Free Radic. Biol. Med. [JOURNAL]
Sun
200 papers
CAND1 drives intestinal ischemia/reperfusion injury via SCF-PKM2-mediated mitochondrial fission and apoptosis.
Qiang M, Zhao Y, Wang G … +8 more , Chen Z, Zhang F, Wang Z, Wang G, Zhuang C, Ning S, Yao J, Tian X
Free Radic Biol Med · 2026 Jun · PMID 42297194 · Publisher ↗
BACKGROUND: Intestinal ischemia/reperfusion (I/R) injury is a critical clinical condition associated with high mortality, in which the ubiquitin‒proteasome system (UPS) plays a pivotal pathogenic role. Cullin-associated...
BACKGROUND: Intestinal ischemia/reperfusion (I/R) injury is a critical clinical condition associated with high mortality, in which the ubiquitin‒proteasome system (UPS) plays a pivotal pathogenic role. Cullin-associated and neddylation-dissociated 1 (CAND1), a critical regulator of cellular protein homeostasis, governs the ubiquitination and degradation of abnormal protein substrates by regulating the assembly of SKP1‒Cullin1‒F-box (SCF) E3 ubiquitin ligase complexes. However, the mechanisms by which CAND1 regulates SCF complex assembly and its potential therapeutic role in intestinal I/R injury remain unclear. OBJECTIVES: This study aims to elucidate the molecular mechanisms by which CAND1 mediates intestinal I/R injury and to identify potential therapeutic strategies targeting CAND1. METHODS: Intestinal I/R was induced by superior mesenteric artery (SMA) occlusion in mice. Four weeks before I/R challenge, AAV-CAND1 was injected into the mice via the tail vein. Evodiamine (evo) was administered daily via intraperitoneal injection for three days before I/R challenge. Caco-2 cells were subjected to hypoxia/reoxygenation (H/R) treatment in vitro to simulate intestinal I/R in mice. RESULTS: Excessive oxidative stress during intestinal I/R injury triggers mitochondrial fission and apoptosis. We identified CAND1 as a key regulator in this process, demonstrating upregulated expression during intestinal I/R injury. CAND1 knockdown attenuated reactive oxygen species (ROS) overproduction, mitochondrial fission, and apoptosis. Mechanistically, CAND1 inhibited Cullin1-FBXO6-PKM2 complex assembly and reduced PKM2 ubiquitination and degradation, thereby increasing PKM2 stability. Phosphorylated PKM2 formed dimers and translocated to mitochondria, where it activated Drp1-dependent fission pathway, worsening oxidative stress and apoptosis. Through molecular docking, evo was identified as a potential small-molecule candidate targeting CAND1. CAND1 may be inhibited by evo, thereby alleviating intestinal I/R injury. CONCLUSION: CAND1 suppresses Cullin1-FBXO6-PKM2 complex assembly and PKM2 ubiquitination, promoting PKM2 dimerization-mediated mitochondrial fission and apoptosis in intestinal I/R injury. CAND1 is likely inhibited by evo, thereby alleviating mitochondrial dynamic alterations and cell death during intestinal I/R injury.
Environmental factors modulate the responsiveness and reversibility of the HO-induced inactivation of GAPDH.
Boms K, Jørgensen SM, Hägglund P … +3 more , Radi R, Davies MJ, Fuentes-Lemus E
Free Radic Biol Med · 2026 Jun · PMID 42297193 · Publisher ↗
The glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) serves as a critical metabolic switch. GAPDH inactivation by hydrogen peroxide (HO) reroutes the carbon flux towards the pentose phosphate pathway to...
The glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) serves as a critical metabolic switch. GAPDH inactivation by hydrogen peroxide (HO) reroutes the carbon flux towards the pentose phosphate pathway to generate NADPH for antioxidant defence enzymes. However, a significant discrepancy exists between the modest in vitro sensitivity of GAPDH to HO with its rapid inactivation within cells. We hypothesized that two commonly neglected characteristics of the intracellular milieu - macromolecular crowding and the presence of bicarbonate - would modulate HO-induced inactivation of GAPDH. To explore this hypothesis, we systematically investigated GAPDH inactivation after exposure to physiologically-relevant HO doses, comparing dilute buffered conditions to systems containing bicarbonate and an inert high molecular mass polymer to simulate the molecular crowding present in vivo. Effects of the substrate and cofactor on enzyme inactivation were also quantified. Enzyme activity assays revealed that both crowded conditions and the presence of bicarbonate significantly enhanced HO-induced inactivation, with NAD further enhancing this responsiveness. LC-MS/MS data support the oxidation of the catalytic cysteine to an intramolecular disulfide bond which results in a loss of activity but prevents irreversible inactivation. The disulfide involving the catalytic cysteine showed an increase in the total occupancy from 3.2 % under dilute conditions to 11.6 % and 31.8 % under crowded + bicarbonate conditions in the absence and presence of 400 μM NAD, respectively. This work bridges the gap in terms of responsiveness and reversibility of a key metabolic enzyme that serves as redox switch highlighting how physico-chemical (crowding) and chemical (bicarbonate, NAD) environmental factors determine metabolic regulation under oxidative stress.
