Peroxiredoxins in the kidney: a Jekyll and Hyde existence in disease pathogenesis

Abstract

Oxidative stress is a well-established driver in the pathogenesis and progression of various kidney diseases. The peroxiredoxin (PRDXs) family, comprising typical 2-Cys, atypical 2-Cys, and 1-Cys members, serves as essential thiol-dependent peroxidases that maintain cellular redox balance. Unlike classical antioxidant enzymes that solely scavenge reactive oxygen species, PRDXs are unique in their ability to undergo redox-sensitive structural transitions, functioning as molecular chaperones and intracellular signaling hubs. In the kidney, PRDXs exert multifaceted protective roles by preserving mitochondrial integrity and attenuating inflammatory and fibrotic signaling. Interestingly, beyond these canonical functions, several PRDX members exhibit context-dependent detrimental effects that paradoxically aggravate renal injury. Such dual functionality is regulated through sophisticated mechanisms, including specific post-translational modifications, molecular chaperone switching, and extracellular release as damage-associated molecular patterns. Although PRDXs represent promising therapeutic targets and biomarkers, their functional duality poses considerable challenges for drug development. Future efforts must focus on spatiotemporally precise regulation to selectively augment PRDXs-mediated defense while mitigating their injury-promoting effects.

1. Introduction

Kidney diseases, including acute kidney injury (AKI), chronic kidney disease (CKD), diabetic nephropathy (DN), and end-stage renal disease, pose a major global health burden. Redox imbalance is a critical driver of their pathogenesis and progression. Excessive reactive oxygen species (ROS) accumulation, coupled with compromised antioxidant defenses, inflicts direct cellular damage and activates pro-inflammatory and pro-fibrotic signaling cascades, ultimately leading to glomerulosclerosis, tubular atrophy, and interstitial fibrosis [1,2].

The peroxiredoxin (PRDXs) family, comprising typical 2-Cys (PRDX1-4), atypical 2-Cys (PRDX5), and 1-Cys (PRDX6) members, serves as essential thiol-dependent peroxidases that maintain cellular redox homeostasis by reducing hydrogen peroxide and other peroxides [3–5]. Beyond their canonical antioxidant functions, emerging evidence reveals a striking functional duality of PRDXs in the kidney – under certain pathological contexts, these same enzymes can paradoxically exacerbate renal injury. For instance, secreted PRDX1 acts as a damage-associated molecular pattern (DAMP) to promote macrophage-mediated inflammation in AKI [6]. PRDX2 undergoes S-nitrosylation at Cys172, shifting from a cytoprotective to a pro-fibrotic and pro-apoptotic role in hyperuricemic nephropathy [7]. This ‘Jekyll and Hyde’ behavior is regulated through molecular chaperone switching, post‑translational modifications, and extracellular release.

Despite growing interest in PRDXs as therapeutic targets, the field lacks a unified conceptual framework that explains how these molecules toggle between protection and pathogenesis in a context-dependent manner. This article therefore synthesizes current knowledge on the dual protective and detrimental roles of PRDXs in kidney diseases, dissects the core regulatory mechanisms underlying their functional switch, and discusses the therapeutic opportunities and challenges arising from this duality.

2. Molecular characteristics and expression of PRDXs family members

2.1. PRDXs exert essential biological functions by catalyzing the reduction of peroxides

PRDXs are a class of thiol-dependent peroxidases that catalyze the reduction of peroxides through a highly conserved catalytic cysteine residue (known as the peroxidatic cysteine). PRDXs not only function in antioxidant defense but also participate in H₂O₂-mediated signaling processes. In this context, PRDXs act as sensors and regulators of H₂O₂, responding to intra- and extracellular signals via oxidation-state changes at their active-site cysteine. This regulatory mechanism enables PRDXs to precisely control intracellular H₂O₂ concentrations, thereby playing a critical role in maintaining cellular redox homeostasis and facilitating signal transduction [8,9].

Based on their catalytic mechanisms and structural characteristics, members of the PRDXs family can be classified into three categories: typical 2-cysteine PRDXs (PRDX1-4), atypical 2-cysteine PRDX (PRDX5), and 1-cysteine PRDX (PRDX6) [10]. Typical 2-Cys PRDXs include PRDX1, PRDX2, PRDX3, and PRDX4, each containing conserved cysteine residues at both the N-terminal (peroxidatic cysteine, Cp) and C-terminal (resolving cysteine, Cr) regions. During the catalytic process, Cp initially performs a nucleophilic attack on peroxides, forming cysteine sulfenic acid (Cp-SOH). This intermediate then forms a disulfide bond with Cr, leading to the oxidation of Cp to cysteine sulfinic acid (Cp-SO₂H). The cycle requires reducing agents (such as thioredoxin) to reduce Cp-SO₂H back to its reduced state, allowing it to reenter the catalytic cycle [11,12]. Through this mechanism, PRDX1-4 efficiently scavenge H₂O₂ and protect cells from oxidative damage. PRDX5 belongs to the atypical 2-Cys PRDX category. While its structure resembles that of typical 2-Cys PRDXs, its catalytic mechanism exhibits distinct differences: the Cp and Cr residues of PRDX5 are positioned at non-conserved locations, and its catalytic cycle relies exclusively on Trx for reduction. Furthermore, PRDX5 is primarily localized to mitochondria and peroxisomes, indicating its unique role in cellular energy metabolism and OS response [10]. PRDX6 is the only 1-Cys PRDX member in the PRDXs family, and its catalytic mechanism distinctly differs from that of typical 2-Cys PRDXs. PRDX6 contains only one conserved cysteine residue, which is oxidized to Cp-SOH during catalysis. The catalytic cycle is completed through the reduction of Cp-SOH by glutathione peroxidase or other reducing agents. Beyond its peroxidase activity, PRDX6 also exhibits phospholipase A2 activity, enabling it to catalyze phospholipid hydrolysis and thereby influence both the lipid composition of cell membranes and signal transduction processes [13].

2.2. Key molecular functions of PRDXs

PRDX1

Beyond its canonical peroxidase activity, PRDX1 possesses molecular chaperone activity that enables it to interact with key signaling proteins such as TRAF6, p58α, Toll-like receptor 4 (TLR4), and C-type lectins, thereby modulating inflammation and cell survival [14]. Under oxidative stress, PRDX1 transitions from a dimer to a HMW oligomer (typically a decamer), acquiring chaperone function that stabilizes client proteins like p53, c-Myc, and NF-κB [15]. In the cytoplasm, PRDX1 inhibits the ASK1/p66Shc/JNK pathway to suppress apoptosis, and in the nucleus, it interacts with p53 to influence mitochondrial apoptosis [15]. PRDX1 also binds Cullin-3 to prevent NRF2 ubiquitination, enhancing antioxidant responses and anti-ferroptosis [16]. These molecular features underlie its context-dependent roles in renal injury, inflammation, and fibrosis.

PRDX2

PRDX2 regulates cytokine and growth factor signaling by modulating intracellular H₂O₂ levels [12,17]. It also exhibits molecular chaperone activity that prevents protein aggregation under stress. A key post-translational modification (PTMs) relevant to kidney disease is S-nitrosylation at Cys172, which converts PRDX2 from a protective to a pro-fibrotic and pro-apoptotic factor in hyperuricemic nephropathy [7]. In diabetic kidney disease, secreted PRDX2 acts as a pro-inflammatory mediator that promotes M1 macrophage polarization via TLR4 signaling [18]. These properties position PRDX2 as a dual regulator in renal pathophysiology.

