Kidney stones are crystalline mineral deposits that are primarily formed in the calyces and pelvis. Calcium-based stones, including calcium oxalate (CaOx) and calcium phosphate (CaP) in pure or mixed phases, are the most prevalent form of nephrolithiasis (Khan et al., 2016). Stone formation results from a cascade of physicochemical processes driven by urinary supersaturation, such as nucleation, growth, aggregation, and retention, often initiated in Randall’s plaques, which serve as nucleation sites (Finlayson, 1978). The global prevalence of nephrolithiasis has increased significantly, with epidemiological studies estimating that nearly 9% of the U.S. population will develop kidney stones during their lifetime (Hill et al., 2022). Clinical manifestations range from hematuria and renal colic to severe complications, such as urinary obstruction, infections, and renal impairment, including both acute kidney injury (AKI) and chronic kidney disease (CKD), depending on the stone location and progression (Sasmaz and Kirpat, 2019; Mulay and Anders, 2017; Ripa et al., 2022; Medina-Escobedo et al., 2022). Current therapeutic approaches include extracorporeal shock wave lithotripsy (SWL; 40%–50% global utilization), ureteroscopy (30%–40%), and percutaneous nephrolithotomy (PCNL; 5%–10%) (Khan et al., 2016). However, the recurrence rates remain high, reaching 50% within 5–10 years and 75% within 20 years of treatment (Siener and Hesse, 2021). Despite advances in basic research, the identification of precise therapeutic targets remains challenging, hindering drug development. The limited progress in developing preventive or therapeutic agents in preclinical and clinical trials underscores the need for comprehensive mechanistic insights into cellular injury during stone formation, which may reveal novel treatment strategies for urolithiasis.

Since Dixon’s initial description of ferroptosis in 2012 as an iron-dependent, non-apoptotic cell death modality driven by lipid reactive oxygen species (ROS) accumulation, this process has been extensively studied in diverse pathological conditions using molecular, morphological, genetic, and immunological approaches (Dixon et al., 2012; Tang et al., 2021). Lipid peroxidation, a hallmark of ferroptosis, is regulated by upstream enzymatic and non-enzymatic reactions, as well as downstream scavenging via the xCT-GSH-GPX4 axis. The non-enzymatic Fenton reaction, associated with iron dysregulation, contributes to ROS generation (Conrad and Pratt, 2019). Enzymatic reactions involve two key lipid-remodeling enzymes: acyl-CoA synthetase long-chain family member 4 (ACSL4) and lysophosphatidylcholine acyltransferase 3 (LPCAT3). These enzymes drive the biosynthesis and modification of phosphatidylethanolamine (PE), a critical phospholipid for ferroptosis (Doll et al., 2017; Dixon et al., 2015), facilitating the remodeling of membrane lipids into polyunsaturated fatty acids (PUFAs) and promoting peroxidation (Kagan et al., 2017). The key downstream regulatory axis of ferroptosis is the cystine/glutamate antiporter (xCT)-glutathione (GSH)-GSH peroxidase 4 (GPX4) pathway, which serves as a central negative regulator. GSH acts as a critical antioxidant and essential cofactor for GPX4, enabling the detoxification of phospholipid peroxides (Dixon et al., 2012; Tang et al., 2021; Dixon et al., 2014). This axis exerts a dual control over ferroptosis by directly and indirectly modulating iron and lipid metabolism. The expression and activity of these regulatory molecules are tightly controlled at the post-transcriptional level during different cellular stages.

