Accumulating evidence demonstrates that the ferroptosis-kidney stone formation loop is a core pathogenic mechanism driving kidney injury and disease progression. This loop has been proposed as a promising therapeutic target, and disrupting it via various inhibitors may produce protective effects.

First, the lipid peroxidation end-products, MDA and 4-hydroxynonenal (4-HNE), along with DAMPs released from ferroptotic cells, activate NF-κB signaling, which in turn promotes the secretion of pro-inflammatory cytokines (TNF-α, IL-6 and IL-1β). These inflammatory mediators exacerbate RTEC injury, create conditions for crystal deposition and further lower the ferroptosis threshold, completing a positive feedback loop (3,25,96). A number of protective agents, such as lycopene, curcumin and mesenchymal stem cells, exert their anti-inflammatory, antioxidant and renoprotective effects precisely by inhibiting NF-κB activation (97-100). Animal studies have indicated that suppressing the NF-κB signaling pathway represents a potentially effective therapeutic strategy for CaOx nephrolithiasis (101,102).

Second, ferroptotic RTECs release DAMPs [high mobility group box 1 (HMGB1), ATP, DNA, mitochondrial DNA, oxidized phospholipids and MDA] that activate the innate immune response, recruiting and activating macrophages. These macrophages secrete mediators, such as macrophage inhibitory protein-1, monocyte chemoattractant protein-1 and IL-8, leading to interstitial inflammation (3). Critically, inflammatory factors released by macrophages act back on RTECs, upregulating adhesion molecules (CD44, osteopontin and hyaluronic acid) on the surface of ferroptosis-susceptible RTECs, promoting crystal adhesion and disposition. This immune-amplification loop contributes to Randall's plaque formation and the transition to fibrosis.

Third, during ferroptosis the 'wave of death' phenomenon amplifies the loop spatially (3,103). When a proximal RTEC undergoes ferroptosis, NADPH diffuses from adjacent cells to the dead cell via gap junctions and tight junctions, reducing the antioxidant capacity of neighboring cells and rendering them more susceptible to ferroptosis. This chain reaction causes large-area tubular damage, releasing more DAMPs and lipid peroxidation products, and further amplifying inflammation (3), in turns promote kidney stone formation. GPX4 serves as a critical negative regulator of the vicious cycle of cellular injury; however, its loss amplifies this feedback loop. GPX4 deficiency exacerbates TGF-β1 production and fibrosis, while elevated GPX4 attenuates NF-κB activation (3,29,44).

In summary, these findings indicated that the ferroptosis-kidney stone formation loop, driven by lipid peroxidation, inflammatory amplification and intercellular propagation, constitutes a key pathogenic mechanism in renal injury and stone disease, and that targeted disruption of this vicious cycle, particularly by GPX4 restoration or NF-κB inhibition, represents a promising therapeutic strategy for clinical intervention.

Ferroptosis can be therapeutically targeted by a couple of small molecules, including natural products and synthetic chemical compounds, which are collectively referred to as ferrostatins. The restoration of this axis via ferrostatin-1, Nrf2 activators or melatonin reinstates GPX4 activity, limits lipid peroxidation, and attenuates CaOx-induced injury and stone formation, thereby identifying the GSH-GPX4 axis as a feasible therapeutic target for nephrolithiasis (2,57,83,84,91,104-106). Several high-quality compounds with acceptable pharmacodynamic and pharmacokinetic properties are currently under development (16,107), and the initiation of clinical trials appears imminent.

Fer-1, as a lead molecule, inhibits ferroptosis by scavenging initiating alkoxyl radicals produced by ferrous iron from lipid hydroperoxides (107). In both in vivo and in vitro models, Fer-1 upregulates the key ferroptosis regulators GPX4 and SLC7A11, downregulates HO-1 and SOD2, attenuates mitochondrial damage, reduces ROS levels and lipid peroxidation, decreases tubular epithelial cell apoptosis and renal tissue injury, reverses the aberrant expression of fibrosis markers including E-cadherin, vimentin and α-SMA, and significantly suppresses CaOx crystal deposition (108). In CaOx models, Fer-1 partially restores the downregulated expression of the hub ferroptosis-related genes lysosome-associated membrane protein 2 and mouse double minute 4, which further enhances its protective effects against oxalate-induced kidney injury and stone formation (109).