PRDX3

PRDX3 is a mitochondrion-specific peroxidase that scavenges H₂O₂ generated within the organelle, thereby preserving mitochondrial integrity and redox balance [19,20]. PRDX3 deficiency leads to mitochondrial membrane potential collapse, cytochrome c release, and caspase-dependent apoptosis [21]. Its stability is regulated by ubiquitin-mediated degradation (TRIM39), which influences renal fibrosis progression [22]. PRDX3 also modulates autophagy and cellular senescence via the MondoA-PRDX3 axis [23]. These mitochondrial functions are central to its protective and, when dysregulated, detrimental roles in kidney diseases.

PRDX4

PRDX4 is the only secretory PRDXs, operating both intracellularly (in the endoplasmic reticulum) and extracellularly. In the kidney, it forms a functional complex with the dopamine D5 receptor (D5R), suppressing H₂O₂ production and pro-inflammatory cytokines [24]. This D5R-PRDX4 axis is renoprotective. Although PRDX4 overexpression is associated with poorer prognosis in certain cancers (breast and lung), its role in the kidney is predominantly protective, though elevated serum PRDX4 correlates with CKD risk [25], suggesting potential context-dependent effects.

PRDX5

PRDX5 is broadly distributed in mitochondria, peroxisomes, cytoplasm, and nucleus [26]. Its renal protective functions are mediated through multiple mechanisms: direct inhibition of STAT3 phosphorylation to attenuate fibrosis [27], negative regulation of the sodium-chloride cotransporter via WNK4-SPAK/OSR1 to lower blood pressure [28], suppression of cyst growth by modulating Plk1 stability in autosomal dominant polycystic kidney disease [29], and mitigation of ischemia-reperfusion (I/R) injury [30]. These diverse actions make PRDX5 a multifunctional guardian in renal homeostasis.

PRDX6

PRDX6 is unique as the only 1-Cys PRDX, possessing both glutathione peroxidase and calcium-independent phospholipase A2 activities [31,32]. In the kidney, it protects against DN by inhibiting TLR4/NF-κB signaling in tubular cells [33] and preventing podocyte ferroptosis via the SLC7A11/GPX4 axis [34]. It also attenuates LPS-induced AKI [35] and maintains acid–base homeostasis through interaction with anion exchanger 1 (AE1) [36]. No detrimental renal functions have been reported to date, but its DAMP activity in other organs suggests potential under-investigated duality.

The PRDXs family (PRDX1-6) functions as master regulators of cellular redox homeostasis by scavenging ROS. Moreover, members of this family possess non-canonical functions, ranging from molecular chaperoning to the regulation of critical signaling pathways, shown in Figure 1. This functional duality is evident in their complex involvement in a spectrum of diseases, particularly those driven by oxidative stress like cancer and aging. Therefore, deepening our understanding of their precise mechanisms holds the key to unlocking novel targeted therapies, pointing to a promising direction for future research.

Figure 1.

Classification and fundamental functions of the PRDXs family. PRDXs are categorized into typical 2-Cys (PRDX1–4), atypical 2-Cys (PRDX5), and 1-Cys (PRDX6) members. For each, the diagram shows catalytic cysteine residues, subcellular localization, and major functions (H₂O₂ scavenging, mitochondrial/ER protection, phospholipase A2 activity, and glutathione peroxidase activity). Cys, cysteine; GP, glutathione peroxidase; PLA, phospholipase A; PRDX, peroxiredoxin.

3. Protective roles of the PRDXs family in kidney diseases

The progression of various kidney diseases is intrinsically linked to the disruption of redox homeostasis [37]. An overproduction of ROS overwhelms the intrinsic antioxidant defense systems, leading to oxidative damage of cellular macromolecules (lipids, proteins, and DNA) in renal intrinsic cells. This oxidative insult directly compromises the function of podocytes and tubular epithelial cells, activates pro-inflammatory and pro-fibrotic signaling pathways, and ultimately drives glomerulosclerosis, tubular atrophy, and interstitial fibrosis [38]. Therefore, targeting oxidative stress represents a critical therapeutic strategy, wherein the PRDXs family emerges as a key cellular guardian.

Given this pathological backdrop, the PRDXs family plays a critical protective role in mitigating renal injury. Within the glomeruli, PRDXs contribute significantly to antioxidant defense. For instance, the presence of glutathione peroxidase in the glomeruli of patients with IgA nephropathy suggests a model where PRDXs may function to protect glomerular structures from oxidative damage [39]. In the renal tubules, PRDXs are implicated in regulating cell survival and adaptive responses to injury. A compelling link is observed through the prorenin receptor, which is expressed in tubular cells and engages in renin-angiotensin system-independent signaling. PRDXs may influence tubular cell responsiveness and adaptability by modulating pattern recognition receptor function [40]. Furthermore, PRDXs are likely involved in regulating tubular cell proliferation and differentiation, processes often dysregulated in disease states. For example, under conditions of chronic proteinuria that induce proximal tubular epithelial cell hyperplasia, PRDXs may help maintain cellular homeostasis by fine-tuning the redox state, thereby controlling proliferation and preserving function [41].

PRDX1 is essential for embryonic kidney (pronephros) development, where it scavenges ROS to sustain normal retinoic acid and Wnt signaling activity, thereby supporting proximal tubule formation. Knockdown of PRDX1 results in elevated ROS, impaired primary cilia formation, and defective renal tubulogenesis, whereas its overexpression effectively rescues these developmental defects [42]. In the context of renal I/R injury, PRDX1 significantly attenuates oxidative stress markers and suppresses inflammatory mediators such as NF-κB, IL-6, and IL-18. It also inhibits the expression of apoptosis-related proteins, including Caspase-3, reduces kidney injury molecule-1 levels, and contributes to the recovery of renal filtration function [43]. Expanding its functional repertoire, PRDX1 confers protection in obstructive nephropathy by counteracting tubular apoptosis. Its expression is preserved by antifibrotic agents, and mechanistically, it blunts hydrogen peroxide-induced apoptosis in tubular cells through suppression of the p38 MAPK signaling cascade [44]. Additionally, PRDX1 modulates cellular senescence processes in DN via a direct interaction with decoy receptor 2. This interaction influences the phosphorylation status of PRDX1 and its ability to restrain the expression of senescence markers and the secretion of SASP factors, thereby positioning PRDX1 as a critical regulator in decoy receptor 2-driven renal senescence and fibrosis [45]. From a translational perspective, PRDX1 shows promise as a diagnostic biomarker in kidney diseases. Elevated serum levels of 2-Cys PRDXs, including PRDX1, have been observed in IgA nephropathy, membranous nephropathy, and lupus nephritis, indicating its potential utility as a noninvasive indicator for these pathologies [46].

