Free Radic. Biol. Med. [JOURNAL]
Sun
200 papers
Deterioration of liver fibrosis by ALR deficiency is associated with reducing MICU1/2 heterodimerization and mitochondrial Ca imbalance in hepatic stellate cells.
Li Y, Liu MQ, Wang J … +6 more , Li ZW, Wang X, Wei YB, Zhang N, Dong LY, An W
Free Radic Biol Med · 2026 Jun · PMID 42242597 · Publisher ↗
Hepatic stellate cells (HSCs) activation is a pivotal event in the pathogenesis of liver fibrosis (LF). Mitochondrial calcium (mCa) dyshomeostasis is a known driver for HSCs activation. Although we previously demonstrate...
Hepatic stellate cells (HSCs) activation is a pivotal event in the pathogenesis of liver fibrosis (LF). Mitochondrial calcium (mCa) dyshomeostasis is a known driver for HSCs activation. Although we previously demonstrated that augmenter of liver regeneration (ALR) inhibits HSCs activation potentially through regulation of mitochondrial calcium uniporter (MCU) and prevention of mCa overload, the precise molecular mechanisms remain poorly understood. In this study we revealed that hepatic ALR expression was continuously reduced with LF progression in both patients and mice, which coincided with a loss of MICU1/2 dimerization. Similarly, Alr deletion (Alr-KO) could exacerbate LF progression in mice fed a choline-deficient high-fat diet, subjected to bile duct ligation or developing spontaneous LF. In vitro studies showed that Alr-KO disrupted the dimerization of mitochondrial calcium uptake 1 and 2 (MICU1/2), core regulatory components of MCU complex, deteriorating mCa overload and promoting HSCs activation. Protein-binding assays revealed that the regulation of MICU1/2 dimerization by ALR appeared indirect; instead, it potentially relied on coiled-coil-helix-coiled-coil-helix domain-containing protein 4 (CHCHD4), a member of the mitochondrial disulfide relay system (DRS). Further data analyses demonstrated that ALR interacted with CHCHD4 at cysteine residues C4, C53 and C55 via modulating its redox status. Alr knockdown or mutation of these cysteine residues in CHCHD4 restrained ALR-CHCHD4 interaction, reduced dimerized MICU1/2 levels, and consequently led to mCa overload and HSCs activation. Overall, this study provides mechanistic insights into how ALR attenuates liver fibrosis by promoting MICU1/2 dimerization and maintaining mCa homeostasis in HSCs.
Excess glucose shapes mitochondrial metabolism and redox state in human primary white adipocytes.
Herbers E, Moisio K, Torregrosa-Muñumer R … +10 more , Karppinen JE, Heinonen S, van der Kolk BW, Hassinen A, Peltoniemi H, Tuominen R, Pirinen E, Hietakangas V, Euro L, Pietiläinen KH
Free Radic Biol Med · 2026 Jun · PMID 42242596 · Publisher ↗
Mitochondrial dysfunction in white adipose tissue (WAT) is a hallmark of obesity, yet nutrient-driven responses in adipocytes remain poorly defined, partly due to widespread use of supra-physiological glucose-rich media...
Mitochondrial dysfunction in white adipose tissue (WAT) is a hallmark of obesity, yet nutrient-driven responses in adipocytes remain poorly defined, partly due to widespread use of supra-physiological glucose-rich media in in vitro adipocyte models. We used integrated transcriptomics, fluxomics, and functional analyses to assess how glucose availability shapes mitochondrial metabolism and redox status during human adipocyte differentiation. Primary human adipocytes (n = 6 donors) were differentiated in commonly used media containing high glucose (DMEM/F12, 17.6 mM; DMEM/HG, 25 mM), physiological glucose (LG, 5.5 mM), or galactose (Gal, 25 mM). High-glucose conditions were associated with a shift from oxidative phosphorylation toward glycolysis, reduced mitochondrial biogenesis, NADH accumulation, and elevated mitochondrial reactive oxygen species, accompanied by impaired insulin sensitivity, reduced adiponectin secretion, together with transcriptional signatures of inflammatory and stress-associated responses. Fluxomics revealed altered pyruvate flux, enhanced anaplerotic pathways, and upregulated anabolic programs. In contrast, LG and Gal conditions preserved mitochondrial and redox features, more closely resembling characteristics of healthy WAT. Collectively, these data define a metabolic phenotype, in which supra-physiological glucose is associated with redox imbalance and metabolic reprogramming in human adipocytes under defined in vitro conditions. Our results highlight the importance of physiological glucose for adipocyte metabolism modeling and provide a framework for interpreting nutrient effects on mitochondrial and redox phenotypes.
Reaction rate calculations indicate that α-tocopherol primarily acts as a membrane protein antioxidant in vivo.
Hajieva P, Moosmann B
Free Radic Biol Med · 2026 Jun · PMID 42242595 · Publisher ↗
Lipid peroxidation is a complex free radical chain reaction in which lipid peroxyl radicals serially attack other components of the lipid bilayer. As a condensed phase, the lipid bilayer contains numerous potentially rea...