Renal tubular epithelial cell (RTEC) injury is an early pathogenic factor in the formation of urinary stones. High concentrations of CaOx crystals trigger ROS generation and oxidative stress, causing inflammatory damage and altering the fate of RTECs. Furthermore, CaOx crystals activate diverse cellular responses, including autophagy, endoplasmic reticulum stress (ERS), and epithelial-mesenchymal transition (EMT), which synergistically contribute to the pathogenesis of urolithiasis. Recent research has highlighted ferroptosis as a critical process that is interconnected with these pathways. In vivo pharmacological experiments by He et al. using the ferroptosis inducer erastin and inhibitor ferrostatin-1 demonstrated that ferroptosis contributes to CaOx stone formation and development via integrated pathophysiological mechanisms (He et al., 2021). Preliminary findings suggest that ferroptosis may be reversible, making it a promising therapeutic target for nephrolithiasis. Despite the growing interest, whether ferroptosis is an initiating factor in stone formation or a secondary consequence of crystal-induced damage remains unknown. We propose that the relationship between ferroptosis and kidney stones is twofold: it can function both as an “active driver” and as a “passive responder.” This review aims to elucidate this critical question from multiple mechanistic perspectives using the most recent experimental evidence. We summarize several core pathways with robust evidence linking ferroptosis and nephrolithiasis, which are discussed in detail below (Figure 1).

Ferroptosis is a specific form of stress-induced cell death in RTECs that responds to different stimuli. The core factors driving ferroptosis are GPX4 dysfunction, iron overload, and oxidative stress. Ferroptosis in RTECs can drive kidney stone formation by creating conditions favorable for the development of stone cores. During ferroptosis, uncontrolled lipid peroxidation disrupts the integrity of the cell membrane, leading to the release of intracellular contents. This triggers local inflammatory responses and reshapes the renal microenvironment. These inflammatory and microenvironmental alterations not only exacerbate RTEC injury but also promote crystal aggregation, adhesion, and deposition, thereby accelerating the initiation and progression of nephrolithiasis. This process forms a vicious cycle of “cellular injury–inflammation–crystal deposition.” Ferroptosis also mediates the downstream biological effects of injury induced by various stone crystals. Persistent mechanical damage and inflammation caused by stone deposition elicit local stress responses in RTECs. This results in an imbalance in iron homeostasis and a lower ferroptosis threshold, aggravating renal tissue injury and chronic inflammation. Consequently, a positive feedback loop is established between stone formation and ferroptosis, driving the progression of kidney disease.

During the initiation and progression of kidney stones, the three core mechanisms of ferroptosis participate in related pathological processes in a coordinated and stage-dependent manner. In the early stages of nephrolithiasis, Beclin-1/ATG6 (BECN1)-nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy disrupts iron homeostasis, resulting in iron overload. This provides abundant iron substrates for lipid peroxidation and promotes crystal nucleation and deposition. Concurrently, activation of the ACSL4-GPX4 axis drives phospholipid peroxidation and compromises cell membrane integrity, establishing a molecular foundation for early stone development. As stone formation progresses to the late injury stage, dysfunction of the xCT-GSH axis and Nrf2/HO-1 pathway causes the collapse of the antioxidant defense system. This increases the sensitivity of RTECs to ferroptosis, exacerbating cellular injury and inflammation. Ultimately, a vicious cycle is established, driving the persistent progression of stone-related renal damage.

RTECs regulate iron homeostasis through coordinated uptake, storage, and export. Iron is primarily taken up via transferrin receptors (TFR), whereas excess iron is exported by ferroportin (FPN) to maintain a dynamic balance (Davaanyam et al., 2023). Surplus iron is stored as ferritin to prevent oxidative stress caused by free iron (Fuhrmann et al., 2020). When required, iron can be released from ferritin through NCOA4-mediated ferritinophagy, supporting cellular metabolism and mitochondrial function (Hou et al., 2016). Disruption of iron metabolism, such as increased iron uptake or impaired iron export, leads to elevated free intracellular iron levels. This excess free iron triggers ROS production via the Fenton reaction, resulting in lipid peroxidation and ferroptosis, and exacerbating tubular epithelial cell injury (Liang et al., 2022; Maus et al., 2023; Zhao et al., 2023) (Figure 2).