PRDX2, as a key member of the 2-Cys PRDXs subfamily, plays a vital cytoprotective role in maintaining renal homeostasis under pathological stress, with its functions extending beyond conventional antioxidant defense. In a murine model of renal I/R injury, administration of recombinant PRDX2 protein significantly attenuated the severity of kidney damage, as evidenced by reduced tubular necrosis, decreased inflammatory cell infiltration, and improved renal functional parameters [43]. Mechanistically, PRDX2 exerts its renoprotective effects not only through its robust peroxidase activity that scavenges hydrogen peroxide and organic hydroperoxides but also by modulating redox-sensitive signaling pathways. It helps maintain cellular integrity by preventing oxidative damage to critical biomolecules and inhibiting stress-induced activation of pro-apoptotic and pro-inflammatory cascades. These findings establish PRDX2 as a significant component of the kidney’s intrinsic defense system against acute injury, with potential implications for therapeutic development.

PRDX3, as a mitochondria-specific antioxidant enzyme, plays a fundamental role in maintaining renal tubular health by preserving mitochondrial integrity and redox balance. Its expression in renal tubules demonstrates a strong positive correlation with the recovery of renal function and glomerular filtration rate, while exhibiting a negative correlation with urinary protein excretion, tubular atrophy, and interstitial fibrosis, underscoring its essential function in tubular protection [47]. This protective role is further substantiated by in vivo evidence showing that Prdx3 deficiency exacerbates renal fibrosis and inflammation in models of obstructive and diabetic kidney disease. Prdx3 knockout accelerates pathological progression by enhancing mitochondrial oxidative stress in tubular cells and promoting macrophage activation. The crosstalk between Prdx3-deficient macrophages and tubular epithelial cells creates a pro-inflammatory and pro-fibrotic feedback loop, highlighting PRDX3 as a critical modulator of the tubular-macrophage interaction in CKD progression [48]. The stability of PRDX3 is critically regulated at the post-translational level. In renal fibrosis, TRIM39 directly interacts with PRDX3 and promotes its ubiquitin-mediated degradation at lysine residues K73 and K149, leading to ROS accumulation, enhanced inflammatory cytokine production, and accelerated fibrotic progression. Conversely, TRIM39 knockdown alleviates renal fibrosis, highlighting the protective role of PRDX3 stability in maintaining renal homeostasis [22]. Beyond its antioxidant function, PRDX3 is integral to mitochondrial quality control and cellular senescence pathways. It operates downstream of the transcription factor MondoA in a regulatory axis that maintains mitochondrial function and autophagy, thereby protecting against cellular senescence. This PRDX3-mediated pathway functions independently of Rubicon-regulated autophagy, and the decline of this protective system is associated with exacerbated senescence in aging and ischemic AKI [23]. In renal cell carcinoma (RCC), PRDX3 exhibits a clear tumor-suppressive function through multiple mechanisms. In clear cell RCC, HIF-1α accumulation directly binds to the PRDX3 promoter and represses its transcription, creating a redox environment favorable for tumor cell proliferation. Restoration of PRDX3 expression suppresses HIF-1α-dependent tumor growth [49]. This tumor-suppressive role is further evidenced by the circNUP98/miR-567 axis, which promotes RCC progression through PRDX3 downregulation, subsequently enhancing cancer cell proliferation, migration, and invasion [50]. Collectively, these findings establish PRDX3 as a crucial guardian of renal tubular integrity, with its dysfunction contributing significantly to fibrotic progression, cellular senescence, and tumor development.

PRDX4 is the only known secretory PRDXs, a unique feature that enables it to operate both intracellularly and extracellularly. In the kidney, PRDX4 exerts protective effects through multiple mechanisms. A key pathway involves its physical interaction with the D5R within the endoplasmic reticulum. This D5R-PRDX4 complex, whose formation is enhanced by D5R activation, effectively suppresses H₂O₂ production and reduces pro-inflammatory cytokines such as IL-1β and TNF-α. The physiological importance is confirmed in Drd5⁻/⁻ mice, which exhibit decreased renal PRDX4 levels alongside elevated oxidative stress and inflammation, establishing the D5R-PRDX4 axis as a significant renoprotective mechanism [24]. Beyond its antioxidant function, PRDX4 is implicated in the unfolded protein response due to its ER localization, where it assists in oxidative protein folding. Although PRDX4 overexpression is linked to poorer prognosis in certain cancers, its role in the kidney remains predominantly protective. Collectively, these findings highlight PRDX4 as a context-dependent regulator whose secretory nature and receptor interaction offer unique therapeutic angles for inflammatory kidney diseases.

PRDX5 is predominantly localized in mitochondria, peroxisomes, and the cytoplasm, that plays multifaceted protective roles across various kidney pathologies, primarily through its antioxidant function and modulation of specific signaling pathways. Its importance is particularly evident in renal fibrosis, where PRDX5 exerts antifibrotic effects via distinct mechanisms. PRDX5 directly interacts with and inhibits the phosphorylation of STAT3, a key profibrotic transcription factor, in a manner dependent on its redox-active cysteine residue (Cys48). This interaction disrupts EGFR/STAT3 signaling, thereby attenuating EMT and fibrotic progression [27]. Furthermore, PRDX5 expression is positively regulated by dimethylarginine dimethylaminohydrolase 1, and its downregulation is a critical mediator in dimethylaminohydrolase 1 deficiency-induced EMT and fibrosis, linking nitric oxide metabolism to redox-mediated fibrotic signaling [51]. The antifibrotic action of PRDX5 is strictly dependent on its peroxidase activity, as a catalytic double mutant fails to suppress TGF-β-induced fibrotic marker expression, again through a STAT3-mediated but SMAD2/3-independent pathway [52]. Beyond fibrosis, PRDX5 is integral to blood pressure regulation within the tubulovascular axis. PRDX5 deficiency exacerbates angiotensin II-induced hypertension by enhancing reactive oxygen and nitrogen species generation and subsequently upregulating the sodium-chloride cotransporter via the WNK4-SPAK/OSR1 signaling pathway in distal convoluted tubules. This identifies PRDX5 as a novel negative regulator of sodium reabsorption and blood pressure [28]. In cystic kidney disease, PRDX5 functions as a crucial suppressor of cystogenesis. It is downregulated in autosomal dominant polycystic kidney disease, and its deficiency promotes cyst growth through multifaceted mechanisms, including induction of oxidative stress, activation of proliferative pathways (Erk, mTORC1), induction of mitotic instability, and impairment of primary cilia function. The Prdx5-Plk1 axis is particularly important, and targeting Plk1 ameliorates cyst growth in Pkd1-deficient models, highlighting a potential therapeutic strategy [29]. Finally, in AKI, PRDX5 provides a vital defense against ischemia/reperfusion injury. PRDX5 knockout mice exhibit exacerbated tubular damage, apoptosis, renal dysfunction, and heightened oxidative stress, endoplasmic reticulum stress, and inflammation following I/R, establishing its non-redundant role in mitigating acute oxidative insult [30]. Collectively, these findings position PRDX5 as a central guardian of renal homeostasis, orchestrating protection through cell-type and context-specific mechanisms that span fibrosis, hypertension, cystogenesis, and acute injury.