Lipid peroxidation is a complex free radical chain reaction in which lipid peroxyl radicals serially attack other components of the lipid bilayer. As a condensed phase, the lipid bilayer contains numerous potentially reactive substrates beyond unsaturated fatty acids, including membrane proteins and dissolved small molecules like α-tocopherol, the major lipid-soluble antioxidant. Despite a long history of investigation, the reaction cascades that do succeed in vivo to produce tocopherol's pronounced antioxidant effect are still arguable. Here, we have revisited the tocopherol reaction cascade problem from a quantitative perspective, by analyzing published rate constants and stereologically derived intramembrane reactant concentrations of various lipid bilayer components. Applying chemical rate laws, we find that in native biological membrane systems, less than 1% - 5% of all radical flux from lipid peroxyl radicals directly attacks α-tocopherol owing to its low concentration. Most radical flux rather attacks aromatic amino acid side chains, whose radical forms are then repaired very efficiently by even highly diluted α-tocopherol. Although tocopherol can also forestall fatty acid oxidation in protein-free oils and artificial lipid-only bilayers, its in vivo activity is predominantly that of a membrane protein antioxidant. Our data provide a potential explanation for the relaxed resorption of nutritional vitamin E by animals.
Metabolic profiling of DNA methylation age acceleration, associations with hearing loss and interaction with genetic susceptibility.
He Y, Niu R, Diao T … +9 more , Huang K, Huang R, Wang Y, Zhang R, Wang Z, Yang L, He M, Kong W, Zhang X
Free Radic Biol Med · 2026 Jun · PMID 42242594 · Publisher ↗
Limited studies have examined the association between DNA methylation age acceleration (DNAm AA) and hearing loss (HL). We aimed to assess whether plasma metabolite alterations are associated with the DNAm AA-HL link and...
Limited studies have examined the association between DNA methylation age acceleration (DNAm AA) and hearing loss (HL). We aimed to assess whether plasma metabolite alterations are associated with the DNAm AA-HL link and explore the potential modifying effect of polygenic risk score (PRS). A total of 2068 individuals aged 65.7 years from the Dongfeng-Tongji cohort in 2013 were included. Hearing threshold was assessed using pure tone average (PTA), and HL was defined as PTA >25 dB. DNAm AA was calculated using 6 epigenetic clocks (HorvathAge, HannumAge, PhenoAge, GrimAge, DunedinPACE and DNAm mortality risk score). Two hundred and ten plasma metabolites were profiled by targeted metabolomics approaches. We applied generalized linear model coupled with enrichment analysis to characterize metabolomic profiles of DNAm AA, and elastic-net regression to construct metabolomic risk score (MRS). A weighted PRS for HL was constructed using 37 single nucleotide polymorphisms. Among 2068 participants, 1075 (52.0%) had HL and exhibited significantly higher DNAm age. HorvathAgeAccel, GrimAgeAccel, and DunedinPACE were associated with poorer PTA thresholds (β range: 0.59-1.56) and greater HL risks (odds ratios range: 1.11-1.21). GrimAgeAccel was linked to 28 metabolites and DunedinPACE to 65, involving 11 enrichment pathways and 6 metabolite sets. The MRSs were positively associated with PTA level or speech- and high-frequency HL (SFHL and HFHL) risk, and explained 33.4% to 48.2% of the associations of GrimAgeAccel and DunedinPACE with PTA or SFHL. Additionally, GrimAgeAccel and DunedinPACE exhibited positive associations with PTA or HL only in the high-PRS subgroup, and significant interaction was found between MRS for DunedinPACE and PRS on the risk of HFHL. GrimAgeAccel and DunedinPACE were associated with poorer PTA thresholds and higher HL risks, with their linked MRS partially explaining these associations. PRS modified the MRS-HFHL risk association, with a potentially amplified effect in high genetic susceptibility subgroups.
Targeting mitochondrial ROS in the liver-brain axis attenuates inflammation and oxidative stress in covert hepatic encephalopathy.
Bai Y, Wang Z, Guo X … +8 more , Yang Z, Xie S, Zhang H, Nan B, Zhang N, Li A, Wang Q, Zhang C
Free Radic Biol Med · 2026 Jun · PMID 42242593 · Publisher ↗
Covert hepatic encephalopathy (CHE) is a debilitating complication of chronic liver disease, in which hyperammonemia and oxidative stress play central pathogenic roles. While mitochondria-targeted antioxidants show promi...