However, Fer-1 has a low in vivo functionality due to potential metabolic and plasma instability. Multiple attempts have been made to improve the potency of this type of molecule (110). A more stable and readily soluble series of Fer-1 analogues have been synthesized in recent studies (110-115). The Fer-1 analog, XJB-5-131, exhibits low nanomolar efficacy against erastin- and RSL3-induced ferroptosis, as well as ferroptosis in AKI and subsequent chronic kidney disease (116). By contrast, has been shown to JP4-039 display significantly higher EC50 values of 3.58 and 1.27 μM, correlating with its lower mitochondrial enrichment (117,118). XJB-5-131 and JP4-039 are multifunctional mitochondria-targeted protective molecules that have been shown to exert tissue-protective effects in various disease models by inhibiting ferroptosis, scavenging ROS, preventing apoptosis and promoting mitophagy (116-120).

New analogues, such as UAMC-3203, UAMC-3234, UAMC-3206 and UAMC-3240, have significantly longer microsomal half-lives and improved solubility, addressing the limitations of Fer-1. Molecular dynamics simulations suggest that these analogues rapidly insert into phospholipid bilayers, consistent with their role in inhibiting lipid peroxidation (111,121). Another Fer-1 analog, Srs11-92, was found to mitigate brain infarct size, neuronal damage and neurological deficits in the mouse model of middle cerebral artery occlusion and reperfusion by inhibiting iron overload, ROS accumulation and neuroinflammation. This was achieved through the upregulation of GPX4, Nrf2 and HO-1, while concurrently suppressing HMGB1 and NF-κB p65 in the injured hippocampus or Alzheimer's disease models (112,122,123). Beyond the analogs listed above, numerous Fer-1 derivatives have been comprehensively reviewed and are summarized in Table I.

Calcium oxalate crystals adhere to renal tubular epithelial cells, inducing substantial ROS generation, which leads to lipid peroxidation and the release of iron ions. This stimulus causes a decrease in GPX4 expression and an upregulation of ACSL4 in renal tubular epithelial cells, ultimately resulting in ferroptosis (82-85,124). The inhibitory effects of Fer-1 and its analogues on ferroptosis have been well-documented in various experimental models; however, their roles in oxalate-induced kidney injury and nephrolithiasis remain largely understudied, and whether they exert protective effects against crystal-induced renal damage remains unclear.

Numerous natural products have been reported to exhibit significant anti-ferroptotic effects, highlighting their potential as therapeutic agents for diseases involving ferroptosis, including urolithiasis. For example, ursolic acid (UA) exerts antitumor effects in malignant tumors of the urinary system (prostate cancer/bladder cancer/renal cell carcinoma) by inducing ferroptosis, specifically by promoting SLC7A11-mediated ferroptosis; however, in subarachnoid hemorrhage, UA inhibits ferroptosis via brain-targeted nanodelivery, thereby exerting neuroprotective effects (125,126). Additionally, UA can alleviate CaOx-induced injury to renal tubular epithelial cells by suppressing oxidative stress and inflammation (127). UA exerts reverse effects in different types of disease, which may be attributed to the expression levels of SLC7A11 or the state of oxidative stress. The application of nanomaterial-based delivery systems to achieve neuroprotection may also be related to how these delivery systems modulate the local concentration, targeting specificity, and functional selectivity of UA. As an upstream multi-target protective agent (inhibiting oxidative stress and inflammation), UA directly alleviate CaOx-induced RTEC injury, suggesting its potential for further research and clinical application in the management of renal stone disease.

Similarly, 6-gingerol can promote ferroptosis in prostate cancer, while inhibiting ferroptosis in inflammatory, metabolic or vascular diseases (15,125,128,129). As an NRF2 activator, 6-gingerol ameliorates atherosclerosis and protects against diabetic cardiomyopathy by inhibiting ferroptosis via NRF2-mediated anti-ferroptotic pathways (15,128,129). It can also alleviate inflammation and oxidative stress by suppressing the JAK/STAT signaling pathway (130), reduce high glucose-induced inflammation and cytotoxicity in THP-1 cells by inhibiting the TLR4/NF-κB pathway (131), and attenuate NNK-induced oxidative damage in lung cells by activating the NRF2 pathway (132).