PRDX6 serves as a crucial guardian in the kidney, distinguished from other PRDXs family members by its unique molecular structure containing only one conserved cysteine residue (C47) compared to the two found in other PRDXs. This structural uniqueness enables PRDX6 to exert its protective influence across diverse cell types and injury models through its specialized peroxidase activity and protein-interaction capabilities. Its cytoprotective mechanisms can be categorized into several distinct but interconnected pathways, demonstrating remarkable functional versatility in maintaining renal homeostasis. In DN, PRDX6 emerges as a key defender against hyperglycemic damage in both tubular and glomerular compartments. In high glucose-stimulated tubular epithelial cells (HK-2), PRDX6 overexpression ameliorates mitochondrial dysfunction, oxidative stress, apoptosis, and inflammation by specifically inhibiting the TLR4/NF-κB signaling pathway [33]. Simultaneously, in glomerular podocytes, PRDX6 transcription is directly regulated by specificity protein 1, and its upregulation protects against high glucose-induced injury by mitigating oxidative stress and inhibiting ferroptosis through the SLC7A11/GPX4 axis [34]. This dual protection in different renal cell types underscores PRDX6’s comprehensive renoprotective potential in diabetic conditions. In AKI, PRDX6 demonstrates significant anti-inflammatory properties. Transgenic mice overexpressing PRDX6 exhibit attenuated LPS-induced renal damage, characterized by reduced infiltration of inflammatory cells, decreased apoptosis, and suppressed activation of p38 MAPK and JNK pathways. This protective effect is mediated through PRDX6’s capacity to scavenge ROS and subsequently dampen ROS-dependent inflammatory signaling [35]. In renal acid-base homeostasis, PRDX6 plays a novel role through its interaction with AE1 in renal α-intercalated cells. The PRDX6-AE1 interaction, dependent on PRDX6’s conserved cysteine residue (C47), is essential for maintaining AE1 stability during metabolic acidosis. PRDX6 deficiency leads to disrupted acid-base balance and impaired AE1 preservation under acidic stress, revealing its critical function in specialized renal tubule segments [36]. Collectively, these findings establish PRDX6 as a multifunctional protector in the kidney, operating through mechanisms spanning from transcriptional regulation and signaling pathway modulation to protein stabilization and ion transport maintenance. Its ability to counteract diabetic injury, acute inflammation, and acid-base disturbances highlights PRDX6’s potential as a therapeutic target for various renal pathologies, with its protective efficacy being cell-type specific and context-dependent.

In summary, the PRDXs family plays a crucial role in kidney diseases, with its members participating in the regulation of renal physiological and pathological processes through diverse mechanisms. They exert antioxidant, anti-inflammatory, anti-fibrotic, and reparative effects, highlighting their potential as therapeutic targets (Figure 2). These findings suggest that targeting the PRDXs family may offer novel strategies for the clinical treatment of renal diseases.

Figure 2.

Cellular localization and protective mechanisms of the PRDXs family in the kidney. The schematic illustrates PRDX distribution across renal cell types (glomerular, tubular, endothelial, immune) and summarizes renoprotective functions. PRDXs mitigate oxidative stress via ROS scavenging and regulate key pathways: inhibiting fibrosis (MAPK, EGFR/STAT3, TRIM39, DDAH1, SMAD2/3), suppressing inflammation (NF-κB, MAPK), preventing apoptosis/senescence (DcR2, Caspase-3/p38), blocking cyst growth (Plk1), and maintaining blood pressure (WNK4-SPAK axis). DcR2, decoy receptor 2; PRDX, peroxiredoxin; ROS, reactive oxygen species.

4. Potential detrimental or disease-promoting roles of the PRDXs family in pathologies

Despite their well-established protective roles, members of the PRDXs family exemplify a ‘double-edged sword’ in biology, demonstrating that their functional impact is profoundly context-dependent. Under specific pathological microenvironments, certain PRDXs can paradoxically acquire disease-promoting properties or see their protective functions subverted. A central mechanism underlying this functional shift is hyperoxidation. As highly efficient peroxidases, PRDXs are tasked with scavenging peroxides, however, when confronted with overwhelming oxidative flux, their peroxidatic cysteine can be hyperoxidized to sulfinic or sulfonic acid. This irreversible modification not only inactivates their antioxidant capacity but can also transform them into a non-dissociating, HMW complex that may aberrantly engage with and disrupt redox-sensitive signaling networks [53]. Beyond mere functional loss, this hyperoxidized state can alter PRDXs’ interactions with key signaling partners, potentially converting them from cytoprotective sentinels into pro-pathological entities that perpetuate cellular dysfunction.

PRDX1 exhibits context-dependent, disease-promoting effects across various pathologies, extending beyond its canonical antioxidant role. Notably, PRDX1 can function as a DAMP. Under inflammatory stimuli, it is secreted via a non-classical pathway dependent on cysteine oxidation and exosome release. This secreted, disulfide-linked homodimeric form of PRDX1 actively promotes the production of inflammatory cytokines, thereby amplifying the inflammatory response [54]. This pro-inflammatory DAMP function is critically implicated in kidney injury. In models of AKI, PRDX1 is released into the circulation and promotes renal damage by activating the Mincle/Syk/NF-κB signaling axis in macrophages, driving M1 polarization and proinflammatory cytokine production. The clinical relevance is highlighted by elevated serum PRDX1 levels in AKI patients, which correlate with renal function decline [6]. Furthermore, PRDX1 mediates aseptic inflammation in hypoxia-induced renal injury. It activates the TLR4/MAPK/NF-κB pathway in macrophages, and its knockdown attenuates hypoxia-induced renal damage and inflammation, identifying it as a key mediator of sterile inflammatory responses in the kidney [55]. In cancer, PRDX1 demonstrates potent tumor-promoting activities. In osteosarcoma, its overexpression activates the Akt/mTOR pathway, enhancing cell proliferation, migration, and invasion, whereas its knockdown suppresses proliferation and induces apoptosis [56]. Similarly, in cervical cancer, PRDX1 upregulation inhibits apoptosis and promotes proliferation by modulating the expression of Nanog, PCNA, Bcl-2, and BAX. It also enhances migratory and invasive capacities by upregulating Snail and MMP-9 while downregulating E-cadherin [57]. In oral precancerous lesions, PRDX1 overexpression suppresses oxidative stress-induced apoptosis via the ASK1/p38 pathway [58]. The protein’s oncogenic function is further highlighted in RCC, where natural Piericidins target PRDX1 to induce ROS-JNK/p38-dependent apoptosis, suggesting that PRDX1 promotes RCC progression through the same pathway [59]. Collectively, these findings underscore the multifaceted role of PRDX1 in promoting tissue damage and tumor progression in diverse disease models.