Covert hepatic encephalopathy (CHE) is a debilitating complication of chronic liver disease, in which hyperammonemia and oxidative stress play central pathogenic roles. While mitochondria-targeted antioxidants show promise in mitigating multi-organ injury, their efficacy in CHE remains insufficiently studied. To address this gap, this study analyzed clinical samples and observed significant dysregulation of peripheral oxidative stress markers in cirrhotic patients with hyperammonemia. Subsequently, in vitro experiments demonstrated that the mitochondria-targeted antioxidant MitoQ effectively attenuated ammonia-induced mitochondrial reactive oxygen species overproduction, loss of membrane potential, and impaired ATP synthesis in neuronal cells. In a bile duct ligation-induced mouse model of CHE, MitoQ administration not only alleviated hepatic injury and fibrosis but also concurrently reduced oxidative stress and inflammatory cytokine levels in the liver, blood, and brain. These changes were accompanied by marked improvements in motor coordination and systemic energy metabolism stability. Collectively, our findings indicate that MitoQ exerts multi-organ protective effects by targeting mitochondrial ROS along the liver-brain axis, restoring redox homeostasis and suppressing inflammation, thereby proposing a novel integrated therapeutic strategy for CHE. This study contributes to the mechanistic understanding of liver-brain crosstalk in HE and offers preliminary preclinical evidence that suggests a potential role for mitochondrial-targeted antioxidants in the management of hepatic encephalopathy, which also require independent validation in larger cohorts.
Plasma - Activated medium engages redox signaling to activate a VDAC1-TRPML1 lysosomal-mitochondrial Ca2+ death pathway.
Huang P, Zheng Y, Zhou C … +4 more , Ding C, Zhang Q, Feng D, Wu Z
Free Radic Biol Med · 2026 Jun · PMID 42242592 · Publisher ↗
Plasma-activated medium (PAM), a redox-active anticancer modality, induces cytotoxicity in multiple tumor models, but the mechanisms underlying PAM-induced tumor cell death remain incompletely understood. Here, using A54...
Plasma-activated medium (PAM), a redox-active anticancer modality, induces cytotoxicity in multiple tumor models, but the mechanisms underlying PAM-induced tumor cell death remain incompletely understood. Here, using A549 lung cancer cells together with additional tumor models, we identify a lysosome - mitochondria Ca circuit that drives a distinct form of PAM-induced tumor-selective cell death. PAM promotes the coupling of the lysosomal Ca channel TRPML1 to the mitochondrial outer membrane protein VDAC1 at organelle contact sites, leading to lysosomal Ca release, mitochondrial Ca overload, membrane depolarization, cytochrome c release, and cell death. Mechanistically, PAM suppresses mTORC2 - SGK1 signaling, reduces VDAC1 phosphorylation at Ser104, and stabilizes VDAC1 on mitochondria. Accumulated VDAC1 then engages TRPML1 through Lys109 and Arg163 to facilitate pathological Ca transfer. Disrupting this interface, or restoring phosphomimetic control of VDAC1, attenuated mitochondrial Ca overload, improved cell survival, and weakened the antitumor effect of PAM in vivo. Pan-cancer analyses further suggested that although high VDAC1 expression is associated with poor prognosis, it may help stratify tumors more likely to respond to PAM. Together, these findings establish the VDAC1 - TRPML1 axis as a key mechanistic link between PAM-induced redox stress and lysosome - mitochondria Ca-dependent tumor cell death, and highlight this pathway as a potential therapeutic target and response biomarker.
The mitochondrial protein Timm13 promotes liver fibrosis by activating TGFβ signaling through Hsp90aa1.
Liao X, Jiang Z, Li Z … +2 more , Liu J, Tang W
Free Radic Biol Med · 2026 Jun · PMID 42242591 · Publisher ↗
Liver fibrosis is a pathological consequence of chronic liver injury that is reversible but can potentially progress to serious complications. Currently, due to the incomplete elucidation of its key molecular driving mec...
Liver fibrosis is a pathological consequence of chronic liver injury that is reversible but can potentially progress to serious complications. Currently, due to the incomplete elucidation of its key molecular driving mechanisms, effective targeted therapeutic approaches remain lacking in clinical practice. The mitochondrial inner membrane transporter Timm13 has been implicated in cellular stress and disease, yet its role in liver fibrosis remains unclear. This study found that Timm13 is significantly upregulated in human fibrotic liver tissue. Functional studies demonstrated that Timm13 overexpression promotes the activation, proliferation, migration, and extracellular matrix production of hepatic stellate cells (HSCs), whereas Timm13 knockdown inhibits these processes. In a carbon tetrachloride (CCl)-induced mouse model of liver fibrosis, Timm13 overexpression exacerbated collagen deposition and histopathological damage, whereas its knockdown exerted a protective effect. Mechanistically, Co-immunoprecipitation and proteomic analyses identified heat shock protein 90α family member 1 (Hsp90aa1) as a direct binding partner of Timm13. We further demonstrate that this interaction is critical for activating the TGFβ signaling pathway, as Hsp90aa1 silencing reverses the Timm13-driven upregulation of fibrotic markers and TGFβ1 protein levels. This indicates that Timm13 promotes fibrogenic activity by regulating TGFβ1 expression through Hsp90aa1. Furthermore, studies indicate that Timm13 significantly induces mitochondrial dysfunction in hepatic stellate cells, manifested by reduced mitochondrial membrane potential, elevated reactive oxygen species levels, and impaired ATP synthesis. Our results defined a previously unrecognized Timm13/Hsp90aa1/TGFβ signaling axis, revealing how Timm13, through its interaction with Hsp90aa1, concurrently regulates TGFβ1 expression and integrates mitochondrial stress signals to drive the fibrogenic activity of hepatic stellate cells. This study establishes Timm13 as a potential diagnostic biomarker and therapeutic target for liver fibrosis.