Redoxyme: a lightweight graphical user interface for standardized calculation of antioxidant enzyme activities.
Carvalho de Freitas Soares G, Lídia Nunes Varela A, Tarso Facundo H
Free Radic Biol Med · 2026 Jun · PMID 42289223 · Publisher ↗
Redox imbalance results from excessive accumulation of reactive oxygen species (ROS) due to either a low removal or higher production. This imbalance plays a central role in numerous physiological and pathological proces...
Redox imbalance results from excessive accumulation of reactive oxygen species (ROS) due to either a low removal or higher production. This imbalance plays a central role in numerous physiological and pathological processes. Accurate quantification and report of antioxidant enzyme activities are therefore essential in redox biology research. However, data analysis for commonly used antioxidant enzyme activity assays, such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), are frequently performed using spreadsheets or manual calculations, which are time-consuming and prone to error. In this study, we systematically evaluated the reporting practices for SOD, GPx, and CAT across the literature. We identified substantial heterogeneity in the reporting of CAT, SOD, and GPx activities, characterized by inconsistencies in unit definitions and normalization approaches that frequently preclude direct cross-study comparability. To address this, we developed a free, open-source, Python-based graphical user interface (Redoxyme) designed to standardize and automate the calculation of antioxidant enzyme activities. The software integrates protein normalization, enzyme-specific calculation routines, data visualization, and Excel export within an intuitive interface that does not require programming expertise. Redoxyme was validated using experimental data obtained from animal tissues (mice and rats), demonstrating excellent agreement with manual calculations and established analytical methods. Redoxyme provides a practical solution for improving reproducibility and efficiency in antioxidant enzyme activity analysis. The software is currently distributed as a standalone executable for Windows (locally installed), and an interactive web-based calculator implemented in Streamlit, enabling direct use without local installation. The source code and version-controlled development history are openly accessible via GitHub, promoting transparency, reproducibility, community-driven improvements, and may, in principle, be adapted for other operating systems.
Nrf1 regulates lipid metabolism through the PPAR⍺ signaling pathway and influences the fibrotic process in diabetic nephropathy.
Qiu Z, Zhang Y, Zhu L … +4 more , Zhao X, Li X, Gong X, Ci X
Free Radic Biol Med · 2026 Jun · PMID 42285318 · Publisher ↗
BACKGROUND: In diabetic nephropathy (DN), oxidative stress disrupts normal metabolic processes, contributing to progressive kidney injury. Although Nfe2l1 (also known as Nrf1) is known to regulate oxidative stress and me...
BACKGROUND: In diabetic nephropathy (DN), oxidative stress disrupts normal metabolic processes, contributing to progressive kidney injury. Although Nfe2l1 (also known as Nrf1) is known to regulate oxidative stress and metabolism, its specific role in DN remains poorly understood. This study investigated how changes in Nrf1 expression influence DN-associated renal fibrosis. METHODS: Nrf1 function was examined in multiple experimental settings, including: human DN kidney tissues; wild-type and proximal tubule-specific Nfe2l1 knockout mice subjected to high-fat diet plus STZ-induced DN; HK-2 cells exposed to high glucose and palmitic acid; and diabetic mice treated with the Nrf1 activator RUN-47. RESULTS: Nrf1 expression was markedly reduced in kidney tissues from patients with DN, as well as in the renal proximal tubules of DN mice and in high glucose and palmitic acid-treated HK-2 cells. Proximal tubule-specific Nfe2l1 knockout in mice and siRNA-mediated Nfe2l1 knockdown in HK-2 cells both aggravated tubular injury and fibrosis. Transcriptomic profiling indicated that Nrf1 modulates lipid metabolism through the PPARα signaling pathway and that its suppression exacerbates mitochondrial damage and lipid metabolism disorders. Mechanistically, Nrf1 directly binds to the PPARα promoter to transcriptionally activate its expression. Pharmacological inhibition and activation experiments confirmed that Nrf1 exerts its protective effects at least in part via PPARα signaling. Conversely, Nrf1 overexpression in HK-2 cells or pharmacological activation by RUN-47 significantly attenuated tubular damage, fibrotic changes, and lipid metabolism abnormalities. Notably, these protective effects were abrogated in the absence of Nrf1. CONCLUSIONS: Nrf1 downregulation in renal tubules promotes renal fibrosis in DN by impairing PPARα-mediated fatty acid oxidation, inducing mitochondrial dysfunction and lipid accumulation. Mechanistically, Nrf1 directly transcriptionally activates PPARα, and pharmacological activation of Nrf1 attenuates DN progression. These findings identify Nrf1 as a potential therapeutic target for slowing DN progression.
SIRT3 regulates PRDX3 acetylation to support mitochondrial peroxide detoxification and limit oxidative stress-associated ferroptosis vulnerability.
Wang T, Tu J, Wei X … +6 more , Liang Z, Cai R, Fan Q, He J, Wang T, Cheng J
Free Radic Biol Med · 2026 Jun · PMID 42276463 · Publisher ↗
Oxidative stress disrupts mitochondrial redox homeostasis and contributes to ferroptosis-associated vulnerability, yet the molecular link between impaired mitochondrial peroxide detoxification and ferroptosis-associated...