PRDX2 demonstrates a paradoxical role in disease progression, acting as a tumor promoter in various malignancies and as a mediator of kidney injury through distinct molecular pathways. In gastric and colorectal cancers, elevated PRDX2 expression is correlated with poor prognosis, where it enhances tumor cell proliferation and suppresses apoptosis [60,61]. Beyond its oncogenic functions, PRDX2 actively contributes to pathological processes in kidney diseases. In hyperuricemic nephropathy, PRDX2 undergoes S-nitrosylation (SNO) at the Cys172 residue, a key PTMs that transforms its role from protective to pathogenic. This SNO-PRDX2 promotes mitochondrial dysfunction, oxidative stress, and tubular cell apoptosis, ultimately driving renal interstitial fibrosis. Critically, mutation of Cys172 ameliorates these pathological changes, identifying SNO-PRDX2 as a key mediator and potential therapeutic target in hyperuricemia-induced kidney injury [7]. Furthermore, in diabetic kidney disease, PRDX2 abundance is increased in patient urine and correlates with disease progression. High glucose or TNF-α upregulates PRDX2 in renal tubular epithelial cells, from where it is released and functions as a pro-inflammatory mediator. The secreted PRDX2 promotes classically activated (M1) macrophage polarization, enhances macrophage migration and phagocytosis, and sustains chronic inflammation via TLR4 signaling [18]. This aligns with its broader role in exacerbating inflammatory responses, wherein its release can act as a signaling molecule that amplifies inflammation and cellular damage [62]. Additionally, in AKI, PRDX2 has been shown to promote ferroptosis via the exosomal pathway, interacting with KRT20 to worsen renal damage. Inhibiting exosomal PRDX2 secretion or blocking its pro-ferroptotic activity presents a potential therapeutic strategy [63]. Collectively, these findings position PRDX2 as a central injury-promoting molecule across cancer and renal pathologies, highlighting its potential as a novel therapeutic target in renal inflammatory diseases and certain malignancies.

While PRDX3 is recognized for its protective roles, accumulating evidence reveals its context-dependent detrimental effects in various pathologies, particularly in cancer and hyperplastic diseases. PRDX3 is frequently upregulated in multiple malignancies, including liver, breast, cervical, and ovarian cancers, where it supports tumor survival and aggressiveness. By efficiently scavenging mitochondrial ROS, PRDX3 shields cancer cells from oxidative stress-induced apoptosis, thereby enhancing their proliferation, invasion, metastatic potential, and resistance to chemotherapeutic agents, ultimately contributing to poorer clinical outcomes [64]. Beyond its oncogenic functions, PRDX3 contributes to the pathogenesis of benign prostatic hyperplasia through mechanisms involving disrupted autophagy and enhanced inflammation. It inhibits autophagic flux and activates pyroptosis, an inflammatory form of programmed cell death, collectively driving prostatic overgrowth and sustaining a chronic inflammatory microenvironment that facilitates disease progression [65]. In the specific context of kidney cancer, PRDX3 demonstrates a paradoxical role in promoting disease advancement. Research indicates that in clear cell RCC, PRDX3 facilitates cancer progression by enhancing the mitochondrial calcium uniporter (MCU)-dependent induction of ferroptosis. This PRDX3-MCU axis accelerates lipid peroxidation and iron-dependent cell death, thereby creating a permissive environment for tumor growth and evolution [66]. This mechanism underscores the complex, tissue-specific nature of PRDX3 function, positioning it as a potential contributor to renal carcinogenesis under certain conditions.

Emerging evidences reveal that PRDX4, while generally protective, may also exhibit context-dependent detrimental roles in kidney pathology, particularly as a biomarker of disease severity and progression. Clinical cohort studies have demonstrated that elevated serum PRDX4 levels are independently associated with an increased risk of developing CKD in the general population, suggesting that systemic oxidative stress reflected by high PRDX4 may actively contribute to renal functional decline [25]. Furthermore, in the setting of renal cancer, PRDX4 upregulation is linked to more aggressive disease phenotypes. Pan-cancer analyses identify PRDX4 as a negative prognostic marker in kidney renal papillary cell carcinoma (KIRP), where its overexpression correlates with poor survival outcomes and advanced clinicopathological features. Mechanistically, PRDX4 in this context appears to facilitate tumor progression by modulating pathways related to hypoxia, endoplasmic reticulum stress, and protein homeostasis, creating a microenvironment conducive to cancer advancement [67]. Collectively, these findings position PRDX4 as a double-edged sword in renal pathologies – its elevated expression not only serves as a clinical indicator of CKD risk and cancer aggressiveness but may also actively participate in disease pathogenesis through distinct stress-response pathways.

Unlike PRDX1-4, for which context-dependent harmful roles have been well documented in the kidney, no direct evidence to date has demonstrated that PRDX5 or PRDX6 actively promotes renal pathology. The vast majority of studies, as detailed in Section 3, underscore their consistently protective functions in the kidney. Why might this be the case? One plausible explanation lies in their structural and mechanistic classification. PRDX5 is an atypical 2-Cys PRDXs, and PRDX6 is the sole 1-Cys member of the family, whereas PRDX1-4 are typical 2-Cys PRDXs. The typical 2-Cys PRDXs share a conserved catalytic cycle involving a resolving cysteine that forms an intramolecular disulfide bond, which is readily hyperoxidized under oxidative stress, a key trigger for their functional conversion into molecular chaperones or DAMPs. By contrast, the non-canonical catalytic mechanisms of PRDX5 and PRDX6 may render them less prone to the hyperoxidation-driven functional switching that underlies the ‘Jekyll and Hyde’ behavior observed in typical members. This biochemical distinction might explain why their detrimental side has not yet been uncovered in the kidney.

Importantly, the absence of renal evidence should not be mistaken for evidence of absence. In non-renal diseases, both PRDX5 and PRDX6 have been implicated in pro-pathogenic processes. For PRDX5, its oxidized form acts as a DAMP that binds to TLR4 and promotes inflammatory cytokine production in immune cells [68,69]. Moreover, high PRDX5 expression correlates with poor overall survival in ovarian cancer, suggesting a tumor-promoting role under certain contexts [70]. For PRDX6, extracellular release from injured alveolar epithelial cells drives macrophage activation and exacerbates acute lung injury via TLR4/MD2 signaling [71], and it has also been shown to facilitate ferroptosis in various cancer models [72,73]. These findings demonstrate that, given the appropriate pathological microenvironment, both PRDX5 and PRDX6 are capable of acquiring detrimental functions.

Therefore, we propose that the current lack of reported harmful effects of PRDX5 and PRDX6 in the kidney reflects an under-investigated area rather than an intrinsic biological difference. We anticipate that context-dependent pro-injury roles for PRDX5 and PRDX6 in kidney diseases will likely be uncovered in the near future. For now, the ‘Jekyll and Hyde’ paradigm is most robustly supported for PRDX1-4, while PRDX5 and PRDX6 remain predominantly protective in the kidney based on available data. This knowledge gap, rather than weakening the central theme, highlights exciting directions for future investigation into the full spectrum of PRDXs duality in renal diseases.

5. The potential core regulatory mechanisms underlying the dual roles of PRDXs

5.1. The role of PTMs in the functional regulation of PRDXs

PTMs represent a fundamental mechanism for regulating protein function, modulating activity, stability, subcellular localization, and protein–protein interactions [74–76]. Among the PRDXs family, PTMs have been best characterized for PRDX1-3, where they govern the functional switch between cytoprotective and pro-injurious roles in kidney diseases. Table 1 summarizes the known PTMs and their functional consequences for PRDXs members.

Table 1.

Known post-translational modifications of PRDXs and their functional consequences.

