Enhancing microbial superoxide generation and conversion to hydroxyl radicals for enhanced bioremediation using iron-binding ligands.

Harnessing bacteria for superoxide production in bioremediation holds immense promise, yet its practical application is hindered by slow production rates and the relatively weak redox potential of superoxide. This study delves into a cost-effective approach to amplify superoxide production using an Arthrobacter strain, a prevalent soil bacterial genus. Our research reveals that introducing a carbon source along with specific iron-binding ligands, including deferoxamine (DFO), diethylenetriamine pentaacetate (DTPA), citrate, and oxalate, robustly augments microbial superoxide generation. Moreover, our findings suggest that these iron-binding ligands play a pivotal role in converting superoxide into hydroxyl radicals by modulating the electron transfer rate between Fe(III)/Fe(II) and superoxide. Remarkably, among the tested ligands, only DTPA emerges as a potent promoter of this conversion process when complexed with Fe(III). We identify an optimal Fe(III) to DTPA ratio of approximately 1:1 for enhancing hydroxyl radical production within the Arthrobacter culture. This research underscores the efficacy of simultaneously introducing carbon sources and DTPA in facilitating superoxide production and its subsequent conversion to hydroxyl radicals, significantly elevating bioremediation performance. Furthermore, our study reveals that DTPA augments superoxide production in cultures of diverse soils, with various soil microorganisms beyond Arthrobacter identified as contributors to superoxide generation. This emphasizes the universal applicability of DTPA across multiple bacterial genera. In conclusion, our study introduces a promising methodology for enhancing microbial superoxide production and its conversion into hydroxyl radicals. These findings hold substantial implications for the deployment of microbial reactive oxygen species in bioremediation, offering innovative solutions for addressing environmental contamination challenges.

Iron oxide nanozymes enhanced by ascorbic acid for macrophage-based cancer therapy.

In recent years, using pharmacological ascorbic acid has emerged as a promising therapeutic approach in cancer treatment, owing to its capacity to induce extracellular hydrogen peroxide (H2O2) production in solid tumors. The H2O2 is then converted into cytotoxic hydroxyl free radicals (HO˙) by redox-active Fe2+ inside cells. However, the high dosage of ascorbic acid required for efficacy is hampered by adverse effects such as kidney stone formation. In a recent study, we demonstrated the efficient catalytic conversion of H2O2 to HO˙ by wüstite (Fe1-xO) nanoparticles (WNPs) through a heterogenous Fenton reaction. Here, we explore whether WNPs can enhance the therapeutic potential of ascorbic acid, thus mitigating its dose-related limitations. Our findings reveal distinct pH dependencies for WNPs and ascorbic acid in the Fenton reaction and H2O2 generation, respectively. Importantly, WNPs exhibit the capability to either impede or enhance the cytotoxic effect of ascorbic acid, depending on the spatial segregation of the two reagents by cellular compartments. Furthermore, our study demonstrates that treatment with ascorbic acid promotes the polarization of WNP-loaded macrophages toward a pro-inflammatory M1 phenotype, significantly suppressing the growth of 4T1 breast cancer cells. This study highlights the importance of orchestrating the interplay between ascorbic acid and nanozymes in cancer therapy and presents a novel macrophage-based cell therapy approach.

Cytotoxic and radical activities of metal-organic framework modified with iron oxide: Biological and physico-chemical analyses.

