX4 and FSP1 in oxalate-induced acute kidney injury
Abstract Ferroptosis has emerged as a crucial driver of injury in various organs, including acute kidney injury (AKI). However, the regulatory roles and underlying mechanisms of key genes involved in ferroptosis during oxalate-induced AKI are not fully understood. In this study, we conducted single-...
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Nature Publishing Group
2025-06-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-025-02557-y |
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| author | Keng Ye Ruilong Lan Zhimin Chen Kunmei Lai Yankun Song Guoping Li Huabin Ma Hong Chen Yanfang Xu |
| author_facet | Keng Ye Ruilong Lan Zhimin Chen Kunmei Lai Yankun Song Guoping Li Huabin Ma Hong Chen Yanfang Xu |
| author_sort | Keng Ye |
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| description | Abstract Ferroptosis has emerged as a crucial driver of injury in various organs, including acute kidney injury (AKI). However, the regulatory roles and underlying mechanisms of key genes involved in ferroptosis during oxalate-induced AKI are not fully understood. In this study, we conducted single-cell RNA sequencing (scRNA-seq) analysis of kidney samples, revealing the occurrence of ferroptosis in renal tubular cells of an oxalate-induced AKI mouse model, which was confirmed in subsequent in vitro experiments. Furthermore, renal tubule-specific deficiency of Acsl4 conferred significant protection against oxalate-induced AKI, as evidenced by alleviated structural and functional renal damage, reduced oxidative stress and decreased inflammatory cell infiltration, all of which collectively contribute to a reduction in ferroptosis. In contrast, Fsp1 deficiency exacerbated these pathological processes. Consistent with the in vivo findings, Acsl4 knockout in mouse renal tubular epithelial cell lines (MTECs) resulted in decreased lipid peroxidation and mitigation of mitochondrial dysfunction, thus reducing calcium oxalate (CaOX)-induced ferroptosis. Conversely, Fsp1 knockout in MTECs had the opposite effects. In addition, as expected, overexpression of the ferroptosis inhibitors GPX4 or FSP1 in MTECs significantly reduced CaOX-induced lipid peroxidation and cell ferroptosis. In summary, these findings indicated that oxalate exposure upregulated ferroptosis driver ACSL4 and downregulated inhibitors like GPX4 and FSP1, leading to lipid peroxidation and mitochondrial dysfunction, which collectively triggered ferroptosis in renal tubular cells. Modulating ACSL4/GPX4 and FSP1 axes presents a promising therapeutic strategy for oxalate-induced AKI. |
| format | Article |
| id | doaj-art-caee59b9683a47e6ad7781d828fa3259 |
| institution | OA Journals |
| issn | 2058-7716 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Nature Publishing Group |
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| series | Cell Death Discovery |
| spelling | doaj-art-caee59b9683a47e6ad7781d828fa32592025-08-20T02:10:34ZengNature Publishing GroupCell Death Discovery2058-77162025-06-0111111210.1038/s41420-025-02557-yRoles of ACSL4/GPX4 and FSP1 in oxalate-induced acute kidney injuryKeng Ye0Ruilong Lan1Zhimin Chen2Kunmei Lai3Yankun Song4Guoping Li5Huabin Ma6Hong Chen7Yanfang Xu8Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical UniversityCentral Laboratory, the First Affiliated Hospital, Fujian Medical UniversityDepartment of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical UniversityDepartment of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical UniversityDepartment of Pathology, the First Affiliated Hospital, Fujian Medical UniversityDepartment of Pathology, the First Affiliated Hospital, Fujian Medical UniversityCentral Laboratory, the First Affiliated Hospital, Fujian Medical UniversityDepartment of Pathology, the First Affiliated Hospital, Fujian Medical UniversityDepartment of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical UniversityAbstract Ferroptosis has emerged as a crucial driver of injury in various organs, including acute kidney injury (AKI). However, the regulatory roles and underlying mechanisms of key genes involved in ferroptosis during oxalate-induced AKI are not fully understood. In this study, we conducted single-cell RNA sequencing (scRNA-seq) analysis of kidney samples, revealing the occurrence of ferroptosis in renal tubular cells of an oxalate-induced AKI mouse model, which was confirmed in subsequent in vitro experiments. Furthermore, renal tubule-specific deficiency of Acsl4 conferred significant protection against oxalate-induced AKI, as evidenced by alleviated structural and functional renal damage, reduced oxidative stress and decreased inflammatory cell infiltration, all of which collectively contribute to a reduction in ferroptosis. In contrast, Fsp1 deficiency exacerbated these pathological processes. Consistent with the in vivo findings, Acsl4 knockout in mouse renal tubular epithelial cell lines (MTECs) resulted in decreased lipid peroxidation and mitigation of mitochondrial dysfunction, thus reducing calcium oxalate (CaOX)-induced ferroptosis. Conversely, Fsp1 knockout in MTECs had the opposite effects. In addition, as expected, overexpression of the ferroptosis inhibitors GPX4 or FSP1 in MTECs significantly reduced CaOX-induced lipid peroxidation and cell ferroptosis. In summary, these findings indicated that oxalate exposure upregulated ferroptosis driver ACSL4 and downregulated inhibitors like GPX4 and FSP1, leading to lipid peroxidation and mitochondrial dysfunction, which collectively triggered ferroptosis in renal tubular cells. Modulating ACSL4/GPX4 and FSP1 axes presents a promising therapeutic strategy for oxalate-induced AKI.https://doi.org/10.1038/s41420-025-02557-y |
| spellingShingle | Keng Ye Ruilong Lan Zhimin Chen Kunmei Lai Yankun Song Guoping Li Huabin Ma Hong Chen Yanfang Xu Roles of ACSL4/GPX4 and FSP1 in oxalate-induced acute kidney injury Cell Death Discovery |
| title | Roles of ACSL4/GPX4 and FSP1 in oxalate-induced acute kidney injury |
| title_full | Roles of ACSL4/GPX4 and FSP1 in oxalate-induced acute kidney injury |
| title_fullStr | Roles of ACSL4/GPX4 and FSP1 in oxalate-induced acute kidney injury |
| title_full_unstemmed | Roles of ACSL4/GPX4 and FSP1 in oxalate-induced acute kidney injury |
| title_short | Roles of ACSL4/GPX4 and FSP1 in oxalate-induced acute kidney injury |
| title_sort | roles of acsl4 gpx4 and fsp1 in oxalate induced acute kidney injury |
| url | https://doi.org/10.1038/s41420-025-02557-y |
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