Pathology illustrates pathogenesis of indium lung diseases in rats induced by indium-tin oxide nanoparticles.
Liu N, Wan P, Cao C … +4 more , Cao F, Yu Y, Xue L, Li G
Free Radic Biol Med · 2026 Jun · PMID 42242590 · Publisher ↗
Indium lung disease remains an ultra-rare interstitial lung disease with no initiative effective in changing the trial. It is related to excessive protein deposition, the development of interstitial inflammation, and sub...
Indium lung disease remains an ultra-rare interstitial lung disease with no initiative effective in changing the trial. It is related to excessive protein deposition, the development of interstitial inflammation, and subsequent pulmonary fibrosis. This is a "destructive" pulmonary disease. The pathogenesis of indium lung disease remains unclear because the disease progresses continuously, making early diagnosis difficult. This study aimed to identify the histopathological features of pulmonary injury during and after Nano-ITO intratracheal instillation. Male Sprague-Dawley rats were intratracheally instilled (single and multiple) with dispersed Nano-ITO at low (0.6 mg/kg) and high (6 mg/kg) doses and were sacrificed at 1, 4, 8 and 12 weeks after exposure to test inflammation, pulmonary alveolar proteinosis (PAP), and interstitial fibrosis in the lungs. The results demonstrated that even low-dose Nano-ITO exposure made the lungs susceptible to various types of lung injuries that may lead to PAP and disorders of lipid metabolism. The pro-inflammatory action of Nano-ITO-induced progressive interstitial fibrosis may promote this process by aggravating PAP, including the acute aggravation of foamed alveolar macrophages (AM) and lipid metabolism disorders. When inspecting the effects of these inflammatory responses, the current study uncovered the significance of prospective relationships between PAP, lipid metabolism disorders, and pulmonary fibrosis. Nano-ITO induces a large amount of reactive oxygen species production and mitochondrial damage to trigger redox imbalance, ultimately leading to indium lung disease. Nano-ITO causes pulmonary parenchymal lesions, and its pathological features mainly include: foam macrophage accumulation in respiratory bronchioles and alveolar cavities, fibrosis in alveolar septa (collagen deposition in alveolar septa), epithelial-mesenchymal transition (decreased expression of E-cadherin, increases expression of alpha smooth muscle actin and vimentin), intracytoplasmic lipid droplets (Oil Red-O-positive AM), and cholesterol clefts forming small nodules and granuloma. These findings suggest that intratracheal instillation of rats for 12 weeks is sufficient to observe progressive lung lesions caused by Nano-ITO and is an appropriate experimental scheme to evaluate the early stages of indium lung disease.
Redox imbalance and mitochondrial dysfunction in gestational diabetes mellitus: Implications for maternal health, placental function, and offspring metabolic programming.
Burzynska-Pedziwiatr I, Wozniak LA, Bukowiecka-Matusiak M
Free Radic Biol Med · 2026 Jun · PMID 42242082 · Publisher ↗
Mitochondrial dysfunction and redox imbalance are increasingly recognised as essential factors in the pathophysiology of gestational diabetes mellitus (GDM). Impaired oxidative phosphorylation in the placenta, increased...
Mitochondrial dysfunction and redox imbalance are increasingly recognised as essential factors in the pathophysiology of gestational diabetes mellitus (GDM). Impaired oxidative phosphorylation in the placenta, increased production of reactive oxygen species (ROS), and insufficient antioxidant protection impair bioenergetics and affect maternal-foetal nutrient exchange. Such changes promote excessive foetal growth and metabolic programming while predisposing mothers to future type 2 diabetes. Current research indicates alterations in mitochondrial dynamics and mitophagy as additional risk factors for placental disease. The placenta is not only a passive recipient of maternal hyperglycaemia; it actively participates in metabolic signalling at the maternal-foetal interface. This structure identifies placental mitochondria as potential therapeutic targets. Preclinical studies on mitochondrial antioxidants (SS-31, MitoQ), uncoupling factors, and biogenesis-supporting substances have shown great potential in restoring mitochondrial integrity and reducing oxidative stress. However, there is still no clinical confirmation of their effectiveness during pregnancy. A comprehensive understanding of mitochondrial redox processes during gestational diabetes offers unique potential for improving pregnancy outcomes and may contribute to reducing the intergenerational inheritance of metabolic diseases.
Corrigendum to "Inhibiting Endoplasmic Reticulum/Plasma Membrane contact ameliorates endometrial fibrosis by preventing senescence in endometrial epithelial cells" [Free Radic. Biol. Med. 247 (2026) 251-266].
