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Human Peroxiredoxin 6 (hPrdx6): Structure, Biological Functions and Pathophysiological Importance

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Lucas G. Viviani and Sayuri Miyamoto

Submitted: 26 January 2026 Reviewed: 17 February 2026 Published: 02 April 2026

DOI: 10.5772/intechopen.1015082

Peroxidase Biochemistry in the Biotech Era IntechOpen
Peroxidase Biochemistry in the Biotech Era Edited by Ana Maria Carmona-Ribeiro

From the Edited Volume

Peroxidase Biochemistry in the Biotech Era [Working Title]

Prof. Ana Maria Carmona-Ribeiro and Dr. Iseli Nantes

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Abstract

The human peroxiredoxin 6 (hPrdx6) is a 1-Cys peroxiredoxin possessing peroxidase, acidic calcium-independent phospholipase A2 (aiPLA2), and lysophosphatidylcholine acyltransferase (LPCAT) activities. The multiple enzyme activities of hPrdx6 are associated with its biological roles in defense against oxidative stress, repair of peroxidized cell membranes, and biosynthesis of lung surfactant. An additional role for Prdx6 as a selenium carrier, with important consequences for the biosynthesis of selenoproteins and the regulation of ferroptosis, has been recently discovered. In addition to its physiological importance, hPrdx6 has been shown to be implicated in several pathophysiological processes and diseases, including inflammation, cancer, infectious diseases, and neurodegenerative diseases. Nevertheless, details on the mechanisms by which hPrdx6 exerts its functions at molecular and/or cellular levels in health and disease are not completely unveiled. Additionally, only a few hPrdx6 inhibitors, which might be useful either as chemical probes to study its biological roles or as potential drug candidates, have been reported in the literature. In this chapter, we provide an overview of the structure, biological functions, and pathophysiological importance of hPrdx6, which might be helpful to guide structure-based design of hPrdx6 inhibitors or further studies aiming at validating hPrdx6 as a biological target to be exploited in the treatment of human diseases.

Keywords

  • cysteine-based peroxidases
  • human peroxiredoxin 6 (hPrdx6)
  • 1-Cys peroxiredoxin
  • glutathione peroxidase
  • phospholipid hydroperoxides

1. Introduction

Peroxiredoxins (Prxs, E.C. 1.11.1.15) are a widely distributed family of peroxidases that use a cysteine (Cys) residue to catalyze the reduction of hydroperoxides very efficiently, with second-order rate constants in the 104– 108 M−1.s−1 range [1]. Prxs belong to the thioredoxin (Trx) superfamily, sharing the Trx fold, which consists of a central core of four-stranded antiparallel beta sheets surrounded by three alpha-helices [1–3]. Prxs are highly abundant proteins and act mainly as antioxidant enzymes, protecting cells against oxidative stress [1], but other important cellular functions have been reported in the literature for different Prxs, including regulation of H2O2-mediated cell signaling [4], modulation of innate immunity and inflammation processes [5, 6], and protection against protein misfolding and aggregation through a chaperone function [7].

Prxs can be classified as 1-Cys and 2-Cys Prxs, depending on the number of conserved Cys residues that play a role in the catalytic cycle [1, 8]. In the first step of the catalytic cycle of both 1-Cys and 2-Cys Prxs, the thiolate group of a Cys residue, called peroxidatic Cys (CP), is oxidized to sulfenic acid by the hydroperoxide substrate via nucleophilic bimolecular substitution (SN2) (Figure 1). In 2-Cys Prxs, the sulfenic acid intermediate undergoes a fast condensation reaction with the thiolate group of a second Cys residue, called resolving Cys (CR), forming a disulfide, which is, in most cases, reduced by the Trx/Trx reductase system to restore the catalytically active form of CP (Figure 1-A). In 1-Cys Prxs, CR is absent, and sulfenic acid is reduced by sulfur-based reductants, such as glutathione (GSH), after heterodimerization with GSH S-transferase π (πGST) (Figure 1-B) [9–12], or by other reductants, such as ascorbate [13–15].