Metal-organic framework (MOF) modified with iron oxide, Fe3O4-MOF, is a perspective drug delivery agent, enabling magnetic control and production of active hydroxyl radicals, •OH, via the Fenton reaction. This paper studies cytotoxic and radical activities of Fe-containing nanoparticles (NPs): Fe3O4-MOF and its components - bare Fe3O4 and MOF (MIL-88B). Luminous marine bacteria Photobacteriumphosphoreum were used as a model cellular system to monitor bioeffects of the NPs. Neither the NPs of Fe3O4-MOF nor MOF showed cytotoxic effects in a wide range of concentrations (<10 mg/L); while Fe3O4 was toxic at >3·10-3 mg/L. The NPs of Fe3O4 did not affect the bacterial bioluminescence enzymatic system; their toxic effect was attributed to cellular membrane processes. The integral content of reactive oxygen species (ROS) was determined using a chemiluminescence luminol assay. Bacteria mitigated excess of ROS in water suspensions of Fe3O4-MOF and MOF, maintaining bioluminescence intensity closer to the control; this resulted in low toxicity of these NPs. We estimated the activity of •OH radicals in the NPs samples with physical and chemical methods - spin capture technology (using electron paramagnetic resonance spectroscopy) and methylene blue degradation. Physico-chemical interpretation of cellular responses is provided in terms of iron content, iron ions release and •OH radical production.

Hydrogen therapy: recent advances and emerging materials.

Hydrogen therapy, leveraging its selective attenuation of hydroxyl radicals (˙OH) and ONOO-, has emerged as a pivotal pathophysiological modulator with antioxidant, anti-inflammatory, and antiapoptotic attributes. Hydrogen therapy has been extensively studied both preclinically and clinically, especially in diseases with an inflammatory nature. Despite the substantial progress, challenges persist in achieving high hydrogen concentrations in target lesions, especially in cancer treatment. A notable breakthrough lies in water/acid reactive materials, offering enhanced hydrogen generation and sustained release potential. However, limitations include hydrogen termination upon material depletion and reduced bioavailability at targeted lesions. To overcome these challenges, catalytic materials like photocatalytic and sonocatalytic materials have surfaced as promising solutions. With enhanced permeability and retention effects, these materials exhibit targeted delivery and sustained stimuli-reactive hydrogen release. The future of hydrogen therapy hinges on continuous exploration and modification of catalytic materials. Researchers are urged to prioritize improved catalytic efficiency, enhanced lesion targeting effects, and heightened biosafety and biocompatibility in future development.

Dual-Site Chemosensor for Visualizing •OH-GSH Redox and Tracking Ferroptosis-Inducing Pathways In Vivo.

Oxidative stress, characterized by an imbalance between oxidative and antioxidant processes, results in excessive accumulation of intracellular reactive oxygen species. Among these responses, the regulation of intracellular hydroxyl radicals (•OH) and glutathione (GSH) is vital for physiological processes. Real-time in situ monitoring these two opposing bioactive species and their redox interactions is essential for understanding physiological balance and imbalance. In this study, we developed a dual-site fluorescence chemosensor OG-3, which can independently image both exogenous and endogenous •OH and GSH in separate channels both within cells and in vivo, eliminating issues of spatiotemporal inhomogeneous distribution and cross-interference. With its imaging capabilities of monitoring •OH-GSH redox, OG-3 elucidated two different pathways for ferroptosis induction: (i) inhibition of system xc- to block cystine uptake (extrinsic pathway) and (ii) GPX4 inactivation, leading to the loss of antioxidant defense (intrinsic pathway). Moreover, we assessed the antiferroptotic function and effects of ferroptosis inhibitors by monitoring •OH and GSH fluctuations during ferroptosis. This method provides a reliable platform for identifying potential ferroptosis inhibitors, contributing to our understanding of relevant metabolic and physiological mechanisms. It shows potential for elucidating the regulation of ferroptosis mechanisms and investigating further strategies for therapeutic applications.

A Customized Biohybrid Presenting Cascade Responses to Tumor Microenvironment.