PRDX member	PTM type	Functional consequence	Renal relevance	Reference
PRDX1	Phosphorylation	Inactivates peroxidase activity	Implicated in cell cycle regulation	[77]
PRDX1	SUMOylation	May affect stability (high-MW bands)	Not directly shown in the kidney	[78]
PRDX1	Nitration	Impairs antioxidant capacity	Potential role in oxidative stress	[79]
PRDX2	S-Nitrosylation	Converts from protective to pro-fibrotic, pro-apoptotic	Key mediator in hyperuricemic nephropathy	[7]
PRDX3	Acetylation	SIRT3-mediated deacetylation enhances activity, acetylation inhibits	I/R injury, fibrosis	[80]

For PRDX1, multiple PTMs regulate its enzymatic activity and protein interactions. Phosphorylation at Thr90 by cyclin-dependent kinase Cdc2 or mammalian sterile 20-like 1 (Mst1) leads to inactivation of its peroxidase activity [77]. Although direct evidence for ubiquitination is limited, HMW bands of PRDX1 may result from SUMOylation by SUMO1 [78]. Additionally, thioredoxin 1-mediated nitration of PRDX1 impairs its antioxidant capacity [79]. PRDX2 is also subject to redox-based PTMs that influence its role in kidney injury. In hyperuricemic nephropathy, PRDX2 undergoes S-nitrosylation (SNO) at Cys172, which transforms its function from protective to pathogenic. This SNO-PRDX2 promotes mitochondrial dysfunction, oxidative stress, and tubular cell apoptosis, ultimately driving renal interstitial fibrosis. Notably, mutation of Cys172 ameliorates these pathological changes, identifying SNO-PRDX2 as a key mediator and potential therapeutic target in hyperuricemia-induced kidney injury [7]. PRDX3 is regulated primarily by acetylation modifications. SIRT3 enhances PRDX3 activity by deacetylating it at lysine 253 (K253), thereby strengthening its antioxidant function. Acetylation at this site inhibits PRDX3, whereas deacetylation restores its activity. Elevated PRDX3 acetylation has been observed in I/R injury, underscoring its pathological relevance under oxidative stress [80].

In contrast, for PRDX4, PRDX5, and PRDX6, no PTMs have been functionally characterized in the kidney to date. This knowledge gap likely reflects current research trends and the biological context of these members. First, the majority of studies on PRDXs have concentrated on their well-established antioxidant functions and protective phenotypes. Given that PRDX4-6 exhibit robust renoprotective effects, researchers have naturally prioritized phenotypic characterizations, such as measuring oxidative stress markers, inflammation, and organ damage, over in-depth mechanistic investigations into PTMs. Second, and more importantly, PTM studies are often driven by the observation of functional duality or context-dependent switches. For PRDX1-3, the existence of both protective and detrimental roles has motivated extensive PTM research to explain how the same protein can exert opposite effects. In contrast, PRDX5 and PRDX6 have so far been reported almost exclusively as protective factors in the kidney, with no established detrimental or pro-injury roles. The absence of such functional duality removes a key incentive to explore whether PTMs might serve as molecular switches for these two members. Consequently, even if PTMs of PRDX5 or PRDX6 exist under certain conditions, they have not yet attracted sufficient research attention.

In summary, PTMs serve as critical molecular switches that modulate the functional states of PRDX1-3, contributing to their dual roles in renal pathophysiology. Further investigation is needed to elucidate whether PRDX4-6 are similarly regulated by PTMs and how such modifications might influence their functional in renal disorders.

5.2. Molecular chaperone functions of PRDXs

Under oxidative stress, several PRDXs family members undergo a functionally consequential transition from peroxidases to molecular chaperones, a key intracellular mechanism contributing to their context-dependent roles in renal protection and pathology. This functional switch, best characterized in PRDX1, PRDX2, and PRDX3, is often triggered by the hyperoxidation of the peroxidatic cysteine. This PTM induces a profound conformational change, transforming the proteins from low-molecular-weight dimers into high-molecular-weight (HMW) oligomeric complexes. This structural transition effectively turns off their peroxidase activity and turns on a potent molecular chaperone function. PRDX1 serves as the archetype. Upon hyperoxidation of Cys83, oligomeric PRDX1 gains the ability to interact with a diverse array of client proteins, including GSTP1, NF-κB, and c-Myc [15]. Through these interactions, PRDX1 modulates critical cellular processes such as drug metabolism, inflammatory signaling, and cell cycle progression, thereby influencing cell survival and death decisions [14,16]. Its function is dynamically regulated by cellular reduction systems like thioredoxin, which can reduce the hyperoxidized cysteine and revert PRDX1 back to its peroxidase-active state [81].

PRDX2 also exhibits significant chaperone activity. It has been demonstrated to bind and stabilize other proteins, a function crucial for maintaining cellular homeostasis under stress. For instance, in granulosa cells, the chaperone function of PRDX2, facilitated by its interaction with mitochondrial glutamic acid-rich protein, is essential for repairing mitochondrial damage and suppressing excessive ROS production, highlighting a protective role [82]. Conversely, in acute myocardial infarction, the chaperone activity of PRDX2 is co-opted to promote pathological processes, contributing to TLR4-mediated inflammation and adverse myocardial hypertrophy, underscoring its detrimental potential [83].

PRDX3 is a mitochondrial-specific peroxidase that efficiently scavenges H₂O₂ produced within mitochondria, thereby protecting cells from oxidative damage. However, under certain pathological conditions, PRDX3 undergoes a functional shift, transforming from a ROS scavenger into a promoter of metabolic dysregulation and fibrosis. For instance, in tumor cells, mitochondrial dysfunction leads to elevated ROS levels, and the decline in PRDX3′s antioxidant capacity may instead facilitate cancer cell proliferation and invasion [84,85]. Furthermore, studies indicate that the expression and activity of PRDX3 are closely linked to transcriptional regulation by c-Myc. Aberrant activation of c-Myc upregulates PRDX3, which in turn alters mitochondrial function and cellular metabolism [86]. In fibrotic diseases, PRDX3 plays a complex role; it can mitigate fibrosis by clearing mitochondrial ROS, but when overwhelmed, its functional compromise or switch may exacerbate oxidative stress and tissue damage [87].

This chaperone switch profoundly impacts renal pathology. In AKI, the chaperone activity of PRDX1 and PRDX2 may initially be protective, helping to stabilize misfolded proteins and support the survival of stressed tubular epithelial cells. However, in the context of CKD, the sustained activation of this switch can be maladaptive. For example, the PRDX1 chaperone complex may promote the abnormal survival of profibrotic cells or stabilize key components of pro-fibrotic signaling pathways, thereby paradoxically driving the progression of renal fibrosis. Thus, the intracellular transition from a ‘scavenger’ to a ‘regulator’ is a critical mechanism that allows PRDXs to function as either guardians against or promoters of kidney injury, depending on the intensity and duration of the stress signals.

5.3. Novel DAMPs

Upon passive release from necrotic cells or active secretion under stress, specific PRDXs can translocate to the extracellular space, where they function as potent DAMPs. This transition from intracellular protectors to extracellular inflammatory mediators represents a core mechanism for their detrimental roles, particularly in acute kidney pathologies. PRDX1, PRDX5, and PRDX6 have been firmly established as functional DAMPs. They are recognized by pattern recognition receptors on immune cells, such as TLR4, TLR2, and macrophage-inducible C-type lectin (Mincle), initiating potent pro-inflammatory cascades.