Yang H, Zhang Y, Li M … +8 more , Zeng K, Xu Y, Pan R, Huang J, Sun L, Yao Y, Luo J, Li T
Free Radic Biol Med · 2026 Aug · PMID 42236335 · Publisher ↗
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Electrophilic monocarbonyl curcumin derivatives reveal differential vulnerabilities in the selenium metabolic network.
Yinuo W, Toyama T, Yamakoshi H … +14 more , Taguchi H, Takashima H, Watanabe R, Mita Y, Ito J, Mishima E, Akiyama Y, Shibata H, Noguchi N, Takamura T, Conrad M, Tomikoka Y, Iwabuchi Y, Saito Y
Free Radic Biol Med · 2026 Jun · PMID 42235614 · Publisher ↗
Selenium is an essential trace element whose biological functions are exerted through selenoproteins, synthesized by a highly coordinated and redox-regulated network. How this network responds to electrophilic stimulus,...
Selenium is an essential trace element whose biological functions are exerted through selenoproteins, synthesized by a highly coordinated and redox-regulated network. How this network responds to electrophilic stimulus, however, remains incompletely understood. Here, we employed a focused library of monocarbonyl curcumin derivatives as electrophilic chemical tools to interrogate the selenium metabolic network. Screening based on intracellular selenoprotein P abundance identified GO-Y015 as a potent and low-toxicity compound capable of strongly changing expression of selenoprotein P and glutathione peroxidase. In cultured hepatocytes, GO-Y015 suppressed selenoprotein expression by inhibiting de novo selenoprotein synthesis, rather than promoting lysosomal degradation. Biochemical analyses revealed that GO-Y015 covalently modified multiple selenium-handling enzymes, including PRDX6, SCLY, and SEPHS2, and impaired selenium incorporation into Sec-tRNA, indicating broader alternation of selenium metabolism. Short-term administration of GO-Y015 in mice resulted in a selective reduction of circulating selenoprotein P, with limited effects on other selenoproteins and no overt hepatotoxicity. Under these conditions, no body-weight loss and hepatotoxicity was observed, supporting the interpretation that the observed molecular effects reflect acute metabolic alteration. Together, these findings establish electrophilic monocarbonyl curcumin derivatives as chemical tools that reveal differential vulnerabilities within the selenium metabolic network, with selenoprotein P serving as a particularly sensitive indicator of selenium metabolic modulation.
Corrigendum to "Identification of the redox-stress signaling threshold (RST): Increased RST helps to delay aging in C. elegans" [Free Radic Biol Med. 178 (2022) 54-58].
Meng J, Lv Z, Wang Y … +1 more , Chen C
Free Radic Biol Med · 2026 Aug · PMID 42230165 · Publisher ↗
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Luteolin rescues high-fat diet-induced hippocampal mitochondrial oxidative stress and cognitive decline by regulating gut microbiota-kynurenine-aryl hydrocarbon receptor axis.
An X, Li C, Chai Y … +14 more , Wang H, Yang L, Qin L, Soprun LA, Gavrilova NY, Wen Z, Xu J, Li Q, Yang D, Li W, Guo J, Li Y, Wang N, Yu H
Free Radic Biol Med · 2026 Jun · PMID 42229822 · Publisher ↗
High-fat diet (HFD)-induced gut dysbiosis precipitates hippocampal mitochondrial oxidative stress, a pivotal driver of synaptic failure and cognitive decline. However, the molecular conduits linking intestinal microbial...
High-fat diet (HFD)-induced gut dysbiosis precipitates hippocampal mitochondrial oxidative stress, a pivotal driver of synaptic failure and cognitive decline. However, the molecular conduits linking intestinal microbial shifts to cerebral redox imbalance remain poorly defined, limiting therapeutic strategies. Here, we show that luteolin attenuates HFD-induced cognitive impairment in association with modulation of the gut microbiota-kynurenine (Kyn)-aryl hydrocarbon receptor (AhR) axis and improved mitochondrial redox homeostasis. Luteolin treatment ameliorated HFD-induced memory deficits and metabolic abnormalities in mice, effects that were markedly reduced after gut microbiota depletion and were transmissible via fecal microbiota transplantation. Consistent with this pathway, luteolin suppressed HFD-induced expansion of Proteobacteria (e.g., Escherichia coli), diminished intestinal lipopolysaccharide (LPS) leakage, and normalized colonic indoleamine 2,3-dioxygenase 1 (IDO1) expression. Consequently, luteolin reduced peripheral and hippocampal Kyn accumulation, thereby restricting AhR nuclear translocation and preventing the aberrant transcription of AhR-target genes implicated in mitochondrial respiratory chain disruption. Functionally, luteolin restored hippocampal mitochondrial bioenergetics, attenuated pathological reactive oxygen species (ROS) overload, and preserved synaptic long-term potentiation (LTP). The protective efficacy of luteolin against mitochondrial oxidative insult and cognitive decline was phenocopied by AhR inhibition and abrogated by exogenous Kyn supplementation. Collectively, our findings identify the gut Proteobacteria-Kyn-AhR signaling axis as an important contributor to hippocampal mitochondrial oxidative stress in HFD-challenged brains. Luteolin emerges as a promising microbiota-targeted antioxidant intervention that safeguards cognitive function by rectifying this gut-brain redox relay.