Intrinsic characteristics of microorganisms, including non-specific metabolism sites, toxic byproducts, and uncontrolled proliferation constrain their exploitation in medical applications such as tumor therapy. Here, the authors report an engineered biohybrid that can efficiently target cancerous sites through a pre-determined metabolic pathway to enable precise tumor ablation. In this system, DH5α Escherichia coli is engineered by the introduction of hypoxia-inducible promoters and lactate oxidase genes, and further surface-armored with iron-doped ZIF-8 nanoparticles. This bioengineered E. coli can produce and secrete lactate oxidase to reduce lactate concentration in response to hypoxic tumor microenvironment, as well as triggering immune activation. The peroxidase-like functionality of the nanoparticles extends the end product of the lactate metabolism, enabling the conversion of hydrogen peroxide (H2O2) into highly cytotoxic hydroxyl radicals. This, coupled with the transformation of tirapazamine loaded on nanoparticles to toxic benzotriazinyl, culminates in severe tumor cell ferroptosis. Intravenous injection of this biohybrid significantly inhibits tumor growth and metastasis.

Oxidative photocatalysis on membranes triggers non-canonical pyroptosis.

Intracellular membranes composing organelles of eukaryotes include membrane proteins playing crucial roles in physiological functions. However, a comprehensive understanding of the cellular responses triggered by intracellular membrane-focused oxidative stress remains elusive. Herein, we report an amphiphilic photocatalyst localised in intracellular membranes to damage membrane proteins oxidatively, resulting in non-canonical pyroptosis. Our developed photocatalysis generates hydroxyl radicals and hydrogen peroxides via water oxidation, which is accelerated under hypoxia. Single-molecule magnetic tweezers reveal that photocatalysis-induced oxidation markedly destabilised membrane protein folding. In cell environment, label-free quantification reveals that oxidative damage occurs primarily in membrane proteins related to protein quality control, thereby aggravating mitochondrial and endoplasmic reticulum stress and inducing lytic cell death. Notably, the photocatalysis activates non-canonical inflammasome caspases, resulting in gasdermin D cleavage to its pore-forming fragment and subsequent pyroptosis. These findings suggest that the oxidation of intracellular membrane proteins triggers non-canonical pyroptosis.

Oxidation effects on Microcystis aeruginosa inactivation through various reactive oxygen species: Degradation efficiency, mechanisms, and physiological properties.

The study investigated the inactivation of Microcystis aeruginosa using a combined approach involving thermally activated peroxyacetic acid (Heat/PAA) and thermally activated persulfate (Heat/PDS). The Heat/PDS algal inactivation process conforms to first-order reaction kinetics. Both hydroxyl radical (•OH) and sulfate radical (SO4-•) significantly impact the disruption of cell integrity, with SO4-• assuming a predominant role. PAA appears to activate organic radicals (RO•), hydroxyl (•OH), and a minimal amount of singlet oxygen (1O2). A thorough analysis underscores persulfate's superior ability to disrupt algal cell membranes. Additionally, SO4-• can convert small-molecule proteins into aromatic hydrocarbons, accelerating cell lysis. PAA can accelerate cell death by diffusing into the cell membrane and triggering advanced oxidative reactions within the cell. This study validates the effectiveness of the thermally activated persulfate process and the thermally activated peroxyacetic acid as strategies for algae inactivation.

Myofibrillar protein hydrolysis under hydroxyl radical oxidative stress: Structural changes and their impacts on binding to selected aldehydes.

In this study, a hydroxyl radical oxidation system was established to simulate the oxidation process in fermented meat products. This system was employed to examine the structural changes in myofibrillar proteins (MPs) resulting from tryptic hydrolysis after a hydroxyl radical oxidative regime. The effect of these changes on the ability of MPs to bind selected aldehydes (3-methyl butanal, pentanal, hexanal, and heptanal) was also investigated. Moderate oxidation (H2O2 ≤ 1.0 mM) unfolded the structure of MPs, facilitating trypsin-mediated hydrolysis and increasing their binding capacity for the four selected aldehydes. However, excessive oxidation (H2O2 ≥ 2.5 mM) led to cross-linking and aggregation of MPs, inhibiting trypsin-mediated hydrolysis. The oxidised MPs had the best binding capacity for heptanal. The interaction of the oxidised trypsin-hydrolysed MPs with heptanal was driven by hydrophobic interactions. The binding of heptanal affected the structure of the oxidised trypsin-hydrolysed MPs and reduced their α-helix content.