PRDX1 is the most extensively studied DAMP member. In non-renal models, it drives inflammation in acute liver injury [88] and Crohn’s disease [89] by activating the NLRP3 inflammasome and NF-κB pathways. Its role as a DAMP can be targeted therapeutically by ferulic acid, for instance, covalently binds to Cys173 of PRDX1, suppressing its dimerization, secretion, and subsequent TLR4 activation [90]. PRDX5′s DAMP activity is exquisitely dependent on its redox state. The oxidized (disulfide) form of PRDX5 exhibits a higher binding affinity for TLR4 and is more potent in inducing proinflammatory cytokine secretion (IL-8) than its reduced counterpart [68]. Single-molecule studies confirm that PRDX5 specifically binds to TLR4, triggering a proinflammatory mechanoresponse in immune cells [69]. PRDX6 has been identified as a novel DAMP in acute lung injury/ARDS. Released from injured alveolar epithelial cells, it activates the TLR4/MD2 complex on macrophages, leading to NF-κB pathway activation and M1 polarization, a process confirmed by direct binding assays [71].

In the context of kidney injury, the DAMP function of PRDXs is predominantly detrimental and acts as a potent amplifier of damage. In AKI models induced by I/R or sepsis, necrotic tubular cells release PRDX1. These extracellular PRDX1 molecules then act as ‘danger signals’, engaging receptors like Mincle and TLR4 on resident renal cells and infiltrating immune cells. This engagement triggers the production of proinflammatory cytokines and chemokines, leading to further leukocyte infiltration, amplification of the initial injury, and extension of tubular cell death. The strategic inhibition of the PRDX1-Mincle axis has been shown to protect mice from AKI, highlighting the therapeutic relevance of this pathway [6]. Further supporting this concept, a very recent study demonstrated that PRDX1 also aggravates hypoxia-induced renal injury by activating the TLR4/MAPK/NF-κB signaling pathway in macrophages [55]. In this model, Prdx1 knockdown or genetic knockout significantly attenuated renal tissue injury and inflammation, while recombinant PRDX1 promoted pro-inflammatory activation. These findings extend the DAMP paradigm of PRDX1 to hypoxic renal injury and underscore the TLR4 pathway as an additional key mediator of PRDX1-driven renal inflammation.

In summary, the functional duality of PRDXs in kidney diseases is not arbitrary but is governed by a sophisticated interplay of core regulatory mechanisms at molecular and cellular levels. PTMs act as precise molecular switches that directly modulate the enzymatic activity, stability, and functional outcomes of PRDX1-3, enabling their rapid adaptation to pathological stimuli. Beyond PTMs, the functional conversion from peroxidases to molecular chaperones under oxidative stress allows PRDXs to shift their role from redox regulators to protein interaction hubs, critically influencing cell survival, metabolic adaptation, and fibrotic responses in a context-dependent manner. Furthermore, the release of specific PRDXs (PRDX1, PRDX5, and PRDX6) as DAMPs represents a pivotal mechanism through which these molecules transition from intracellular guardians to potent extracellular inflammatory mediators, amplifying sterile inflammation and tubular injury in acute kidney settings. Collectively, these mechanisms, PTMs, functional conversion, and DAMP activity, illustrate that the dual roles of PRDXs are an integrated consequence of their dynamic biochemical regulation and spatial localization (Figure 3). A comprehensive understanding of this regulatory network is essential for developing targeted therapeutic strategies that can selectively enhance the protective functions of PRDXs while mitigating their detrimental effects in renal pathologies.

Figure 3.

The dual role of the PRDXs family in kidney diseases. Under mild stress, PRDXs act as antioxidants (H₂O₂ scavenging) to exert anti-fibrotic, anti-inflammatory, anti-apoptotic, and anti-senescent effects. Under severe/chronic stress, they switch to detrimental functions via three mechanisms: (1) hyperoxidation/phosphorylation induces chaperone activity (binding client proteins like GSTP1, NF-κB, c-Myc, MGARP); (2) released PRDXs act as DAMPs, activating macrophage pattern recognition receptors and amplifying inflammation; (3) specific PTMs (PRDX1: phosphorylation/nitration/SUMOylation; PRDX2: S-nitrosylation; PRDX3: acetylation) drive mitochondrial dysfunction and apoptosis. DAMP, damage-associated molecular patterns; MGARP, mitochondrial glutamic acid-rich protein; PRDX, peroxiredoxin; PTMs, post-translational modifications.

6. Potential and challenges of the PRDXs family as biomarkers and therapeutic targets

6.1. PRDXs as diagnostic and prognostic biomarkers in kidney diseases

Beyond their functional roles, several PRDXs members have emerged as potential biomarkers for kidney diseases. Serum PRDX1 levels are elevated in AKI patients and correlate with renal function decline, reflecting its release from injured tubules [6]. Urinary PRDX2 is increased in diabetic kidney disease and promotes M1 macrophage polarization [18]. Serum PRDX4 independently associates with new-onset CKD risk in population-based cohorts [25]. Tubular PRDX3 expression predicts renal recovery from acute tubular necrosis in CKD patients [47]. In kidney renal clear cell carcinoma (KIRC), recent multi-omics analyses have identified PRDX3 as a potential prognostic biomarker: its expression is significantly associated with patient survival, and functional validation shows that PRDX3 overexpression suppresses malignant phenotypes in KIRC cells, suggesting a tumor-suppressive role [91]. These findings collectively support the utility of PRDXs as noninvasive indicators of disease progression and prognosis, although large-scale clinical validation is still needed.

6.2. Therapeutic strategies targeting PRDXs: current agents and mechanisms

Several specific agents have recently been shown to directly or indirectly target PRDXs in kidney injury, as summarized in Table 2. Among these, the marine-derived piericidin glycoside S14 directly binds to Cys83 of PRDX1, enhancing its peroxidase activity and promoting its nuclear translocation to activate the Nrf2/HO-1/NQO1 antioxidant pathway, thereby attenuating tubular injury in AKI models. To overcome its poor bioavailability, a pH-sensitive kidney-targeting nanoparticle system has been developed to improve its renal distribution and therapeutic efficacy [92]. The SGLT2 inhibitor empagliflozin, already approved for type 2 diabetes, exerts a newly discovered renoprotective effect by upregulating PRDX3 expression in renal tubular cells, where PRDX3 interacts with PINK1 to modulate mitochondrial quality control, ameliorating diabetic kidney disease [93]. For PRDX5, several agents have been identified. Salvianolic acid B (SAB) directly binds and enhances PRDX5 redox activity, strengthening the SLC7A11/GPX4 anti-ferroptosis axis in cisplatin-induced AKI [94]. The traditional Chinese medicine Chaihuang Yishen Granule (CHYS) upregulates PRDX5 expression, and the increased PRDX5 interacts with TFAM to restore mitochondrial homeostasis and inhibit renal fibrosis in CKD [95]. Similarly, the Shenkang formula attenuates renal fibroblast activation through PRDX5-mediated regulation of the JAK2/STAT3 pathway, although direct binding to PRDX5 has not been confirmed [96]. Collectively, these agents demonstrate the feasibility of pharmacologically targeting PRDXs in kidney diseases, with strategies ranging from direct enzymatic activation (S14, SAB) to indirect upregulation (empagliflozin, CHYS) and pathway modulation (SK).