Talaroconvolutin A inhibits RSL3-induced ferroptosis, likely by alleviating lipid peroxidation and upregulating NRF2 expression (133). Baicalin activates signaling pathways, such as Nrf2/GPX4, PI3K/AKT/GPX4 and SIRT3/GPX4, thereby reducing lipid peroxidation and ROS accumulation. Additionally, baicalin can directly chelate iron ions, reducing iron deposition and oxidative damage (134-138). Kukoamine A has been shown to exert protective effects in a model of osteoarthritis by inhibiting inflammation and ferroptosis via the SIRT1/GPX4 signaling pathway, and to alleviate nephrolithiasis by inhibiting endogenous oxalate synthesis through the IL-6/JAK/STAT3/D-amino acid oxidase signaling pathway (139,140).

Collectively, these natural products demonstrate significant potential in modulating ferroptosis, either by directly inducing ferroptosis or by protecting cells from ferroptotic damage. Their mechanisms involve regulating key pathways, such as iron metabolism, lipid peroxidation and antioxidant defense systems. These findings provide preliminary evidence that numerous natural products may hold therapeutic potential for the prevention and treatment of kidney stone disease by modulating ferroptosis; however, this remains to be validated by further mechanistic and clinical studies.

A series of existing drugs exhibit novel therapeutic indications. For example, mMetformin, an approved and core first-line medication for type 2 diabetes, can reverse COM-induced oxidative stress by activating the Nrf2/HO-1 signaling pathway, thereby simultaneously inhibiting CaOx crystal formation (dissolving COM and promoting COD conversion) and mitigating renal tubular injury (106). However, metformin also exerts antitumor effects in breast cancer cells by inhibiting the UFMylation of SLC7A11, thereby promoting ferroptosis (141). These opposite effects on ferroptosis may be due to differences in SLC7A11 expression levels across different disease types, as well as the diverse pharmacological effects of metformin in distinct disease contexts. Reserpine is a classic sympatholytic agent, belonging to antihypertensive drugs (142). Previous research has demonstrated that it exerts anti-ferroptotic and anti-inflammatory effects in the context of cisplatin-induced acute kidney injury (143).

Propafenone, a class Ic antiarrhythmic agent clinically applied for rhythm control in patients with atrial fibrillation and supraventricular tachycardia (144), exerts sodium channel blocking (145) and immunomodulatory effects (146). These effects may alleviate oxalate-induced cellular stress and inflammatory responses to a certain degree, thereby indirectly inhibiting ferroptosis and preventing kidney stone formation. Omeprazole, a classic proton pump inhibitor that potently suppresses gastric acid secretion by irreversibly inhibiting the H⁺/K⁺-ATPase in gastric parietal cells. Recent studies have revealed that omeprazole also possesses non-antacid effects, including antioxidant activity, free radical scavenging, regulation of copper metabolism and exhibits ferroptosis-related activity in various disease models (147,148). Lidocaine attenuates hypoxia/reoxygenation-induced inflammation and apoptosis, and inhibits ferroptosis in lung epithelial cells by suppressing the p38 MAPK pathway, thereby exerting a protective effect (149). Promethazine exhibits non-histamine receptor-dependent antioxidant and anti-ferroptosis activities, and can protect multiple organs from ferroptosis-related damage by scavenging lipid peroxyl radicals (147,150,151). Reduced vitamin K (VKH₂ and menadiol) possesses potent antioxidant activity and can inhibit ferroptosis by directly scavenging lipid peroxidation free radicals through various mechanisms (152).