Figure 1.

Schematic representation of the catalytic cycles of (A) 2-Cys Prxs and (B) 1-Cys Prxs. Prdx, peroxiredoxin; Trx, thioredoxin; TrxR, thioredoxin reductase; πGST, π glutathione S-transferase; GSH, glutathione.

1-Cys Prxs are represented mainly by peroxiredoxin 6 (Prdx6), which was first isolated from the ciliary body of the bovine eye and called nonselenium GSH peroxidase [16], before being recognized as a member of the Prx family [9]. Like other Prxs, Prdx6 reduces H2O2, short-chain hydroperoxides, and peroxynitrite but has unique characteristics that differentiate it from other Prx family members [9, 10]. First, Prdx6 is able to bind and reduce phospholipid hydroperoxides, although much less efficiently than GSH peroxidase 4 (GPX4), a selenocysteine-based peroxidase with the same catalytic function [17]. Second, in addition to having peroxidase activity (which is maximum at pH ~ 7.4), Prdx6 has been reported to have acidic calcium-independent phospholipase A2 (aiPLA2) activity (which is maximum at pH ~ 4.0), hydrolyzing phospholipids at the sn-2 position [18–22]. In the literature, it has been proposed that Prdx6 aiPLA2 activity is associated with the turnover of lung surfactant phospholipids, repair of peroxidized cell membranes, and activation of NADPH oxidase type 2 (NOX2), an enzyme that has a role in acute lung injury and in several other diseases [20]. Third, Prdx6 has been reported to have lysophosphatidylcholine acyltransferase (LPCAT) activity, acylating lysophospholipids (mainly lysophosphatidylcholine) to generate a phospholipid (usually phosphatidylcholine) by a transferase reaction [23]. The combination of the aiPLA2 and LPCAT activities of Prdx6 allows phospholipid remodeling through hydrolysis followed by re-acylation at the sn-2 position [23]. Fourth, despite being observed mainly in the cytosol, Prdx6 is also found in lysosomes and lysosomal-related organelles, such as lung lamellar bodies, where lung surfactant is synthesized and stored [24, 25].

Due to the multiple and crucial biological roles of Prdx6, alterations in Prdx6 expression and/or function have been implicated in several pathophysiological processes and diseases, including inflammation, cancer, infectious and neurodegenerative diseases, among others [18, 26, 27]. Therefore, Prdx6 has been recognized as a promising, albeit underexploited, biological target for the treatment of many diseases [18, 26, 27]. The elucidation of the human Prdx6 (hPrdx6) 3D structure by X-ray crystallography [2, 3] has provided the basis for the structure-based design of hPrdx6 inhibitors, which might represent starting points for the development of either potential drug candidates or chemical probes to study its biological functions in more detail at molecular and/or cellular levels. In this chapter, we provide an overview of the current state of knowledge about hPrdx6 3D structure, biological roles, and pathophysiological importance, which might be helpful to guide future studies aiming at discovering novel hPrdx6 inhibitors and/or validating it as a biological target for treating human diseases.

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2. hPrdx6 structure

hPrdx6 3D structure in the oxidized state (sulfenic acid, Cys-SOH) was first elucidated by X-ray crystallography at 2.00 Å resolution in 1998 (PDB code: 1PRX) [3]. Afterward, additional crystallographic structures of hPrdx6 in reduced (Cys-SH) and hyperoxidized states (sulfinic acid, Cys-SO2H) were solved at 2.50 Å and 2.90 Å resolution, respectively (PDB codes: 5B6M and 5B6N) [2].

Regardless of the oxidation state, hPrdx6 crystallizes as a tightly associated homodimer (Figure 2-A), which is maintained by hydrogen bonds and hydrophobic interactions between the residues at the dimer interface [2, 3]. Each ~ 25 kDa monomer is composed of 224 amino acids and can be divided into two domains: a larger amino-terminal domain (residues 1-174), which contains the Trx fold motif (four-stranded β-sheets flanked by three α-helices) and harbors the peroxidatic active site in addition to the putative aiPLA2 and LPCAT active sites, and a smaller carboxi-terminal domain (residues 175-224), which comprises three β-strands and one α-helix (Figure 2-B) [2, 3].