Oxidative stress disrupts mitochondrial redox homeostasis and contributes to ferroptosis-associated vulnerability, yet the molecular link between impaired mitochondrial peroxide detoxification and ferroptosis-associated vulnerability remains incompletely defined. Here, we identify PRDX3 as a candidate SIRT3-regulated effector of mitochondrial peroxide control. In AML12 cells, oxidative stress reduced mitochondrial SENP1, increased SIRT3 SUMOylation and elevated mitochondrial protein acetylation. Mitochondrial acetylome profiling identified PRDX3 K92 as a SIRT3-responsive acetylation site. Genetic activation of SIRT3 reduced PRDX3 acetylation and was associated with enhanced PRDX3 dimerization, improved peroxide clearance and reduced mitochondrial HO, lipid peroxidation, iron accumulation and other ferroptosis-associated changes. Conversely, an acetylation-mimetic PRDX3 mutant impaired peroxide clearance and attenuated the protective phenotype associated with SIRT3 activation, whereas a deacetylation-mimetic mutant improved redox balance and cell viability under oxidative stress. In vivo, activation of the SIRT3-PRDX3 axis mitigated paraquat-induced liver injury. Collectively, these data support a model in which SIRT3-dependent regulation of PRDX3 acetylation helps sustain mitochondrial peroxide detoxification and limits oxidative injury during stress.
Aberrant TIMM8B alternative splicing compromises mitochondrial respiratory chain integrity and redox homeostasis.
Lee SJ, Lee S, Kim KK … +1 more , Lee JY
Free Radic Biol Med · 2026 Jun · PMID 42276462 · Publisher ↗
Mitochondrial redox homeostasis depends on respiratory chain integrity, but whether environmental stress alters this system through alternative splicing remains poorly understood. Here, we identify aberrant TIMM8B altern...
Mitochondrial redox homeostasis depends on respiratory chain integrity, but whether environmental stress alters this system through alternative splicing remains poorly understood. Here, we identify aberrant TIMM8B alternative splicing as a post-transcriptional mechanism that compromises mitochondrial respiratory chain function and redox homeostasis. Using perfluoroundecanoic acid (PFUnDA) as an environmental stressor, transcriptomic profiling of HaCaT cells revealed suppression of mitochondrial bioenergetic programs, including oxidative phosphorylation, the tricarboxylic acid cycle, mitochondrial central dogma, and protein import. Splicing analysis identified TIMM8B exon 1a inclusion as a prominent stress-associated event, which was validated by RT-PCR. The exon 1a-included isoform showed reduced transcript stability and markedly reduced detectable protein abundance. Functionally, PFUnDA impaired mitochondrial respiration in HaCaT and HDF cells. TIMM8B isoform-function analysis further showed that the exon 1a-included isoform failed to preserve ETC activity, mitochondrial membrane potential, and MitoSOX-associated redox signal, whereas the exon 1a-excluded isoform partially restored these mitochondrial readouts toward basal levels. In zebrafish, PFUnDA reduced mitochondrial fluorescence and induced NAC-sensitive oxidant accumulation. Collectively, these findings identify aberrant TIMM8B alternative splicing as a mechanism linking environmental stress to mitochondrial respiratory chain dysfunction and redox dysregulation.
ac4C modification of PDK4 by NAT10 promotes pulmonary fibrosis by reprogramming mitochondrial dynamics in fibroblasts.
Liu D, Li Y, Liu T … +17 more , Du Y, Zhuo J, Du J, Yu Q, Yang H, Huang L, Huang H, Chen Y, Hu M, Jiang X, Chen J, Liang S, Wang Q, Wu Z, Cai S, Zhang J, Dong H
Free Radic Biol Med · 2026 Jun · PMID 42264200 · Publisher ↗
Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disorder with limited therapeutic options, necessitating the identification of novel pathogenic mechanisms and therapeutic targets. Here, we report a cr...
Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disorder with limited therapeutic options, necessitating the identification of novel pathogenic mechanisms and therapeutic targets. Here, we report a critical role for the RNA acetyltransferase NAT10 in driving pulmonary fibrosis through epitranscriptomic regulation of mitochondrial metabolism. We found that NAT10 and its catalyzed N4-acetylcytidine (ac4C) modification were significantly upregulated in fibrotic lungs from IPF patients and bleomycin-challenged mice, particularly within activated fibroblasts. Genetic ablation of NAT10 in fibroblasts markedly attenuated fibrotic progression, whereas its overexpression exacerbated the pathology. Mechanistically, integrated transcriptomic and biochemical analyses identified pyruvate dehydrogenase kinase 4 (PDK4) as a key downstream target whose mRNA stability was enhanced by NAT10-mediated ac4C modification. This post-transcriptional regulation led to PDK4 upregulation, which in turn promoted mitochondrial fission and reactive oxygen species production, thereby facilitating fibroblast-to-myofibroblast transition and excessive extracellular matrix deposition. Furthermore, we delineated the upstream regulation of NAT10, demonstrating that TGF-β1 transcriptionally induces NAT10 expression via direct Smad3 binding to its promoter, forming a positive feedback loop that sustains fibrotic activation. Our study unveils the NAT10-ac4C-PDK4 axis as a central regulator of mitochondrial dynamics in pulmonary fibrosis and highlights NAT10 as a promising therapeutic target for restoring metabolic homeostasis and ameliorating fibrotic lung remodeling.
