ACAA1 mediates arachidonic acid dysregulation and membrane phospholipid remodeling to promote crystal-cell adhesion and ferroptosis susceptibility in calcium oxalate kidney stone

Qinhong Jiang; Yanqi Xie; Chao Song; Caitao Dong; Wenbiao Liao; Qianlin Song; Xiaozhe Su; Heng Xiang; Yunhan Wang; Bobo Cheng; Ziqi He; Sixing Yang

doi:10.1016/j.jpha.2025.101470

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Qinhong Jiang, Yanqi Xie, Chao Song, Caitao Dong, Wenbiao Liao, Qianlin Song, Xiaozhe Su, Heng Xiang, Yunhan Wang, Bobo Cheng, Ziqi He, Sixing Yang. ACAA1 mediates arachidonic acid dysregulation and membrane phospholipid remodeling to promote crystal-cell adhesion and ferroptosis susceptibility in calcium oxalate kidney stone[J]. Journal of Pharmaceutical Analysis. doi: 10.1016/j.jpha.2025.101470

Citation:

Qinhong Jiang, Yanqi Xie, Chao Song, Caitao Dong, Wenbiao Liao, Qianlin Song, Xiaozhe Su, Heng Xiang, Yunhan Wang, Bobo Cheng, Ziqi He, Sixing Yang. ACAA1 mediates arachidonic acid dysregulation and membrane phospholipid remodeling to promote crystal-cell adhesion and ferroptosis susceptibility in calcium oxalate kidney stone[J]. Journal of Pharmaceutical Analysis. doi: 10.1016/j.jpha.2025.101470

Citation:

Qinhong Jiang, Yanqi Xie, Chao Song, Caitao Dong, Wenbiao Liao, Qianlin Song, Xiaozhe Su, Heng Xiang, Yunhan Wang, Bobo Cheng, Ziqi He, Sixing Yang. ACAA1 mediates arachidonic acid dysregulation and membrane phospholipid remodeling to promote crystal-cell adhesion and ferroptosis susceptibility in calcium oxalate kidney stone[J]. Journal of Pharmaceutical Analysis. doi: 10.1016/j.jpha.2025.101470

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ACAA1 mediates arachidonic acid dysregulation and membrane phospholipid remodeling to promote crystal-cell adhesion and ferroptosis susceptibility in calcium oxalate kidney stone

doi: 10.1016/j.jpha.2025.101470

a. Department of Urology, Renmin Hospital of Wuhan University, Wuhan University School of Medicine, Wuhan, 430000, China;
b. Department of Urology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China;
c. Hubei Provincial Clinical Research Center for Urolithiasis, Wuhan, 430000, China

Funds:

This work was supported by the National Natural Science Foundation of China (Grant No.: 82270797), the Natural Science Foundation of Hubei Province, China (Grant No.: 2022CFC020), Nature Science Foundation of Hubei Province, China (Grant No.: 2023AFB752) and the Open Projects Funds for the Research Base of Regulatory Science for Medical Devices of Wuhan University, National Medical Products Administration, China (Grant No.: 2023JDKF002).

Received Date: Jan. 19, 2025
Accepted Date: Oct. 09, 2025
Rev Recd Date: Oct. 08, 2025
Available Online: Oct. 13, 2025

Abstract

Abstract

Crystal adhesion is a key process in the formation of kidney stones, playing a synergistic role at every crystallization stage. Damage to the renal tubular epithelial cell (RTEC) membrane provides essential sites for crystal adhesion. During the terminal phase of ferroptosis, accumulated polyunsaturated phospholipids integrate into the cell membrane, leading to membrane damage and deformation, which may be an important mechanism in calcium oxalate (CaOx) crystallization. In this study, targeted peroxidomics analysis revealed a significant increase in arachidonic acid (AA) levels in a CaOx kidney stone model. Meanwhile, transcriptomic analysis indicated that the key enzyme in fatty acid metabolism, acetyl-coenzyme A (CoA) acyltransferase 1 (ACAA1), was significantly downregulated in the CaOx kidney stone model. Besides, overexpression of ACAA1 (OE-ACAA1) alleviated AA accumulation and reduced oxalate (Ox)-induced RTEC ferroptosis. Notably, the OE-ACAA1 alleviated the accumulation of AA-containing polyunsaturated phospholipids without regulating acyl-CoA synthetase long-chain family member 4 (ACSL4) expression, thereby reducing membrane peroxidative damage and crystal adhesion. Furthermore, transcription factor array analysis identified the downregulation of activating transcription factor 1 (ATF1), an upstream transcriptional regulator of ACAA1, which might be involved in the transcriptional repression of ACAA1. Finally, OE-ATF1 partially alleviated Ox-induced RTEC membrane peroxidative damage and crystal adhesion. These findings demonstrated that ferroptosis participates in the early crystallization process by mediating RTEC membrane peroxidative damage and provided a novel approach to influencing downstream lipid peroxidation by regulating fatty acid activation substrates rather than ACSL4. Therefore, this study offers potential therapeutic targets for the prevention and treatment of CaOx kidney stones.
- Kidney stone,
- Ferroptosis,
- Lipid dysregulation,
- Arachidonic acid,
- ACAA1,
- ATF1

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References(50)

References

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