Figure 2.

Schematic representation of the hPrdx6 3D structure (determined by X-ray crystallography in reduced state; PDB code: 5B6M; resolution: 2.50 Å [2]). (A) Representation of the hPrdx6 dimeric structure. The monomeric subunits are represented as orange and pink cartoons. (B) Representation of the secondary structures in one monomeric subunit of hPrdx6. The amino- and carboxi-terminal domains are colored in green and blue, respectively. The α-helices and β-sheets that form the Trx fold in the amino-terminal domain are highlighted in dark green.

Figure prepared using PyMOL 3.1.6.1.

hPrdx6 has a high degree of amino acid sequence identity with other mammalian Prdx6 (~95% and ~ 91% sequence identities with bovine and rat Prdx6, respectively), which suggests a key role for Prdx6 in mammalian cell metabolism [9]. Notably, bovine and rat Prdx6 have no other Cys residue besides the catalytic CP, while hPrdx6 has an additional Cys residue (Cys-91), which is distant from CP (Cys-47) and does not participate directly in the catalytic cycle. The location of Cys-47 does not allow homodimerization through disulfide formation in the native state. Cys-47 is part of a highly conserved motif (40PRDFTPVCTTE50) and is at the end of the helix α2 at the bottom of a narrow pocket formed between the thioredoxin fold and the C-terminal domain of the adjacent monomer (Figures 3-A and 3-B) [2, 3].

Figure 3.

Schematic representation of the peroxidatic active site of hPrdx6 code: 5B6M; resolution: 2.50 Å [2]), highlighting the residues that form the catalytic triad for peroxidase activity (His-39, Cys-47, and Arg-132). (A) Cartoon representation. (B) Surface representation. Carbon atoms are shown in pink or orange to distinguish between the two monomeric subunits. Oxygen, nitrogen, and sulfur atoms are shown in red, blue, and yellow, respectively.

The positively charged residues His-39 and Arg-132 are close to Cys-47, forming the catalytic triad H39–C47–R132 (Figures 3-A and 3-B) [2, 3, 9]. His-39 and Arg-132 are crucial for lowering the pKa of the peroxidatic Cys-47 thiol group, stabilizing the ionized state (thiolate) [3]. The increase in the nucleophilicity of thiolate due to ionization results in increased reactivity of Cys-47 [3]. It is unclear how large substrates, such as phospholipid hydroperoxides, access the narrow peroxidatic active site’s pocket, and the accommodation of such molecules in the pocket is probably accompanied by protein conformational changes resulting from loop motions and induced fit effects, which may result in alterations in the volume, shape, and physicochemical properties of the pocket, as suggested by molecular dynamics simulations [26]. Substrate binding and specificity may also be influenced by changes in hPrdx6’s oligomerization state. Indeed, studies based on experimental techniques such as mass-spectrometry, dynamic light scattering, size exclusion chromatography, and native gel electrophoresis suggest that, in solution, hPrdx6 (as well as rat Prdx6) exists in a monomer-dimer equilibrium that is influenced by the protein’s redox state and by other factors such as the protein’s concentration in addition to pH and ionic strength of the medium [22, 28–32]. As discussed in the literature, if hPrdx6 is monomeric in the cell, it probably adopts a different conformation from that observed in the dimer to prevent solvent exposure of hydrophobic residues at the dimer interface [3]. Higher oligomeric states of hPrdx6 are also experimentally observed in solution, mainly under conditions that favor hyperoxidized forms of Cys-47 (sulfinic acid, Cys-SO2H, and sulfonic acid, Cys-SO3H) [22, 31].

Figure prepared using PyMOL 3.1.6.1.