Mitochondria-mediated self-cycling nanoreactor enabling uninterrupted oxidative damage for enhanced chemodynamic therapy.

Chemodynamic therapy (CDT), which employs intracellular H2O2 to produce toxic hydroxyl radicals to kill cancer cells, has received great attention due to its specificity to tumors. However, the relatively insufficient endogenous H2O2 and the short-lifetime and limited diffusion distance of •OH compromise the therapeutic efficacy of CDT. Mitochondria, which play crucial roles in oncogenesis, are highly vulnerable to elevated oxidative stress. Herein, we constructed a mitochondria-mediated self-cycling system to achieve high dose of •OH production through continuous H2O2 supply. Cinnamaldehyde (CA), which can elevate H2O2 level in the mitochondria, was loaded in Cu(II)-containing metal organic framework (MOF), termed as HKUST-1. After actively targeting mitochondria, the intrinsic H2O2 in mitochondria of cancer cells could induce degradation of MOF, releasing the initial free CA. The released CA further triggered the upregulation of endogenous H2O2, resulting in the subsequent adequate release of CA and the final burst growth of H2O2. The cycle process greatly promoted the Fenton-like reaction between Cu2+ and H2O2 and induced long-term high oxidative stress, achieving enhanced chemodynamic therapy. In a word, we put forward an efficient strategy for enhanced chemodynamic therapy.

A Combination of Biocatalysis and Fenton-Like Reaction Induced OH• Burst for Cascade Amplification of Cancer Chemodynamic Therapy.

Chemodynamic therapy (CDT) is a novel antitumor strategy that employs Fenton or Fenton-like reactions to generate highly toxic hydroxyl radical (OH•) from hydrogen peroxide (H2O2) for inducing tumor cell death. However, the antitumor efficacy of the CDT strategy is harshly limited by the redox homeostasis of tumor cells; especially the OH • is easily scavenged by glutathione (GSH) and the intracellular H2O2 level is insufficient in the tumor cells. Herein, we propose the Mn2+-menadione (also known as vitamin K3, MK3) cascade biocatalysis strategy to disrupt the redox homeostasis of tumor cells and induce a OH• storm, resulting in enhanced CDT effect. A nanoliposome encapsulating Mn-MK3 (Mn-MK3@LP) was prepared for the treatment of hepatic tumors in this study. After Mn-MK3@LPs were taken up by tumor cells, menadione could facilitate the production of intracellular H2O2 via redox cycling, and further the cytotoxic OH • burst was induced by Mn2+-mediated Fenton-like reaction. Moreover, high-valent manganese ions were reduced by GSH and the depletion of GSH further disrupted the redox homeostasis of tumor cells, thus achieving synergistically enhanced CDT. Overall, both cellular and animal experiments confirmed that the Mn-MK3@LP cascade biocatalysis nanoliposome exhibited excellent biosafety and tumor suppression efficacy. This study may provide deep insights for developing novel CDT-based strategies for tumor therapy.

Heat Shock Protein HSP27 and the Status of the Glutathione System in Dexamethasone-Induced Apoptosis of Jurkat Tumor Cells.

We studied the effect of the HSP27 inhibitor, 5-(5-ethyl-2-hydroxy-4-methoxyphenyl)-4-(4-methoxyphenyl)-isoxazole, at a final concentration of 0.1 µM and/or the apoptosis inducer dexamethasone at a final concentration of 10 µM on the content of hydroxyl radical, reduced and oxidized glutathione, HSP27, activity of glutathione reductase, glutathione peroxidase, caspase-3, and the number of Annexin+ Jurkat tumor cells. The involvement of HSP27 in apoptosis of Jurkat tumor cells was demonstrated. Simultaneous exposure to the HSP27 inhibitor and dexamethasone resulted in an increase in the level of HSP27 against the background of developing oxidative stress (increase in the concentration of hydroxyl radicals and changes in the state of the glutathione system).