Table 2.

Currently reported PRDX-targeting agents in kidney diseases.

Agent	Target PRDX	Mechanism	Diseases	Stage/status
S14 (piericidin glycoside)	PRDX1 (Cys83)	Enhances peroxidase activity, promotes nuclear translocation, activates Nrf2/HO-1/NQO1 pathway	AKI	Preclinical; nano-formulation developed [92]
Empagliflozin (SGLT2 inhibitor)	PRDX3	Upregulates PRDX3 expression, PRDX3 interacts with PINK1 to regulate mitochondrial quality control (mitophagy, dynamics)	Diabetic kidney disease	Approved for diabetes; a renal protective mechanism newly discovered [93]
Salvianolic acid B (SAB)	PRDX5	Directly binds and enhances redox activity, strengthens SLC7A11/GPX4 anti-ferroptosis axis	Cisplatin-induced AKI	Preclinical [94]
CHYS	PRDX5	Upregulates PRDX5, PRDX5 interacts with TFAM to restore mitochondrial homeostasis	CKD-related renal fibrosis	Traditional medicine formulation; preclinical [95]
Shenkang formula	PRDX5 (indirect)	Modulates JAK2/STAT3 pathway via PRDX5-mediated regulation	Renal fibroblast activation	Traditional medicine; preclinical [96]

6.3. Challenges and risks of PRDX-targeted therapies

Despite their promise, PRDX-directed therapies face considerable challenges rooted in the dual nature of these enzymes. First, targeting PRDXs carries an inherent risk of unintended pro-oxidant effects. For instance, indiscriminately enhancing PRDXs activity might inadvertently suppress beneficial ROS signaling required for cellular adaptation, whereas excessive inhibition could lead to oxidative damage. Second, the functional duality of PRDXs means that simply inhibiting or enhancing PRDXs activity might simultaneously block protective functions while curbing detrimental ones, or vice versa. For example, while PRDX1 inhibition might reduce DAMP-mediated inflammation in AKI, it could also compromise its essential antioxidant and chaperone functions in tubular cells, potentially aggravating injury. Third, compensatory mechanisms among PRDXs members could diminish the efficacy of isoform-selective inhibitors. Fourth, the context-dependent switch of PRDXs implies that a single agent might produce opposite effects depending on disease stage, redox environment, or cell type.

Fifth, potential compensatory mechanisms among PRDXs family members in the kidney remain largely unexplored but carry significant therapeutic implications. PRDXs exhibit partially overlapping subcellular localizations and substrate specificities. For instance, PRDX1 and PRDX2 are both predominantly cytoplasmic and share the ability to reduce H₂O₂ and alkyl hydroperoxides [12,97]. In erythrocytes, PRDX1 and PRDX2 display functional redundancy, as single knockouts can be partially compensated by the other [98]. However, in the kidney, direct evidence for such compensation is lacking. It is conceivable that genetic or pharmacological inhibition of one PRDXs member might lead to compensatory upregulation of another to maintain redox homeostasis. Conversely, the absence of compensatory upregulation could explain the severe renal phenotypes observed in some knockout models. This uncertainty directly impacts the feasibility of isoform-selective therapies: an inhibitor designed to block the detrimental DAMP function of PRDX1 might be rendered ineffective if PRDX2 takes over its antioxidant role, or conversely, could lead to unexpected toxicity if compensatory mechanisms are insufficient. Therefore, future studies should systematically examine PRDXs expression networks in the kidney under baseline and disease conditions, using co-knockout models or proteomic approaches to map compensatory responses. Such knowledge will be essential for predicting therapeutic windows and off-target effects of PRDX-targeted interventions.

Therefore, future strategies should aim for spatiotemporally precise regulation, for instance, using kidney-targeting nanoparticles (as with S14) or disease-stage-specific dosing regimens to selectively augment protective PRDXs functions while mitigating pathological ones. Combination therapies may also help balance efficacy and safety.

6.4. Future directions

Personalized medicine approaches integrating proteomics, genomics, and machine learning could identify patients who would most benefit from PRDX-targeted therapies based on their PRDXs expression signatures or genetic variants. The recent discovery of PRDX3 as a tumor suppressor in KIRC suggests that PRDX3-enhancing strategies might be beneficial in certain renal cancers, whereas in other contexts PRDX3 inhibition might be explored [91]. Further mechanistic studies, particularly using conditional knockout models and kidney-specific delivery systems, are urgently needed to dissect the cell type specific and disease stage specific functions of each PRDXs member. Such efforts will pave the way for safe and effective PRDX-targeted therapeutics for kidney diseases.

7. Conclusion

PRDXs exert protective effects in various kidney diseases primarily through their antioxidant capacity, reduction of lipid peroxidation and DNA damage, and suppression of inflammatory responses and apoptosis. Multiple studies have demonstrated that PRDXs can effectively mitigate the severity of renal pathologies by decreasing ROS levels in tissues and modulating OS, thereby significantly alleviating kidney injury. However, under certain conditions, PRDXs activity may also contribute to renal damage by altering intracellular redox states and signaling pathways, potentially exacerbating disease progression. Nevertheless, the precise role of PRDXs in kidney diseases remains incompletely understood, warranting further investigation to elucidate their context-specific mechanisms and functional duality.

Although significant progress has been made in current research, the specific functions and regulatory mechanisms of PRDXs across diverse biological contexts remain to be fully elucidated. Further experimental and theoretical studies are needed to clarify the roles of PRDXs in specific biological processes and their behavior under varying physiological and disease conditions. Such efforts will enhance our understanding of the diversity and complexity of PRDXs in living systems and provide a theoretical foundation for developing novel therapeutic strategies. The application of personalized medicine in kidney diseases holds considerable promise, particularly in the context of PRDX-related mechanisms. Integrating proteomics, genomics, pharmacogenomics, and machine learning technologies could enable more precise and individualized treatment plans, thereby improving clinical outcomes and quality of life for patients. Personalized therapy represents a major direction in modern medicine. For example, analyzing genetic variations and expression levels of antioxidant enzymes in individual patients may allow tailored interventions, such as supplementing or enhancing enzymatic activity in cases where genetic mutations impair PRDXs function. However, the use of antioxidants, including PRDX-targeted treatments, is not without risks. Excessive antioxidant supplementation may disrupt normal redox homeostasis, leading to cellular dysfunction, and could potentially mask disease symptoms, resulting in delayed diagnosis and treatment. Future research should focus on clarifying the precise mechanisms of PRDXs in different diseases and advancing patient-specific therapeutic strategies. For instance, genetic sequencing could help design customized antioxidant regimens based on individual variations in PRDXs genes. Achieving this goal will require overcoming current technological and resource limitations, as well as facilitating policy and practical advancements in clinical implementation.

Funding Statement

This work was supported by the Sichuan Provincial Science and Technology Program (2025ZNSFSC0617), the project of Southwest Medical University (2023ZYYQ08), the Innovation Team of Affiliated Traditional Medicine Hospital of Southwest Medical University (2022-CXTD −03).

Disclosure statement

The authors declare that they have no competing interests.

Data availability statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.