Additionally, as presented above, as part of the catalytic cycle of peroxidase activity, oxidized hPrdx6 forms a heterodimer with πGST harboring bound GSH (Figure 1B) [11, 12]. It has been proposed that after heterodimerization, hPrdx6 is glutathionylated and subsequently forms an intersubunit disulfide with πGST, which is finally reduced by another unit of GSH, restoring the reduced, catalytically active form of Cys-47 (Figure 1B) [11, 12].

The hPrdx6 aiPLA2 active site (Figure 4) is located on the opposite side of the peroxidatic active site and has a lipase motif (30GxSxG34) that is conserved among serine-based lipases [2, 21]. The residues Ser-32, His-26, and Asp-140 are thought to form the catalytic triad for the hPrdx6 aiPLA2 activity, playing a role either in substrate recognition or in catalysis. aiPLA2 activity is regulated by phosphorylation of Thr-177, which is believed to confer structural changes needed for catalysis. However, details on how phospholipids are positioned in the aiPLA2 active site for hydrolysis are yet to be unveiled [2].

Figure 4.

Schematic representation of the key residues for hPrdx6 aiPLA2 LPCAT activities (PDB code: 5B6M; resolution: 2.50 Å [2]). His-26, Ser-32 (from the lipase motif 30GxSxG34), and Asp-140 form the catalytic triad for aiPLA2 activity, while Asp-31 (from the consensus sequence 26HxxxxD31) is essential for LPCAT activity.

Remarkably, the residue Asp-31, which is part of the lipase motif in hPrdx6, is also supposed to be crucial for hPrdx6 LPCAT activity (Figure 4). In hPrdx6, this residue is within the consensus sequence 26HxxxxD31, which is typical of LPCAT enzymes [23]. Site-directed mutagenesis studies have shown that mutation of Asp-31, but not of His-26, results in loss of LPCAT activity [23]. Both the aiPLA2 and LPCAT motifs are observed only in Prdx6, not in other Prx family members [23].

Figure prepared using PyMOL 3.1.6.1.

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3. Biological roles and pathophysiological importance of hPrdx6

3.1 Enzymatic activities and biological roles of hPrdx6

hPrdx6 has broad tissue and organ distribution, with high expression levels in the lungs, brain, kidneys, and testes [20]. The major biological roles of hPrdx6 are related to its multiple enzymatic activities reported in the literature [10, 17, 20, 23, 33, 34]. hPrdx6 peroxidase activity has been associated with its biological role in cell antioxidant defense [9, 17, 34], while hPrdx6 aiPLA2 and LPCAT activities have been associated with its participation in phospholipid turnover, with important physiological consequences for both the biosynthesis of lung surfactant and the repair of peroxidized cell membranes [9, 20, 23]. Recent studies have also suggested a possible role for hPrdx6 in selenocysteine metabolism, which may impact ferroptosis cell death [26, 35, 36], as discussed below in this section.

Peroxidase activity of hPrdx6, which is maximal at pH ~ 7.0 and observed mainly in the cell cytosol [17, 33], has been linked to resistance to oxidative stress based on both cell and in vivo model-based studies [34, 37]. The role of hPrdx6 in antioxidant defense is related to its function as an H2O2 scavenger and to its unique ability to reduce membrane phospholipid hydroperoxides [34, 37]. However, the contribution of Prdx6 to the reduction of phospholipid hydroperoxides is overall outperformed by other proteins, in particular GSH peroxidase 4 (GPX4), which was the first enzyme with this activity described in the literature, having exceptionally high second-order rate constants for phospholipid hydroperoxide reduction (~106 – 108 M−1·s−1) compared to Prdx6 (~104 – 105 M−1·s−1) [26, 38, 39]. Nevertheless, studies with Prdx6 null mice models have suggested that Prdx6 has an important role in protection against oxidative stress resulting from lipid peroxidation in the lungs, where GPX4 expression is significantly low [34]. hPrdx6 peroxidase activity is known to be noncompetitively inhibited by mercaptosuccinate in the low-micromolar range (Ki = 4 μM) [17, 33].