The downregulation of PEPCK mediated cuproptosis is involved in triclosan induced reproductive damage in mouse testes via triggering ROS overproduction.
Ding Y, Hong Y, Zhou X … +10 more , Chen J, Tang H, Sun B, Ji F, Mi J, Long C, Shen L, Wu S, Wei Y, Wei G
Free Radic Biol Med · 2026 Jun · PMID 42264199 · Publisher ↗
Triclosan (TCS) is a widely used broad-spectrum antimicrobial agent that has been demonstrated to induce damage to the male reproductive system. However, the specific mechanisms of testicular injury induced by TCS are no...
Triclosan (TCS) is a widely used broad-spectrum antimicrobial agent that has been demonstrated to induce damage to the male reproductive system. However, the specific mechanisms of testicular injury induced by TCS are not fully understood. In the present study, mice were treated with 0, 20 mg/kg and 40 mg/kg per day TCS from PND 56 to PND 84. Decreased sperm counts, increased sperm deformity rates, downregulation of Phosphoenolpyruvate carboxykinase (PEPCK) and cuproptosis activation were observed. In vitro, TM4 cells were exposed to 0, 5 nM and 10 nM TCS for 24 h, which induced oxidative stress damage, inhibition of PEPCK and cuproptosis activation. Furthermore, inhibition of PEPCK and cuproptosis activation was rescued by reactive oxygen species (ROS) scavengers N-Acetylcysteine (NAC). Besides, cuproptosis activation induced by TCS were rescued after overexpression of PEPCK. Drug prediction with Connectivity Map (cMap) identified flubendazole and cucurbitacin-i as potential therapeutic drug. In conclusion, this study demonstrated that TCS triggered cuproptosis activation in TM4 cells mediated by ROS storm induced PEPCK inhibition. This research also shed new insight into precise treatment of TCS-related testicular injury.
Restoring BECN1-mediated autophagy mitigates acute lung injury caused by zinc oxide nanoparticles.
Mao L, Tan M, Jiang X … +8 more , Zhang J, Xu G, Zhang Y, Zhang S, Gao C, Qin X, Chen C, Zou Z
Free Radic Biol Med · 2026 Jun · PMID 42264198 · Publisher ↗
Pulmonary inhalation of zinc oxide nanoparticles (ZnONPs) triggers metal fume fever in humans and acute lung injury (ALI) in animal experiments. Previous evidence suggests that autophagy is involved in the pathogenesis o...
Pulmonary inhalation of zinc oxide nanoparticles (ZnONPs) triggers metal fume fever in humans and acute lung injury (ALI) in animal experiments. Previous evidence suggests that autophagy is involved in the pathogenesis of ZnONPs-induced ALI, with BECN1/Beclin1-dependent autophagy and mitophagy playing a central role. In the present study, heterozygous-deficient (Becn1) mice exhibit significantly exacerbated ALI compared to Becn1 controls following ZnONPs exposure. Immunoprecipitation-mass spectrometry analysis revealed that ZnONPs remodel the BECN1 protein interactome, enriching pathways related to autophagy, mitophagy, and mitochondrial quality control. Furthermore, Becn1 haploinsufficiency disrupted autophagic progression, causing accumulation of dysfunctional mitochondria within mitophagosomes. Notably, administration of Tat-Beclin1, a cell-permeable autophagy-inducing peptide, effectively ameliorated ZnONPs-induced ALI in both Becn1 and Becn1 mice exposed to ZnONPs. Crucially, macrophage-specific Becn1 knockout mice recapitulated the exacerbated injury phenotype, identifying myeloid BECN1 as the critical cellular protector. Mechanistically, Tat-Beclin1 restored autophagic progression and facilitated mitochondrial degradation, thereby attenuating ROS production and inflammatory cascades. These findings demonstrate that pharmacological restoration of BECN1 via Tat-Beclin1 offers a viable strategy for treating nanoparticle-induced metal fume fever and ALI.
Thiomyristoyl promotes type 2 diabetic wound healing and inhibits scarring via the PPARγ/Sirt3/SOD2 axis.
Ge X, Ye Z, Qin H … +6 more , Yuan C, Han Y, Gao Y, Shen Y, Chu W, Xu J
Free Radic Biol Med · 2026 Jun · PMID 42264197 · Publisher ↗
Fibroblasts are essential for the process of wound healing. However, under diabetic conditions, they often exhibit functional impairment and fibrosis, leading to impaired healing. Currently, there are limited effective i...