Recent studies have demonstrated that NCOA4-mediated autophagy is the primary pathway for the degradation of ferritin. The autophagy regulator BECN1 works with NCOA4 to promote ferritin breakdown and iron release. BECN1, a central regulator of autophagy initiation, serves as a reliable indicator of autophagy activation when upregulated (Cicchini et al., 2014). As the core component of the BECN1-PIK3C3-PIK3R4 complex, BECN1 orchestrates autophagosome formation and vesicular trafficking (Han et al., 2018; Xia et al., 2014). Evidence suggests that BECN1 plays multiple roles in ferroptosis regulation, particularly by inhibiting xCT, revealing a mechanistic link between autophagy and ferroptosis (Guo et al., 2019; Tan et al., 2022; Su et al., 2023; Lee et al., 2022; Song et al., 2018). NCOA4, a selective cargo receptor, mediates ferritin phagocytosis, thereby modulating iron release, storage, and homeostasis (Bogdan et al., 2016). In response to cellular iron demands, NCOA4 directs ferritin towards lysosomal degradation, facilitating iron liberation. This selective autophagy pathway tightly controls intracellular iron levels by regulating ferritin turnover (Mancias et al., 2014). Song et al. demonstrated that CaOx induces ferroptosis in RTECs by activating BECN1-NCOA4-mediated ferritin autophagy (Song et al., 2021). In animal models of kidney stones, upregulated NCOA4 expression and increased iron pools are closely associated with tubular injury, potentially contributing to the formation of a lithogenic microenvironment (Jin et al., 2023). These findings indicate that ferritin autophagy is a critical mechanistic link between autophagy and ferroptosis in kidney stone formation.

Lipid peroxidation is the key molecular mechanism of ferroptosis. Untargeted metabolomics studies have revealed that palmitic acid (PA), a major regulator of intracellular free fatty acid (FFA) metabolism, is the only FFA that is significantly upregulated in patients with CaOx kidney stones compared to healthy controls (Wang et al., 2024a). Several experimentally validated pathways contribute to this process, including the Hippo-YAP/TAZ (36), PPARα-FADS1/2, PKC-PEBP-1/15-LOX (35), and AMPK signaling pathways (Figure 3). These canonical pathways collectively drive lipid metabolism toward the enhanced synthesis of PUFA-containing phospholipids (PUFA-PLs).

Among these regulators, ACSL4 has been identified as a pathologically upregulated molecule in both in vivo and in vitro studies of kidney stone disease. ACSL4-driven lipid peroxidation is a key factor in promoting crystal adhesion, deposition, and ferroptosis-mediated cellular injury in the kidney-stone microenvironment. This is supported by evidence from animal models showing that specific ferroptosis inhibitors reduce the expression of cell adhesion molecules, decrease the levels of ferroptosis-related proteins, and restore cell viability (Wang et al., 2024a). Notably, specific inhibition of ACSL4 by Abemaciclib reduces crystal deposition (Li et al., 2023), whereas the broad ferroptosis inhibitor Ferrostatin-1, which also downregulates ACSL4 expression, primarily alleviates tissue injury (He et al., 2021). These findings strongly support the critical role of ACSL4-mediated lipid peroxidation in the initiation, progression, and injury associated with kidney stone disease. In the following sections, we will focus on the upstream regulatory mechanisms of ACSL4, including the Hippo-YAP/TAZ Pathway and PPARα-FADS1/2 axis, as well as the recently discovered auxiliary regulatory pathways represented by LOX, which synergize with ACSL4 in regulating lipid metabolism.

Ferroptosis, an iron-dependent form of regulated cell death, is characterized by GSH depletion and GPX4 inactivation, both of which are key components of the cellular antioxidant defense system (Hirschhorn and Stockwell, 2019; Mou et al., 2019). In the pathogenesis of CaOx nephrolithiasis, an imbalance between oxidative stress and antioxidant defense drives crystal deposition and renal injury. GPX4 serves as a central node in this process, with its functional collapse resulting from the synergistic action of three major upstream pathways: the Nrf2–GSK3β/GPX4 axis, p53/SLC7A11/GPX4 axis, and ERS–CHAC1/GSH axis. These pathways collectively mediate oxidative membrane damage, promoting crystal nucleation, cell adhesion, and injury to tubular epithelial cells (Figure 4). Among these, Nrf2-GPX4 collapse contributes to the long-term consequences of ferroptosis in RTECs, leading to renal fibrosis. Recent findings have highlighted the reduction in GSH levels induced by ERS, while the role of the P53/SLC7A11/GPX4 axis has been recognized in several studies. As the terminal effector molecule shared by these three regulatory pathways, GPX4 plays a central role in the maintenance of redox homeostasis. In the following sections, we review the three key upstream mechanisms that govern GPX4 regulation.