hPrdx6 aiPLA2 and LPCAT activities are observed mainly in the acidic environments of lysosomes and lysosome-related organelles, such as the lung lamellar bodies of type II pneumocytes [20, 23]. hPrdx6 aiPLA2 activity is maximal at pH ~ 4.0 [20]. Through the aiPLA2 activity, hPrdx6 hydrolyzes acyl or alkyl linkages at the sn-2 position of phospholipids, using the Ser-Asp-His catalytic triad, as described in Section 2. hPrdx6 aiPLA2 activity is known to be competitively inhibited by the fluorinated phospholipid transition state analog 1-hexadecyl-3-(trifluoroethyl)-sn-glycero-2-phosphomethanol (MJ33) [33].

hPrdx6 kinetics studies on phospholipid hydrolysis through its aiPLA2 activity reveal strong affinities for phospholipids having phosphatidylcholine (PC) as a head group, but no preference for the fatty acyl group at the sn-2 position [20, 23]. Kinetics studies on hPrdx6 LPCAT activity reveal a preference for lysophosphatidylcholine (LPC) as the lysolipid substrate and for palmitoyl CoA as the fatty acid substrate [23]. Therefore, through the combination of aiPLA2 and LPCAT activities, hPrdx6 plays a role in the remodeling of sn-2 unsaturated PC into sn-2 palmitoyl PC, contributing to the synthesis of dipalmitoylphosphatidylcholine (DPPC), which is the main surface-active lipid component of lung surfactant [23]. This agrees with the proposed biological role of hPrdx6 in phospholipid remodeling in lung lamellar bodies, where its expression has been associated with secretion and re-uptake of lung surfactant by lung epithelium [23]. Additionally, the integration of hPrdx6 aiPLA2 and LPCAT activities allows the release of oxidized fatty acids from the sn-2 position of PC for subsequent introduction of non-oxidized palmitoyl in LPC, contributing to the repair of peroxidized cell membranes [23].

Beyond its well-known biological functions, hPrdx6 has been shown to play a role in the regulation of ferroptosis [26, 35, 36], a non-apoptotic and iron-dependent form of cell death characterized by massive lipid peroxidation of cell membrane phospholipids [40, 41]. hPrdx6’s role in ferroptosis has not been directly linked to its peroxidase activity [26, 35, 36], even though it is able to reduce phospholipid hydroperoxides, as discussed above. Instead, it has been proposed that Prdx6 acts as a selenium acceptor protein, contributing decisively to the biosynthesis of selenoproteins [26, 35, 36], including GPX4, which is recognized as the main ferroptosis suppressor due to its exceptionally high-rate constants for phospholipid hydroperoxide reduction. It has been proposed that Prdx6 reacts with selenide (HSe-) and subsequently interacts with selenophosphate synthetase 2 (SEPHS2) [26]. This protein phosphorylates HSe- to generate monoselenophosphate (H2SePO3-), which is required for the synthesis of Sec-tRNA and, consequently, for selenocysteine incorporation into selenoproteins such as GPX4 [26]. hPrdx6-mediated selenocysteine production seems to be independent of the “classical” pathway that requires selenocysteine lyase (SCLY) for transferring HSe- to SEPHS2 [26].

3.2 Pathophysiological importance of hPrdx6

In addition to its physiological functions, hPrdx6 has been recognized as playing key roles in several pathophysiological processes, which makes it an attractive biological target to be exploited in the treatment of multiple human diseases [27].

hPrdx6 expression has been shown to favor the proliferation of human cancer cells from several lines, including lung cancer 549 cells [35, 42], HepG2 hepatoblastoma cells [43], SNU-398 hepatocellular carcinoma cells [44], MDA-MB-435 and MDA-MB-231 breast cancer cells [45], SiHa, HeLa, Caski, MS751, and C33A cervical cancer cells [46], PC-9 non-small lung cancer cells [47], SK–N–DZ [26, 36] and NB-1 [36] neuroblastoma cells, and Panc-1 and MIA PaCa-2 pancreatic cancer cells [36]. Protection of these cancer cells against oxidative stress is the underlying mechanism by which hPrdx6 favors their growth and survival, which makes hPrdx6 a promising therapeutic target to be exploited for treating cancer.