Fibroblasts are essential for the process of wound healing. However, under diabetic conditions, they often exhibit functional impairment and fibrosis, leading to impaired healing. Currently, there are limited effective interventions for fibroblast dysfunction. Through preliminary screening of small-molecules, Thiomyristoyl(TM), which enhances cellular plasticity and possesses anti-fibrotic properties, was selected for this research to investigate its involvement and mechanism in the wound healing process in type 2 diabetes. Experimental results indicated that wound healing was delayed in diabetic mice, accompanied by reduced cell proliferation and significant fibrosis. Under high glucose conditions, mouse dermal fibroblasts (MDFs) exhibited decreased viability, proliferation, and migration, accompanied by excessive accumulation of reactive oxygen species (ROS). TM intervention effectively restored the multi-differentiation potential of MDFs and ameliorated the aforementioned cellular functional impairments. Transcriptome analysis and related experiments indicated that TM upregulates SIRT3 expression via the PPARγ signaling pathway, reduces the acetylation level of superoxide dismutase 2 (SOD2), thereby alleviating oxidative stress and inhibiting the expression of fibrosis-related proteins. The strategy of activating the PPARγ/Sirt3/SOD2 axis with TM provides a potential therapeutic target for treating diabetic wounds.
The AMPK-PGC-1α-SIRT3 axis mediates mitochondrial metabolic dysfunction and neuronal senescence induced by Al(mal) exposure in HT22 hippocampal neuronal cells.
Zhang H, Gao X, Jin Z … +3 more , Liu Y, Yin J, Zhang R
Free Radic Biol Med · 2026 Jun · PMID 42263892 · Publisher ↗
Aluminum (Al) is a widely distributed environmental metal whose chronic exposure has been implicated in neurotoxicity and increased risk of neurodegenerative disorders. However, the molecular mechanisms linking aluminum...
Aluminum (Al) is a widely distributed environmental metal whose chronic exposure has been implicated in neurotoxicity and increased risk of neurodegenerative disorders. However, the molecular mechanisms linking aluminum exposure to neuronal metabolic dysfunction and senescence remain incompletely understood. In this study, mouse hippocampal neuronal HT22 cells were exposed to aluminum maltolate [Al (mal), 60-240 μM] to investigate alterations in mitochondrial bioenergetics and senescence-associated pathways. Aluminum exposure significantly increased senescence-associated β-galactosidase (SA-β-gal) activity and upregulated p16 and p21 expression, accompanied by G2/M phase arrest. Seahorse metabolic analysis revealed marked reductions in basal respiration, ATP-linked respiration, maximal respiratory capacity, glycolytic activity, and glycolytic reserve, indicating impaired mitochondrial function and metabolic flexibility. Mechanistically, aluminum exposure suppressed the AMPK-PGC-1α-SIRT3 signaling axis at both transcriptional and protein levels and reduced SOD2 and IDH2 enzymatic activities. Pharmacological activation of AMPK (AICAR) or SIRT3 (honokiol) partially restored mitochondrial respiration, glycolysis, antioxidant enzyme activity, and attenuated aluminum-induced neuronal senescence. Combined treatment also alleviated mitochondrial metabolic dysfunction and senescence-related alterations induced by aluminum exposure. Collectively, these findings suggest that disruption of the AMPK-PGC-1α-SIRT3 axis contributes to mitochondrial metabolic dysfunction and neuronal senescence under aluminum exposure. This study provides mechanistic insight into aluminum-induced neurotoxicity from a bioenergetic perspective and highlights mitochondrial metabolic regulation as a potential therapeutic target in environmental metal-associated neurological risk.
PARS2 deficiency impairs mitochondrial homeostasis and activates ferroptotic to drive developmental and epileptic encephalopathy.
Li Z, Xu Z, Zhang G … +4 more , Ma A, Zhou Z, Qin J, Yang Z
Free Radic Biol Med · 2026 Jun · PMID 42259431 · Publisher ↗
PARS2, encodes a mitochondrial aminoacyl-tRNA synthetase associated with developmental and epileptic encephalopathy (DEE), a severe neurological disorder characterized by refractory epilepsy and intellectual disability....
PARS2, encodes a mitochondrial aminoacyl-tRNA synthetase associated with developmental and epileptic encephalopathy (DEE), a severe neurological disorder characterized by refractory epilepsy and intellectual disability. While genetic associations between PARS2 and DEE have been established, the underlying molecular mechanisms remain poorly understood. This study integrates genetic analyses of clinical cases of infantile epileptic spasms syndrome (IESS) with functional assessments in PARS2-deficient animal models and cell models to elucidate these mechanisms. Our findings indicate that PARS2 deficiency disrupts mitochondrial integrity and impairs oxidative phosphorylation, resulting in elevated intracellular calcium levels. This calcium overload activates CaMKK2-AMPK-Drp1 signaling, promoting excessive mitochondrial fission and PINK1-Parkin-mediated mitophagy, ultimately leading to degradation of GPX4 and subsequent ferroptosis. Notably, pharmacological inhibition of Drp1 using Mdivi-1 successfully rescued mitochondrial fragmentation and mitigated ferroptosis. These results unveil a novel calcium-mitophagy-ferroptosis pathway as a crucial mechanism in PARS2-related DEE and propose a potential therapeutic strategy for DEE.