Collectively, the examples discussed above, metformin, reserpine, propafenone, omeprazole, lidocaine, promethazine and reduced VKH₂, illustrate a compelling yet largely unexplored phenomenon: A range of established drugs, originally developed for distinct therapeutic purposes, may exert unexpected renoprotective and anti-lithogenic effects via the common pathway of ferroptosis inhibition. Given the vast arsenal of clinically approved drugs with previously unrecognized anti-ferroptotic properties, it is highly probable that a number of other molecules await identification and systematic evaluation. Future drug repurposing efforts, leveraging high-throughput screening, computational approaches and ferroptosis-specific biomarker assays, are urgently required to uncover additional candidates that could effectively prevent or treat nephrolithiasis by targeting ferroptosis. Such discoveries may open new avenues for non-surgical, mechanism-based intervention in kidney stone disease.

7-Dehydrocholesterol (7-DHC) is a direct precursor of cholesterol in the cholesterol biosynthetic pathway, produced from the catalytic reaction of 7-DHC reductase (DHCR7), and is also an endogenous sterol possessing a conjugated diene structure. Recently, Multiple studies have demonstrated that 7-DHC can inhibit phospholipid autoxidation through its conjugated diene structure, thereby protecting cells from ferroptosis (153-155). As a naturally occurring potent ferroptosis inhibitor, 7-DHC has been shown to protect renal tubular epithelial cells in a renal ischemia-reperfusion injury model (155). Ferroptosis can be significantly suppressed by either inhibiting DHCR7 or directly supplementing 7-DHC (153,154,156,157).

In 2019, Doll et al (158) first identified FSP1 (AIFM2) as a glutathione-independent ferroptosis suppressor. FSP1 reduces CoQ10 to ubiquinol in an NAD(P)H-dependent manner; ubiquinol then functions as a lipid peroxyl radical trapping agent, thereby inhibiting phospholipid peroxidation and ferroptosis (158). Mishima et al (155) found that FSP1 can also reduce vitamin K to its hydroquinone form, which is a potent lipid peroxyl radical trapping agent. Nakamura et al (159) demonstrated that phase separation leads to a loss of FSP1 function, inhibits its ability to suppress lipid peroxidation, thereby synergizing with GPX4 inhibitors to potentiate ferroptotic cell death, which represents a fundamentally new paradigm for pharmacological targeting of ferroptosis. Recently, Ye et al (12) demonstrated that Fsp1 deficiency significantly exacerbated oxalate-induced AKI, as evidenced by aggravated renal function, enhanced oxidative stress and increased ferroptosis. Conversely, the overexpression of FSP1 in renal tubular epithelial cells markedly reduced CaOx-induced lipid peroxidation and cellular ferroptosis (12). Oxalate exposure downregulated the expression of endogenous FSP1 and GPX4, while upregulating the pro-ferroptotic gene, ACSL4, thereby disrupting the redox balance and promoting ferroptosis (12). These findings suggest that FSP1 may function as an endogenous protective factor that assists renal tubular cells in resisting oxalate-induced ferroptosis. Therefore, FSP1 may be a potential target for the prevention and treatment of kidney stone disease, particularly CaOx-associated renal injury; however, further validation is warranted.

With the rapid advancement of biochemical and structural biology techniques, novel small molecules and theoretical concepts for modulating ferroptosis have emerged continuously, opening up new directions for the treatment of ferroptosis-related diseases. However, current findings are based predominantly on in vitro cell lines and in vivo rodent models, which still have several limitations on their translational to human kidney stone disease. First, in vitro experiments rely almost exclusively on proximal tubular epithelial cell lines, whereas stones develop in the renal papilla, and the roles of other renal resident cells and infiltrating immune cells during stone formation remain unexplored (160). Second, current in vivo models do not fully reproduce human nephrolithiasis: Experimentally induced hyperoxaluria generates animal models with CaOx crystal deposition, which may more effectively represent hyperoxaluria-driven conditions than common idiopathic stone disease. Third, the association between ferroptosis and stone pathogenesis remains to be rigorously validated in humans. There is still a lack of clinical cohort data confirming whether ferroptosis biomarkers (e.g., GPX4 downregulation and lipid peroxide accumulation) are genuinely elevated in kidney stone patients, and whether targeting ferroptosis can reduce stone formation or recurrence in patients. Collectively, these model limitations underscore the need for more representative, human-relevant models for ferroptosis related therapeutic agent selection and investigation for nephrolithiasis.