Copper peroxide nanodot-decorated gold nanostar/silica nanorod Janus nanostructure with NIR-II photothermal and acid-triggered hydroxyl radical generation properties for the effective treatment of wound infections.

Recently, bacterial infections have become a global crisis, greatly threatening the health of human beings. The development of a non-antibiotic biomaterial is recognized as an alternative way for the effective treatment of bacterial infections. In the present work, a multifunctional copper peroxide (CP) nanodot-decorated gold nanostar (GNS)/silica nanorod (SiNR) Janus nanostructure (GNS@CP/SiNR) with excellent antibacterial activity was reported. Due to the formation of the Janus nanostructure, GNS@CP/SiNR displayed strong plasmonic resonance absorbance in the near infrared (NIR)-II region that enabled the nanosystem to achieve mild photothermal therapy (MPTT). In acidic conditions, CP decorated on GNS@CP/SiNR dissociated rapidly by releasing Cu2+ and H2O2, which subsequently transformed to ˙OH via the Fenton-like reaction for chemodynamic therapy (CDT). As a result, GNS@CP/SiNR could effectively inhibit both Gram-negative Escherichia coli (E. coli) and Gram-positive Staphylococcus aureus (S. aureus), and eradicate the associated bacterial biofilms by exerting the synergistic MPTT/CDT antibacterial effect. Moreover, GNS@CP/SiNR was also demonstrated to be effective in treating wound infections, as verified on the S. aureus-infected full thickness excision wound rat model. Our mechanism study revealed that the synergistic MPTT/CDT effect of GNS@CP/SiNR firstly caused bacterial membrane damage, followed by boosting intracellular ROS via the severe oxidative stress effect, which subsequently caused the depletion of intracellular GSH and DNA damage, finally leading to the death of bacteria.

A ROS storm generating nanocomposite for enhanced chemodynamic therapy through H2O2 self-supply, GSH depletion and calcium overload.

Catalytic generation of toxic hydroxyl radicals (˙OH) from hydrogen peroxide (H2O2) is an effective strategy for tumor treatment in chemodynamic therapy (CDT). However, the intrinsic features of the microenvironment in solid tumors, characterized by limited H2O2 and overexpressed glutathione (GSH), severely impede the accumulation of intracellular ˙OH, posing significant challenges. To circumvent these critical issues, in this work, a CaO2-based multifunctional nanocomposite with a surface coating of Cu2+ and L-buthionine sulfoximine (BSO) (named CaO2@Cu-BSO) is designed for enhanced CDT. Taking advantage of the weakly acidic environment of the tumor, the nanocomposite gradually disintegrates, and the exposed CaO2 nanoparticles subsequently decompose to produce H2O2, alleviating the insufficient supply of endogenous H2O2 in the tumor microenvironment (TME). Furthermore, Cu2+ detached from the surface of CaO2 is reduced by H2O2 and GSH to Cu+ and ROS. Then, Cu+ catalyzes H2O2 to generate highly cytotoxic ˙OH and Cu2+, forming a cyclic catalysis effect for effective CDT. Meanwhile, GSH is depleted by Cu2+ ions to eliminate possible ˙OH scavenging. In addition, the decomposition of CaO2 by TME releases a large amount of free Ca2+, resulting in the accumulation and overload of Ca2+ and mitochondrial damage in tumor cells, further improving CDT efficacy and accelerating tumor apoptosis. Besides, BSO, a molecular inhibitor, decreases GSH production by blocking γ-glutamyl cysteine synthetase. Together, this strategy allows for enhanced CDT efficiency via a ROS storm generation strategy in tumor therapy. The experimental results confirm and demonstrate the satisfactory tumor inhibition effect both in vitro and in vivo.