Sagittaria sagittifolia polysaccharide extract attenuates inflammation and senescence through dual involvement of TLR4/NF-κB and SIRT1/NF-κB in vivo and in vitro models of COPD.
Liu B, Zhao X, Liang Y … +4 more , Zhou M, Gao X, Liu X, Liao Y
Free Radic Biol Med · 2026 Jun · PMID 42252066 · Publisher ↗
Sagittaria sagittifolia polysaccharide (SSP) extract, a key bioactive component of the natural herb Sagittaria sagittifolia, possesses multiple biological activities, including anti-inflammatory and antioxidant effects,...
Sagittaria sagittifolia polysaccharide (SSP) extract, a key bioactive component of the natural herb Sagittaria sagittifolia, possesses multiple biological activities, including anti-inflammatory and antioxidant effects, demonstrating potential in the prevention and treatment of chronic obstructive pulmonary disease (COPD). This study aims to investigate the efficacy of SSP extract in COPD and explore whether its anti-inflammatory and anti-aging effects involve the regulation of NF-κB. A COPD mouse model and BEAS-2B cell injury model were established using lipopolysaccharide (LPS) combined with cigarette smoke (CS). RNA sequencing was employed to identify potential targets of SSP extract. SSP extract significantly reduced the expression levels of NF-κB, pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6), and the number of Ly6g-labeled neutrophils in COPD mice. SSP extract also inhibited the expression levels of COX-2 and CXCL1 in BEAS-2B cells. TLR4 and SIRT1 are important upstream regulatory proteins of NF-κB. This study showed that SSP extract effectively suppressed the expression of TLR4, MyD88, IRAK1, TRAF6, increased SIRT1 protein expression, and inhibited senescence markers (p53, p21, p16, and RB) in COPD mice. In BEAS-2B cells, SSP extract decreased acetylated NF-κB levels, reduced the number of β-gal-positive cells, and alleviated G1 phase cell cycle arrest, thereby partially inhibiting senescence. These findings suggest that SSP extract holds potential for prevention and treatment of COPD. Its effects are associated with changes in the TLR4/NF-κB and SIRT1/NF-κB pathways, as well as reduced inflammation and senescence.
Membrane instability as a propagation-repair imbalance in ferroptosis.
Lee J, Roh JL
Free Radic Biol Med · 2026 Jun · PMID 42252065 · Publisher ↗
Ferroptosis is commonly described as an iron-dependent form of cell death driven by lipid peroxidation. However, lipid peroxidation is pervasive across aerobic systems, whereas catastrophic membrane rupture is selective....
Ferroptosis is commonly described as an iron-dependent form of cell death driven by lipid peroxidation. However, lipid peroxidation is pervasive across aerobic systems, whereas catastrophic membrane rupture is selective. Membrane fate cannot be inferred from oxidative burden alone. Instead, failure reflects a dynamical transition that occurs when radical propagation outpaces membrane repair within a metabolically sustained, nonequilibrium system. We propose a propagation-repair framework organized around a conceptual propagation-repair state (Φ), in which propagation capacity captures lipid radical amplification and spatial spread, and repair capacity integrates hydroperoxide detoxification, radical termination, lipid remodeling, and membrane resealing. In biochemical terms, Φ approximates the ratio between lipid peroxidation flux and NAD(P)H-dependent detoxification capacity, linking membrane stability to redox-constrained metabolic throughput. This framework suggests that ferroptotic commitment may arise from cofactor-limited detoxification rather than discrete molecular triggers and can be uncoupled from bulk ROS levels. Ferroptosis thus represents a regime of membrane failure defined by flux imbalance under constrained redox buffering.
Troxerutin mitigates ferroptosis-related neuroinflammation by regulating the microglial NOX4/Nrf2 axis in Parkinson's disease.
Wang Q, Xu X, Liu Z … +10 more , Wang R, Lan X, Li J, Wang S, Sun Z, Shi L, Gao Y, Pan J, Li W, Qian L
Free Radic Biol Med · 2026 Jun · PMID 42252064 · Publisher ↗
Parkinson's disease (PD) is characterized by progressive dopaminergic neurodegeneration and chronic neuroinflammation. Increasing evidence suggests that microglial ferroptosis plays a critical role in the pathogenesis of...
Parkinson's disease (PD) is characterized by progressive dopaminergic neurodegeneration and chronic neuroinflammation. Increasing evidence suggests that microglial ferroptosis plays a critical role in the pathogenesis of PD. Troxerutin (TRX), a natural flavonoid derivative with potent antioxidant and anti-inflammatory activities, has shown neuroprotective potential; however, its effects on microglial ferroptosis and the underlying mechanisms in PD remain unclear. Here, we investigated the effects of TRX in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD and MPP-stimulated BV2 cells. TRX improves motor performance, preserves nigrostriatal dopaminergic neurons, and attenuates microglial activation and pro-inflammatory cytokine expression in vivo. In BV2 cells, TRX attenuated ferroptosis-related changes, reduced lipid reactive oxygen species accumulation, and restored GPX4 and SLC7A11 expression. Furthermore, treatment with erastin, a classical ferroptosis inducer, reactivates ferroptosis-related responses and reverses the anti-inflammatory effects of TRX, linking ferroptotic stress to microglial inflammatory activation. Mechanistically, the cellular thermal shift assay supported target engagement between TRX and NOX4. TRX enhances K48-linked polyubiquitination of NOX4 and promotes its proteasomal degradation, which restores Nrf2 nuclear accumulation and activates downstream antioxidant responses. These results reveal that TRX alleviates ferroptosis-related neuroinflammation by modulating the microglial NOX4/Nrf2 axis in PD.