Notably, recent studies have shown that Prdx6 depletion in in vivo models of both neuroblastoma and lung cancer has been associated with lower GPX4 expression levels, leading to a significant decrease in tumor growth [26, 35] and, in the case of neuroblastoma mice models, higher survival rates [26]. These findings agree with the recent proposal of a possible role for Prdx6 as a selenium carrier [26, 35, 36], which allows efficient selenium incorporation into selenoproteins like GPX4, the main ferroptosis suppressor, as discussed in Section 3.1. Additional studies have shown that loss of hPrdx6 suppressed cell growth in pancreatic cancer and neuroblastoma cell models, with increased sensitivity to iron-induced ferroptosis in neuroblastoma cells [36]. Together, these studies suggest that hPrdx6 inhibition might be exploited as a therapeutic strategy to sensitize cancer cells to ferroptosis, but further studies are still needed to validate hPrdx6 as a biological target for cancer treatment [26, 35, 36].

hPrdx6 has also been recognized as a potential biological target for treating infectious diseases. Remarkably, hPrdx6 from human host erythrocytes has been shown to be internalized by Plasmodium falciparum during hemoglobin uptake in the blood-stage of the parasite’s life cycle [48]. Internalized hPrdx6 favors P. falciparum development and growth due to its role in lipid peroxidation damage repair, protecting the parasite against oxidative stress [48]. Darapladib, a PLA2 inhibitor, has been shown to inhibit hPrdx6 aiPLA2 activity and block P. falciparum growth. Therefore, hPrdx6 has been suggested to be a potential host-based biological target for the development of anti-malaria drugs [48]. As discussed in the literature, approaches that target host proteins are attractive in the treatment of infectious diseases because parasites are unable to mutate host genes, which diminishes the chance of drug resistance development [48].

The potential roles of hPrdx6 in the pathogenesis of central nervous system disorders, including neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), have also been the focus of several studies, as recently reviewed in the literature [49]. Remarkably, a recent study has suggested that Prdx6 is upregulated in cytotoxic A1 astrocytes from the lumbar spinal cord of SOD1G93A mouse model of ALS [50]. Prdx6 overexpression in A1 astrocytes has been associated with the production of inflammatory cytokines that contribute to neuron degeneration in ALS, possibly via aiPLA2 activity [50]. However, further studies are needed to confirm the association between Prdx6 overexpression in A1 astrocytes and inflammation in ALS, and to elucidate the mechanisms by which Prdx6 would contribute to cytokine production in A1 astrocytes.

In the respiratory system, hPrdx6 aiPLA2 activity is thought to be required for agonist-induced activation of NADPH oxidase 2 (NOX2) in neutrophils and in pulmonary microvascular endothelial cells [18, 51]. It has been suggested that hPrdx6-mediated activation of NOX2 is a key event in hyperoxic acute lung injury because NOX2 is responsible for reactive oxygen species (ROS) generation as part of the oxidative burst promoted by inflammatory cells in response to continuous exposure of lung tissue to high O2 concentrations [18, 51]. Consistent with this hypothesis, inhibition of hPrdx6 aiPLA2 activity by MJ33 and by a peptide inhibitor has been reported to protect against acute lung injury associated with hyperoxia in mouse models, possibly by blocking NOX2 activation [18, 19]. However, further studies are needed to confirm this hypothesis and to validate the inhibition of hPrdx6 aiPLA2 activity as an effective therapeutic strategy in the prevention of lung injury associated with hyperoxia. Additionally, the specific products of hPrdx6 aiPLA2-mediated phospholipid hydrolysis that are responsible for triggering NOX2 activation, as well as details on the mechanisms by which they act, remain to be unveiled, as discussed in the literature [18].