Systemic remodeling of the glioblastoma microenvironment via plasma-induced vascular disruption and CSF-propelled oxidative therapy.
Chen Y, Luo Z, Zhang C … +6 more , Hou S, Zhang J, Song W, Tong H, Cheng C, Ni G
Free Radic Biol Med · 2026 Jun · PMID 42229821 · Publisher ↗
Cold atmospheric plasma (CAP) exhibits potent anti-tumor activity against glioblastoma in vitro, yet the in vivo therapeutic efficacy of CAP may be restricted by the limited direct penetration depth of CAP. In glioblasto...
Cold atmospheric plasma (CAP) exhibits potent anti-tumor activity against glioblastoma in vitro, yet the in vivo therapeutic efficacy of CAP may be restricted by the limited direct penetration depth of CAP. In glioblastoma, effective drug delivery to tumor tissue is crucial to glioblastoma treatment. The complex tumor microenvironment (TME) of glioblastoma and the limited permeability of the blood-brain barrier (BBB) are major obstacles to drug delivery into tumor tissue. Through comprehensive in vitro and in vivo studies, we characterize a novel tripartite mechanism of CAP therapy that overcomes these limitations. Rather than the conventional penetration-limited mechanisms, the results reveal that CAP exerts its therapeutic effects via three distinct but synergistic pathways: BBB integrity modulation, exploitation of cerebrospinal fluid (CSF)-mediated ROS distribution to deep tumor regions, and tumor-endothelial paracrine signaling network activation. This multimodal action collectively overcomes glioblastoma TME barriers, establishing CAP as a systemic microenvironmental regulator rather than merely a local cytotoxic agent. These findings provide a transformative framework for clinical translation of CAP-based glioblastoma therapy.
Probiotic-driven gut-liver redox crosstalk modulates hepatic Nrf2 signaling pathway and attenuates metabolic dysfunction-associated steatohepatitis.
Lee DH, Kim DY, Joung H … +10 more , Kim H, Jeon Y, Lee S, Shin CH, Lee YS, Bang JY, Lee EJ, Cha SY, Bae SH, Lee HW
Free Radic Biol Med · 2026 Jun · PMID 42229820 · Publisher ↗
Metabolic dysfunction-associated steatohepatitis (MASH) is a chronic liver disease characterized by persistent inflammation, oxidative stress, and progressive fibrosis. There is currently no effective pharmacological the...
Metabolic dysfunction-associated steatohepatitis (MASH) is a chronic liver disease characterized by persistent inflammation, oxidative stress, and progressive fibrosis. There is currently no effective pharmacological therapy for MASH. We investigated whether two defined probiotic bacteria strains, Lactobacillus delbrueckii subsp. lactis (L. lactis) CKDB001 and Lactiplantibacillus plantarum (L. plantarum) Q180, attenuate MASH pathology in association with modulation of gut-liver redox signaling. Using diet-induced preventive and therapeutic mouse models of MASH, we showed that oral administration of these strains significantly improved hepatic steatosis, robustly attenuates fibrosis, and reduced inflammatory and oxidative stress markers. Probiotic treatment was associated with increased intestinal glutathione availability, and was accompanied by activation of hepatic nuclear factor erythroid 2-related factor 2 (Nrf2) signaling and upregulation of canonical antioxidant enzymes, consistent with improved hepatic redox homeostasis and reduced hepatocellular injury. Microbiome profiling revealed successful intestinal persistence of the administered strains and enrichment of other bacterial taxa associated with gut barrier integrity and metabolic resilience, including Akkermansia muciniphila, Parabacteroides goldsteinii, and Mediterraneibacter butyricigenes. Functional prediction analysis further suggested enhancement of microbial glutathione metabolism pathways, supporting a potential role for microbiota-driven redox modulation in host protection. Therapeutic efficacy was maintained after disease establishment and under conditions recapitulating features of a lean MASH-like phenotype, highlighting obesity-independent mechanisms of action. Collectively, our findings support a probiotic-driven association between intestinal glutathione dynamics and hepatic Nrf2 activation within the gut-liver axis, providing a mechanistically informed and translationally relevant framework for MASH intervention.
G protein-coupled receptor 87 promotes lung adenocarcinoma progression and metastasis via a histone lactylation-driven glycolytic feed-forward circuit.
Zhang Y, Li X, Han R … +5 more , Guo M, Lin E, Yang C, Ning J, Zhao Y
Free Radic Biol Med · 2026 Jun · PMID 42229819 · Publisher ↗
Metastatic progression is the leading cause of mortality in lung adenocarcinoma (LUAD), yet how oncogenic signals are translated into stable metabolic and epigenetic programs that sustain tumour progression remains poorl...