Cystathionine γ-lyase deficiency exacerbates high-fat diet-induced kidney and liver injury associated with disrupted glutathione homeostasis.
Jang G, Park YR, Han YK … +3 more , Ishii I, Jang SY, Park KM
Free Radic Biol Med · 2026 Jun · PMID 42252063 · Publisher ↗
Obesity is a major risk factor for chronic kidney disease (CKD), partly mediated by oxidative stress. The liver is the primary source of glutathione (GSH), a key antioxidant that maintains tissue redox balance. Cystathio...
Obesity is a major risk factor for chronic kidney disease (CKD), partly mediated by oxidative stress. The liver is the primary source of glutathione (GSH), a key antioxidant that maintains tissue redox balance. Cystathionine γ-lyase (CSE) regulates cysteine availability for GSH synthesis; however, whether disruption of CSE-dependent GSH metabolism contributes to kidney injury under high-fat diet (HFD)-induced metabolic stress remains unclear. To investigate the role of CSE in HFD-induced kidney injury, CSE-deficient (Cse) and wild-type (Cse) mice were fed a normal-fat diet (NFD) or HFD for 16 weeks. Glutathione metabolism, oxidative stress, tissue damage, and function in the liver and kidney were analyzed. HFD feeding markedly reduced total GSH (tGSH) levels in the liver, plasma, and kidney, with more severe reductions in Cse mice, suggesting impaired antioxidant capacity. Concomitantly, HFD induced greater oxidative stress in Cse mice than in Cse mice, as evidenced by greater increases in hydrogen peroxide levels, lipid peroxidation, and the oxidized GSH-to-tGSH ratio. In addition, HFD decreased creatinine clearance, increased urinary protein, reduced renal hydrogen sulfide (HS) levels, and increased collagen deposition, transforming growth factor-β1, collagen I, plasminogen activator inhibitor-1, mitochondrial fission 1, Bcl-2-associated X protein expression, and TUNEL staining, with more pronounced changes in the kidneys of Cse mice than in those of Cse mice, indicating that CSE deficiency aggravates HFD-induced renal fibrosis and dysfunction. These findings suggest that CSE deficiency exacerbates HFD-induced kidney injury in association with disrupted CSE-cysteine-GSH status, enhanced oxidative stress, and fibrosis, suggesting that this pathway may be a potential therapeutic target for HFD-associated kidney injury.
Mitochondrial disease: mechanisms, signalling, and therapeutic opportunities.
Corrà S, Young L, Moore AL … +1 more , Viscomi C
Free Radic Biol Med · 2026 Jun · PMID 42250784 · Publisher ↗
Mitochondria are central hubs of cellular metabolism and signalling, and their dysfunction underlies a broad spectrum of human diseases, including rare mitochondrial disorders as well as common neurodegenerative and meta...
Mitochondria are central hubs of cellular metabolism and signalling, and their dysfunction underlies a broad spectrum of human diseases, including rare mitochondrial disorders as well as common neurodegenerative and metabolic conditions. Mitochondrial diseases are genetically heterogeneous disorders caused by mutations in nuclear or mitochondrial DNA that impair oxidative phosphorylation (OXPHOS), resulting in reduced ATP production and cellular energy failure. Despite a shared bioenergetic defect, these diseases display marked clinical variability, and the mechanisms underlying this heterogeneity remain poorly understood. At present, no curative therapies are available, although several metabolic and experimental approaches have shown promise in preclinical models. Mitochondrial dysfunction is commonly associated with altered redox homeostasis and increased production of reactive oxygen species (ROS), which can damage mitochondrial components, including mitochondrial DNA, and further impair respiratory chain function. At the same time, ROS also act as context-dependent signalling molecules, with effects that vary according to concentration, localization, and cell type complicating their interpretation in disease mechanisms and therapy development. In this review, we summarize current concepts in mitochondrial disease pathophysiology focusing on unresolved questions that limit mechanistic understanding and clinical translation. We critically evaluate the role of ROS in disease progression and signalling, discuss how the alternative oxidase (AOX) has emerged as a valuable experimental tool to dissect ROS-related mechanisms and reveal unexpected aspects of mitochondrial dysfunction and disease variability.
Nicotinamide nucleotide transhydrogenase deficiency impairs neuronal function via energy metabolism dysregulation in Alzheimer's disease.
Wan X, Lu W, Liu S … +7 more , Zhao Y, Hu J, Ding X, Gu P, Zou Y, Jiang B, Yang Y
Free Radic Biol Med · 2026 Jun · PMID 42250783 · Publisher ↗
Alzheimer's disease (AD) is characterized by mitochondrial dysfunction and oxidative stress, which drive synaptic damage. Proteomic analysis in an AD mouse model identified significant downregulation of Nicotinamide Nucl...
