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

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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. • In CaOx kidney stone model, accumulation of AA and its downstream metabolites exacerbates ferroptosis and oxidative stress in RTECs. • The key fatty acid β-oxidation enzyme ACAA1 is downregulated in a lithogenic environment,which enhances RTEC ferroptosis susceptibility by altering the fatty acid activation substrate AA, rather than directly regulating ACSL4. • ACAA1 downregulation in a lithogenic environment mediates phospholipid remodeling, increasing the abundance of polyunsaturated phospholipids, which integrate into the cell membrane, promoting crystal-cell adhesion. • ATF1, an upstream regulator of ACAA1, is downregulated in a lithogenic environment, contributing to the transcriptional repression of ACAA1. • Modulation of ATF1 alters ferroptosis susceptibility and crystal-cell adhesion in RTECs in a kidney stone model.

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