Recent studies have identified several peripheral regulatory pathways involved in ferroptosis during the formation of kidney stones. These include epigenetic modifications, such as histone methylation and post-translational modifications, including acetylation and ubiquitination, which influence ferroptosis sensitivity. Mechanisms such as EZH2-mediated histone methylation and SIRT1-dependent p53 deacetylation have been directly implicated in kidney stone-related renal injury through ferroptosis regulation.

Epigenetic Modifications: The SOX4-EZH2-SLC7A11 axis plays a crucial role in CaOx crystal-induced renal injury (Yan et al., 2024) (Figure 5). SOX4 upregulates EZH2, leading to H3K27 trimethylation and epigenetic silencing of SLC7A11, thereby promoting ferroptosis and renal damage (Yan et al., 2024). Both genetic knockdown and pharmacological inhibition of EZH2 have shown protective effects against renal injury and ferroptosis in experimental models (Su et al., 2024).

Protein Interactions: CAV1, a membrane scaffolding protein (Nwosu et al., 2016), protects against CaOx-induced renal tubular injury by upregulating LRP6 and activating the Wnt/β-catenin pathway, thereby suppressing autophagy-dependent ferroptosis. CaOx reduces the expression of CAV1, LRP6, and Wnt/β-catenin components, underscoring the protective role of this axis (Yang Y. et al., 2022).

Exosomal Communication: Exosomes facilitate intercellular communication by transferring bioactive molecules between renal tubular cells (Noonin and Thongboonkerd, 2021; Liu W. Z. et al., 2022) (Figure 2). AMBRA1, an autophagy-related protein, has been identified as a ferroptosis biomarker in CaOx-induced nephrolithiasis, highlighting the crosstalk between autophagy and ferroptosis in stone-induced kidney injury. Oxalate-treated cells release AMBRA1-enriched exosomes that promote autophagy and ferroptosis in recipient cells via the PINK1/Parkin pathway and by modulating BECN1(91). These effects were reduced when AMBRA1 was knocked down in exosomes, supporting the role of exosomal AMBRA1 in mitophagy and ferroptosis during CaOx-induced injury. However, direct AMBRA1 depletion in HK-2 cells did not significantly affect basal autophagy or ferroptosis, indicating that its function may be cell context-dependent and requires further investigation (Su et al., 2024).

AMPK Signaling: Although AMPK is a key energy sensor, its involvement in the regulation of ferroptosis remains controversial. In kidney stone disease models, Zhou et al. found that melatonin enhanced mitophagy and AMPK phosphorylation in both rats and oxalate-treated HK-2 cells (Zhou et al., 2023). Mechanistically, melatonin activates the AMPK-PINK1-Parkin pathway, promoting mitophagy and suppressing oxalate-induced ferroptosis. The protective effects of melatonin are lost when AMPK or PINK1 is inhibited, highlighting this pathway as a potential therapeutic target for kidney stone prevention. These findings emphasize the need for further studies to clarify the stage-specific mechanisms of stone disease.

These findings emphasize the need for further studies to clarify the stage-specific mechanisms of ferroptosis and kidney stone formation.

Conventional treatments, such as SWL, ureteroscopic lithotripsy, and PCNL, remain essential for the effective removal of kidney stones in clinical practice. However, these approaches primarily address existing stones and are largely ineffective in preventing the formation of new stones. Recent advances in mechanism-based pharmacological therapies show promise for preventing stone recurrence by targeting the molecular pathways involved in stone pathogenesis (Table 1). These strategies can interrupt the cycles of renal injury, inflammation, and crystal deposition. Specifically, the inhibition of ferroptosis-mediated tubular damage may help prevent disease progression and recurrence. These pharmacological advances have the potential to complement existing surgical interventions and improve the long-term outcomes of patients with kidney stones. However, further studies are required to comprehensively assess the potential nephrotoxicity of these agents before their widespread use in clinical settings.