UV-aged polystyrene nanoplastics aggravate intestinal barrier damage by overproduction of ROS.

UV irradiation significantly alters nanoplastics (NPs) physicochemical properties, thus affecting their biological toxicity. This study is the first to assess the influence of virgin and UV-aged polystyrene NPs (v-PS NPs, a-PS NPs) on the intestinal barrier of ICR mice. We found that a-PS NPs can cause more severe intestinal barrier damage compared with v-PS NPs. The reason may be attributed to that a-PS NPs produced more ROS in intestinal tissue. Moreover, the strong oxidizing property of hydroxyl radicals (·OH) generated from the a-PS NPs can damage cell membranes through lipid peroxidation, thereby leading to a low clearance rate of ·OH due to the impaired intestinal tissue function, in turn, causing more ROS to accumulate and inducing severe oxidative damage. This research underscores the crucial role of ·OH in mediating oxidative damage from UV-aged nanoparticles, emphasizing the need to consider environmental factors in assessing NPs toxicity.

Recent Advances in Detection of Hydroxyl Radical by Responsive Fluorescence Nanoprobes.

Hydroxyl radical (•OH), a highly reactive oxygen species (ROS), is assumed as one of the most aggressive free radicals. This radical has a detrimental impact on cells as it can react with different biological substrates leading to pathophysiological disorders, including inflammation, mitochondrion dysfunction, and cancer. Quantification of this free radical in-situ plays critical roles in early diagnosis and treatment monitoring of various disorders, like macrophage polarization and tumor cell development. Luminescence analysis using responsive probes has been an emerging and reliable technique for in-situ detection of various cellular ROS, and some recently developed •OH responsive nanoprobes have confirmed the association with cancer development. This paper aims to summarize the recent advances in the characterization of •OH in living organisms using responsive nanoprobes, covering the production, the sources of •OH, and biological function, especially in the development of related diseases followed by the discussion of luminescence nanoprobes for •OH detection.

Fenton-like Reaction Inspired "·OH Catalyzed" Osteogenic Process for the Treatment of Osteoporosis.

Inspired by the Fenton-like reaction, this work combines copper peroxide (CP) nanoparticles with black phosphorus (BP) nanosheets to form a hydroxyl radical (·OH)-centered "catalytic" osteogenic system. CP-produced ·OH interacts with BP to rapidly produce a large amount of phosphate ions, thus accelerating self-mineralization and promoting bone formation. In turn, BP not only exerts anti-inflammatory effects, thereby providing a favorable microenvironment for bone formation, but also offsets the potential toxicity of CP induced by reactive oxygen species (ROS). Together with copper ions (Cu2+), phosphate ions are also released as a byproduct of this process, which can contribute to the comprehensive promotion of osteogenesis.

Enhanced ·OH-Scavenging Activity of Cu-CeOx Nanozyme via Resurrecting Macrophage Nrf2 Transcriptional Activity Facilitates Diabetic Wound Healing.

Diabetic wounds are a prevalent and devastating complication of diabetes, which may impede their healing and regeneration. In diabetic wounds, excess reactive oxygen species (ROS) activate the nuclear factor kappa-B pathway, leading to transcriptional silencing of nuclear factor erythroid 2-related factor 2 (Nrf2), resulting in a vicious cycle of oxidative stress and inflammation. Conventional nanozymes have limitations in preventing the continuous production of ROS, including the most oxidizing reactive hydroxyl radical (·OH), although they can remove pre-existing ROS. Herein, a novel antioxidant nanoplatform addresses this challenge by incorporating JSH-23 into the mesoporous of cupric-doped cerium oxide nanozymes. Additionally, for rapid wound adaptability and durable tissue adhesion, a nanozyme hydrogel spray consisting of oxidized sodium alginate and methacrylate gelatin is constructed, named OG@CCJs. This platform resurrects Nrf2 transcriptional activity of macrophages in vitro, curbing the production of ROS at its source, particularly ·OH, while enabling the nanozymes to scavenge previously generated ROS. OG@CCJs significantly alleviate oxidative stress in diabetic wounds in vivo, promoting wound healing. Overall, the proposed nanozyme-hydrogel spray with enhanced ·OH-scavenging activity uses a "two-track" antioxidant strategy to rebuild the antioxidant defense barrier of macrophages. This pioneering approach highlights the tremendous potential of OG@CCJs for facilitating diabetic wound healing.