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4. Concluding remarks and perspectives

In summary, much progress has been made regarding the elucidation of the structure, biological functions, and pathophysiological roles of hPrdx6 over the last decades. hPrdx6 has been recognized to be crucial for the maintenance of cell homeostasis through its well-known peroxidase, aiPLA2, and LPCAT activities, which are tightly associated with the unique structural features that differentiate it from other Prx family members, as revealed by X-ray crystallography studies [2, 3]. At the same time, an increasing number of studies have shown the impact of alterations in hPrdx6 expression levels and/or functions in multiple pathophysiological processes and diseases, including inflammation [18, 19, 51], cancer [26, 35, 36, 42–47], infectious diseases [48], and neurodegenerative diseases [49, 50].

The recent discovery of a novel function for hPrdx6 as a selenium acceptor protein, which is implicated in the biosynthesis of selenoproteins like GPX4, has contributed significantly to the understanding of hPrdx6's role in ferroptosis regulation, opening the field for exploiting hPrdx6 inhibition as a possible strategy to sensitize tumor cells to ferroptosis [26, 35, 36]. This has been supported by both in vivo studies and patient-based models of different tumor types, including neuroblastoma [26], lung adenocarcinoma [35], and hepatocellular carcinoma [44], which have shown a clear association between hPrdx6 overexpression and increased tumor growth, in addition to poor survival outcomes. As discussed in the literature, targeting hPrdx6, in combination with complementary therapeutic approaches, has emerged as a promising strategy to circumvent ferroptosis resistance and/or resistance against conventional antitumor (chemo)therapies, which represents a major challenge to be addressed in cancer treatment [26, 35, 36].

Despite the recent advances in the field, the real therapeutic benefit of triggering ferroptosis through hPrdx6 inhibition is still to be proven, and further studies are needed to validate hPrdx6 as a biological target for treating cancer and other human diseases. There is also a need for additional studies to investigate details of hPrdx6’s action in specific biochemical pathways at molecular and/or cellular levels, including the interaction with its biomolecular binding partners, such as SEPHS2, and/or with potential small-molecule substrates. hPrdx6 inhibitors acting as chemical probes for manipulating its multiple enzymatic activities in vitro might be very helpful in this regard. Nevertheless, only a few hPrdx6 inhibitors have been reported in the literature so far, and some of them lack selectivity toward hPrdx6, which is a requirement for their successful use as chemical probes in cell-based assays [17, 18, 33, 52, 53]. Additionally, hPrdx6 remains underexploited as a putative drug target, and the few known hPrdx6 inhibitors have structural, physicochemical, and/or pharmacological properties that limit their applicability as potential drug candidates. Therefore, the discovery of novel hPrdx6 inhibitors representing either chemical probes or potential drug candidates would be highly beneficial. As a perspective, in advanced stages of drug discovery efforts targeting hPrdx6, the design of pharmaceutical nanoformulations may be helpful as a strategy to address potential limitations of known and novel hPrdx6 inhibitors in terms of drug development, such as low aqueous solubility, poor bioavailability, and high in vivo toxicity, contributing ultimately to improving their pharmacokinetics and safety profiles (Figure 5).

Figure 5.

Overview of the steps in the exploitation of hPrdx6 as a biological target for inhibitor design and drug development.

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Acknowledgments

The authors acknowledge Prof. Luis E. S. Netto (Biosciences Institute, University of São Paulo), Prof. Flavia C. Meotti (Insitute of Chemistry, University of São Paulo) and Prof. Jose Pedro Friedmann Angeli (University of Würzburg, Germany) for scientific discussions.

L.G.V. acknowledges his postdoctoral fellowships from FAPESP (#2021/10514-8) and CNPq (#154337/2025-0). S.M. acknowledges funding from FAPESP CEPID – Redoxoma (#2013/07937-8), CAPES-Finance code 001, INCT (#408213/2024-8) and CNPq (#313926/2021-2).

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Conflict of Interest

The authors declare no conflict of interest.

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Written By

Lucas G. Viviani and Sayuri Miyamoto

Submitted: 26 January 2026 Reviewed: 17 February 2026 Published: 02 April 2026

© 2026 The Author(s). Licensee IntechOpen. This content is distributed under the terms of the Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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