Dimethyl fumarate (DMF), an oral Nrf2 activator approved for multiple sclerosis treatment, enhances antioxidant defense by activating the Nrf2–GPX4 pathway in the liver. DMF inhibits lipid peroxidation and ferroptosis by upregulating GPX4 expression. Although its clinical use in nephrolithiasis remains unknown, DMF has shown renoprotective effects in preclinical models, suggesting potential to mitigate kidney stone-induced damage (Zhen et al., 2021). Other Nrf2 activators, such as omaveloxolone (OMA), widely used in the treatment of Friedreich ataxia, may exert renoprotective effects through similar mechanisms. However, their efficacy in kidney stone management requires further investigation (Lynch et al., 2021). Rosiglitazone, a PPAR-γ agonist used in type 2 diabetes mellitus management (Balfour and Plosker, 1999), downregulates ACSL4 expression by activating PPAR-γ, thereby reducing PUFA-PE production. In ischemia-reperfusion-induced kidney injury models, rosiglitazone decreases ferroptosis markers and protects renal tissues, providing a potential therapeutic strategy for kidney stone-related renal damage (Wang et al., 2016).

Several therapeutic candidates are currently in clinical trials, indicating progress in the management of kidney stone-related injuries. Pharmacological agents approved for other clinical indications are being investigated for their potential renoprotective effects in nephrolithiasis. Bardoxolone methyl enhances Nrf2 activity by inhibiting Keap1, thereby reducing oxidative stress and kidney injury. It also suppresses the NF-κB pathway, decreasing proinflammatory cytokine production and crystal-induced inflammation (Ruiz et al., 2013; Wang et al., 2014). These effects may help prevent complications of nephrolithiasis. Bardoxolone methyl is currently undergoing clinical trials to evaluate its long-term safety and efficacy in patients with CKD. Pemafibrate (K-877), a novel selective PPARα modulator (SPPARMα) that improves lipid metabolism, has completed phase 3 trials, advancing next-generation fibrate therapy (Maki et al., 2017). A recent case-control study demonstrated that K-877 significantly reduced the risk of cardiovascular events in patients with CKD, highlighting the therapeutic potential of fibrates in kidney disease (Goto et al., 2024).

Several emerging therapeutic agents and strategies remain in the preclinical stage. The ferroptosis inhibitor liproxstatin-1 and mitochondria-targeted antioxidant XJB-5-131 have shown efficacy in animal models of AKI (Yang K. et al., 2022; Chen et al., 2023; Shi et al., 2024; Zhao et al., 2020). GW7647, a selective PPARα agonist, and SC-26196, a FADS1 inhibitor, are currently limited to laboratory studies (Qu et al., 2022; Li et al., 2025). The experimental plant flavonoid luteolin and the ALDH2 activator Alda-1 have demonstrated potential in vitro and in animal studies (Ye et al., 2025; Zhang et al., 2025). Gene editing approaches, such as CRISPR-dCas13d-eIF4G, have been investigated in cell and animal models of CaOx-induced kidney injury, but their clinical application is lacking (He et al., 2024). Other novel pathways and targets, including cGAS-STING signaling, DHODH, FSP1, and GSH metabolic regulation, remain in the early stages of experimental investigation (Liang et al., 2023).

Ferroptosis, an iron-dependent form of regulated cell death mediated by lipid peroxidation, plays a crucial role in the pathogenesis of kidney stones. Evidence suggests that ferroptosis is associated with renal tubular epithelial injury, oxidative stress, iron and lipid metabolic disorders, and impaired antioxidant defenses. This creates a cycle that promotes crystal adhesion, aggregation, and persistent inflammation in the case of nephrolithiasis. The core mechanisms include BECN1-NCOA4-mediated ferritinophagy, which disrupts iron homeostasis, ACSL4-driven lipid peroxidation, and collapse of the GPX4-centered antioxidant system. Upstream regulation involves the Hippo-YAP/TAZ pathway, PPARα-FADS1/2 axis, PKCζ-PEBP1/15-LOX pathway, and epigenetic modifications such as SOX4-EZH2-SLC7A11 and SIRT1-p53 signaling. Finally, clinical and preclinical evidence highlights the translational potential of emerging therapeutic strategies targeting ferroptosis, including the repurposing of clinically approved drugs and the development of novel preclinical candidates.