Alzheimer's disease (AD) is characterized by mitochondrial dysfunction and oxidative stress, which drive synaptic damage. Proteomic analysis in an AD mouse model identified significant downregulation of Nicotinamide Nucleotide Transhydrogenase (NNT), a mitochondrial enzyme crucial for maintaining redox balance by regenerating NADPH. This loss created a pro-oxidant shift, sensitizing neurons to amyloid-β (Aβ) toxicity and triggering mitochondrial collapse-evidenced by loss of membrane potential and depletion of energy and antioxidants. NNT deficiency alone was sufficient to induce AD-like synaptic loss and cognitive deficits, independent of amyloid or tau pathology. Functionally, NNT acted as a metabolic-transcriptional hub, promoting pro-synaptic gene expression and synaptic protein homeostasis. It supported synaptic resilience through dual mechanisms: preserving redox balance to protect synaptic components and facilitating clearance of toxic Aβ accumulation. These findings could position NNT dysfunction as a critical, non-amyloid factor in AD pathogenesis, linking mitochondrial bioenergetics to synaptic integrity. Enhancing NNT activity thus represents a promising therapeutic strategy to bolster metabolic resilience and cognitive function in AD.
Ferro-aging: A novel paradigm linking iron overload, lipid peroxidation and cellular senescence.
Gao S, Qi L, Bai W … +5 more , Zhang J, Xu Z, Zhang Z, Li N, Liu W
Free Radic Biol Med · 2026 Jun · PMID 42250782 · Publisher ↗
Iron is a double-edged sword in aging, and age-related iron accumulation acts as a critical amplifier, rather than a sole driver, of ageing; disrupted iron homeostasis with progressive iron accumulation drives oxidative...
Iron is a double-edged sword in aging, and age-related iron accumulation acts as a critical amplifier, rather than a sole driver, of ageing; disrupted iron homeostasis with progressive iron accumulation drives oxidative stress, mitochondrial damage and inflammaging. Ferroptosis and cellular senescence, two critical aging-related processes, share upstream drivers like oxidative stress and lipid peroxidation. This study proposed the novel ferro-aging paradigm, a cascade pathway where age-related iron overload initiates iron-catalyzed reactive oxygen species production and lipid peroxidation, ultimately inducing cellular senescence and ferroptosis to exacerbate, rather than independently cause, tissue dysfunction and age-related diseases. Iron accumulation in senescent cells stems from dysregulated iron uptake, storage, efflux, impaired ferritinophagy, and critical mitochondrial dysfunction. Senescent cells acquire ferroptosis resistance, leading to persistent tissue accumulation and chronic inflammation. Ferroptosis and senescence interact dynamically and form a positive feedback loop, with lipid peroxidation as the core executor. Ferro-aging participates in multiple age-related diseases of the nervous, cardiovascular, metabolic and skeletal systems. Targeting iron homeostasis, lipid peroxidation, senescent cells, and mitochondrial function provides promising anti-aging interventions. This review clarifies the connotation and mechanism of ferro-aging, and reveals its potential as a unified target for delaying aging and treating age-related diseases.
Therapeutic potential of 2-hexyl-1-decanol in Cutibacterium acnes-induced skin inflammation via modulation of oxidative and inflammatory pathways.
Shin JH, Heo YJ, Kim SS … +4 more , Lim DH, Han YJ, Park J, Seo SR
Free Radic Biol Med · 2026 Jun · PMID 42242598 · Publisher ↗
Acne vulgaris is a multifaceted inflammatory disorder in which Cutibacterium acnes-driven oxidative stress and innate immune activation play central pathogenic roles. Despite the clinical need, mechanistically targeted t...
Acne vulgaris is a multifaceted inflammatory disorder in which Cutibacterium acnes-driven oxidative stress and innate immune activation play central pathogenic roles. Despite the clinical need, mechanistically targeted therapies with favorable safety profiles remain limited. Here, we identify 2-hexyl-1-decanol (HD), a naturally derived alkanol, as a potent modulator of C. acnes-induced redox imbalance and inflammatory signaling. Across RAW 264.7 macrophages, primary human peripheral blood mononuclear cells (PBMCs), and a murine inflammation model, HD markedly suppressed ROS accumulation, IL-1β and TNF-α release, and induction of iNOS and COX-2. Mechanistically, HD triggered rapid Nrf2 nuclear translocation and robust HO-1 upregulation, establishing a strong antioxidant response. This redox reprogramming was tightly coupled to selective inhibition of NF-κB activation, while MAPK pathways remained largely unaffected, revealing an unexpected specificity in HD's mode of action. In vivo, HD significantly reduced ear edema, immune-cell infiltration, and cytokine expression, recapitulating its molecular signatures observed in vitro. Together, these findings define HD as a dual-acting Nrf2 activator and NF-κB suppressor that intercepts key pathogenic events in C. acnes-mediated inflammation, positioning it as a promising mechanistically guided candidate for complementary acne therapy.
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