Metastatic progression is the leading cause of mortality in lung adenocarcinoma (LUAD), yet how oncogenic signals are translated into stable metabolic and epigenetic programs that sustain tumour progression remains poorly understood. Here, through integrated single-cell, bulk, and spatial transcriptomic analyses, we identify the orphan G protein-coupled receptor GPR87 as a progression-associated regulator linked to enhanced glycolytic activity and adverse clinical outcome in LUAD. Mechanistically, GPR87 activates the cAMP/PKA/CREB pathway to induce acetyl-CoA synthetase 2 (ACSS2) transcription, thereby promoting histone H3 lysine 27 lactylation (H3K27la). H3K27la directly enhances transcription of dihydrolipoamide S-acetyltransferase (DLAT), reinforcing glycolytic flux and lactate production in a self-sustaining metabolic-epigenetic circuit. In parallel, GPR87 physically stabilizes lactate dehydrogenase A (LDHA), further amplifying lactate output. Genetic disruption of ACSS2 suppresses GPR87-driven tumour growth and metastatic colonization in vivo. Consistently, coordinated activation of this axis is enriched in advanced-stage human LUAD. Together, these findings define a GPR87-centered metabolic-epigenetic circuit that sustains glycolytic dominance and supports LUAD progression and metastasis.
Cigarette Smoke-Induced ClC-3 Deficiency Drives Chronic Bronchitis via the AKT/CREB1 Axis and Lysosomal-Autophagic Impairment.
Zhang X, Ye D, Xiong Z … +9 more , Qiu X, Yu J, Yu J, Li M, Huang Y, Yin H, Guo X, Xu B, Mao J
Free Radic Biol Med · 2026 Jun · PMID 42229818 · Publisher ↗
Cigarette smoke (CS) exposure disrupts bronchial epithelial redox homeostasis, serving as a primary etiology of chronic bronchitis; however, the specific mechanisms linking ion transport dysregulation to CS-induced cytot...
Cigarette smoke (CS) exposure disrupts bronchial epithelial redox homeostasis, serving as a primary etiology of chronic bronchitis; however, the specific mechanisms linking ion transport dysregulation to CS-induced cytotoxicity remain poorly understood. This study identifies a critical protective role for the voltage-gated chloride channel ClC-3, a Cl/H exchanger, in maintaining airway epithelial integrity against oxidative insult. We report significant downregulation of ClC-3 in the bronchial epithelium of chronic bronchitis patients and CS-exposed mice. Using transgenic overexpression and conditional knockout mouse models, we demonstrate that ClC-3 deficiency exacerbates, while its overexpression mitigates, CS-induced airway inflammation, systemic oxidative stress (SOD/MDA), and lung injury. Mechanistically, we show that CS exposure suppresses AKT phosphorylation, leading to the inactivation of the transcription factor CREB1. We validate that CREB1 acts as a direct transcriptional activator of CLCN3 by binding to its promoter; thus, the CS-mediated inhibition of the AKT/CREB1 axis results in transcriptional silencing of ClC-3. At the cellular level, loss of ClC-3 disrupts lysosomal acidification, resulting in a blockade of autophagic flux. This impairment prevents the effective clearance of oxidative damage, thereby promoting epithelial cell death and amplifying inflammatory responses. Collectively, these findings delineate a novel "CS-AKT/CREB1-ClC-3-Lysosome" axis, suggesting that restoring ClC-3-mediated lysosomal function represents a promising therapeutic strategy to restore redox balance in chronic bronchitis.
Antiandrogen therapy induces mitochondrial oxidative phosphorylation to promote castration resistance in prostate cancer.
Li K, Luo C, Zhang H … +8 more , Yue T, Wang T, Ban Y, Li Z, Liu X, An L, Luo G, Ma Z
Free Radic Biol Med · 2026 May · PMID 42219062 · Publisher ↗
Tumor recurrence and therapy resistance are frequently accompanied by alterations in cellular metabolism. However, how metabolic remodeling occurs and contributes to castration-resistant prostate cancer (CRPC) remains la...
Tumor recurrence and therapy resistance are frequently accompanied by alterations in cellular metabolism. However, how metabolic remodeling occurs and contributes to castration-resistant prostate cancer (CRPC) remains largely elusive. Here, we demonstrate that mitochondrial oxidative phosphorylation (OXPHOS) is critical for development of androgen receptor signaling inhibitors (ARSI) resistance. Our findings indicate that prostate cancer cells exhibit increased mitochondrial OXPHOS following ARSI treatment. Notably, there is no significant change in glycolytic activity. Importantly, this metabolic remodeling relies on glucose and glutamine utilization. Mechanistically, ARSI treatment activates reactive oxygen species/AMPK/SIRT1/PGC-1α signaling axis, leading to nuclear accumulation of PGC-1α and enhancement of mitochondrial OXHPOS and tricarboxylic acid cycle. High mitochondrial OXPHOS in turn renders prostate cancer cells resistant to ARSI. Inhibitors of PGC-1α and mitochondrial OXPHOS restore drug sensitivity and synergize with ARSI to inhibit CRPC growth. Our findings demonstrate the metabolic plasticity of prostate cancer cells following ARSI treatment, identifying PGC-1α/mitochondrial OXPHOS axis as a potential metabolic target for CRPC treatment.