Metabolism-Regulating Nanozyme System for Advanced Nanocatalytic Cancer Therapy.

Nanocatalytic therapy, an emerging approach in cancer treatment, utilizes nanomaterials to initiate enzyme-mimetic catalytic reactions within tumors, inducing tumor-suppressive effects. However, the targeted and selective catalysis within tumor cells is challenging yet critical for minimizing the adverse effects. The distinctive reliance of tumor cells on glycolysis generates abundant lactate, influencing the tumor's pH, which can be manipulated to selectively activate nanozymatic catalysis. Herein, small interfering ribonucleic acid (siRNA) targeting lactate transporter-mediated efflux is encapsulated within the iron-based metal-organic framework (FeMOF) and specifically delivered to tumor cells through cell membrane coating. This approach traps lactate within the cell, swiftly acidifying the tumor cytoplasm and creating an environment for boosting the catalysis of the FeMOF nanozyme. The nanozyme generates hydroxyl radical (·OH) in the reversed acidic environment, using endogenous hydrogen peroxide (H2O2) produced by mitochondria as a substrate. The induced cytoplasmic acidification disrupts calcium homeostasis, leading to mitochondrial calcium overload, resulting in mitochondrial dysfunction and subsequent tumor cell death. Additionally, the tumor microenvironment is also remodeled, inhibiting migration and invasion, thus preventing metastasis. This groundbreaking strategy combines metabolic regulation with nanozyme catalysis in a toxic drug-free approach for tumor treatment, holding promise for future clinical applications.

Morc2a variants cause hydroxyl radical-mediated neuropathy and are rescued by restoring GHKL ATPase.

Mutations in the Microrchidia CW-type zinc finger 2 (MORC2) GHKL ATPase module cause a broad range of neuropathies, such as Charcot-Marie-Tooth disease type 2Z; however, the aetiology and therapeutic strategy are not fully understood. Previously, we reported that the Morc2a p.S87L mouse model exhibited neuropathy and muscular dysfunction through DNA damage accumulation. In the present study, we analysed the gene expression of Morc2a p.S87L mice and designated the primary causing factor. We investigated the pathological pathway using Morc2a p.S87L mouse embryonic fibroblasts and human fibroblasts harbouring MORC2 p.R252W. We subsequently assessed the therapeutic effect of gene therapy administered to Morc2a p.S87L mice. This study revealed that Morc2a p.S87L causes a protein synthesis defect, resulting in the loss of function of Morc2a and high cellular apoptosis induced by high hydroxyl radical levels. We considered the Morc2a GHKL ATPase domain as a therapeutic target because it simultaneously complements hydroxyl radical scavenging and ATPase activity. We used the adeno-associated virus (AAV)-PHP.eB serotype, which has a high CNS transduction efficiency, to express Morc2a or Morc2a GHKL ATPase domain protein in vivo. Notably, AAV gene therapy ameliorated neuropathy and muscular dysfunction with a single treatment. Loss-of-function characteristics due to protein synthesis defects in Morc2a p.S87L were also noted in human MORC2 p.S87L or p.R252W variants, indicating the correlation between mouse and human pathogenesis. In summary, CMT2Z is known as an incurable genetic disorder, but the present study demonstrated its mechanisms and treatments based on established animal models. This study demonstrates that the Morc2a p.S87L variant causes hydroxyl radical-mediated neuropathy, which can be rescued through AAV-based gene therapy.