MitoQ attenuates maternal immune activation-induced mitochondrial and ER stress programs and ameliorates psychiatric-like behavioral deficits.
Zhang X, Zhang J, Shen M
Free Radic Biol Med · 2026 May · PMID 42217685 · Publisher ↗
Maternal immune activation (MIA) increases risk for neurodevelopmental and psychiatric disorders, yet the stress programs linking prenatal immune challenge to persistent neuronal dysfunction remain incompletely defined....
Maternal immune activation (MIA) increases risk for neurodevelopmental and psychiatric disorders, yet the stress programs linking prenatal immune challenge to persistent neuronal dysfunction remain incompletely defined. Here, we show that MIA engages convergent oxidative and ER stress programs accompanied by mitochondrial dysfunction across brain regions. Transcriptomic profiling of offspring hippocampus (HIP) revealed coordinated downregulation of oxidative phosphorylation (OXPHOS) and upregulation of ER protein-processing pathways, consistent with increased neuronal oxidative damage and ER stress markers. In parallel, hippocampal neurons exhibited mitochondrial fragmentation, reduced membrane potential, and a marked reduction in respiratory capacity. In the prefrontal cortex (PFC), MIA induced broad transcriptional remodeling that again highlighted ER stress-related pathways together with a region-specific OXPHOS signature, and these changes were accompanied by mitochondrial structural abnormalities and elevated inflammatory signaling. Finally, the mitochondria-targeted antioxidant MitoQ restored mitochondrial respiration and ameliorated anxiety-like and social behavioral abnormalities in MIA offspring. Together, these findings identify mitochondrial redox imbalance as a mechanistic node linking prenatal immune challenge to circuit-relevant cellular stress programs and support mitochondrial redox modulation as a potential intervention strategy.
Circadian Rhythms, NRF2 Signalling and Redox Homeostasis: A Holy Grail for a Healthy Life Course?
Sutton E, Pekovic-Vaughan V
Free Radic Biol Med · 2026 May · PMID 42217684 · Publisher ↗
SIGNIFICANCE: The circadian ∼24h timing system coordinates physiological and metabolic processes to anticipate daily environmental changes, yet how molecular clock-driven signals interface with redox signalling to shape...
SIGNIFICANCE: The circadian ∼24h timing system coordinates physiological and metabolic processes to anticipate daily environmental changes, yet how molecular clock-driven signals interface with redox signalling to shape health across the life course remain incompletely understood. Redox homeostasis encompasses the adaptive maintenance of a biological steady state through the regulation of reduction-oxidation (redox) reactions. Redox reactions are vital in maintaining cellular functions, from regulating cellular proliferation and differentiation to detoxification of harmful substances and metabolic regulation. This adaptive homeostasis allows cells and tissues to transiently adapt to fluctuating levels of internal and external environmental stressors and build stress resilience to potential damaging stimuli. As we age, our baseline stress-protective systems rise, and our cells and tissues lose the ability to transiently and temporally increase their adaptive capacity further, leading to chronic redox shifts in pathophysiological direction and increased susceptibility to disease and frailty. RECENT ADVANCES: Here we integrate circadian timing, NRF2 signalling and redox balance into a unified circadian-NRF2-redox axis as a life course framework for maintaining health from development through ageing. We propose that circadian clocks regulate NRF2 activity through rhythmic modulation of various redox-sensitive transcriptional and post-translational co-regulators, kinases and miRNAs, thereby shaping the amplitude and timing of antioxidant and metabolic responses. Conversely, NRF2-driven transcriptional programmes modulate mitochondrial function, glutathione synthesis and xenobiotic defence in a time-of-day manner, reinforcing circadian robustness in tissues with high oxidative flux. CRITICAL ISSUES: The bidirectional interplay between circadian clocks and NRF2-driven redox adaptations generates predictable redox oscillations that gate energy metabolism, cellular repair and immune responses, influencing susceptibility to chronic diseases, from metabolic and cardiorespiratory to neurodegenerative diseases and cancer. We review evidence from in vitro and in vivo experimental models and human studies showing that circadian/NRF/redox misalignments, whether from shiftwork, light pollution, irregular sleep or chronic feeding, amplify oxidative stress and diminish adaptive responses, accelerating health decline with age. FUTURE DIRECTIONS: We propose that lifestyle interventions that realign circadian timing (consistent sleep/wake or feeding/fasting schedules) and pharmacological strategies that enhance NRF2 activity can restore redox balance and improve disease risk profiles, highlighting a unifying target to predict health trajectories and promote lifelong health. Understanding redox-circadian interactions will help optimise person-centred chronomedicine approaches for advocating preventative health across the life course and for designing smarter therapeutic treatments for redox-based diseases, utilising time-of-day administration of drug treatments and clinical interventions.
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