Free Radic. Biol. Med. [JOURNAL]
Sun
200 papers
DRP1-mediated mitophagy facilitates oral squamous cell carcinoma tumor cell survival under glucose restriction.
Yu Q, Xiao T, Li Z … +5 more , Jing Y, Song Y, Zhang X, Huang X, Ni Y
Free Radic Biol Med · 2026 Jun · PMID 42364552 · Publisher ↗
Oral squamous cell carcinoma (OSCC) can progress within a nutrient-limited microenvironment, especially under low-glucose conditions. However, the mechanisms enabling tumor cells to cope with glucose limitation, particul...
Oral squamous cell carcinoma (OSCC) can progress within a nutrient-limited microenvironment, especially under low-glucose conditions. However, the mechanisms enabling tumor cells to cope with glucose limitation, particularly those that counteract reactive oxygen species (ROS) accumulation, remain largely unknown. Here, we showed that dynamin-related protein 1 (DRP1)-mediated mitophagy promoted OSCC cell survival under glucose restriction. High expression of DRP1 was observed in OSCC tumor cells and identified as an indicator of poor prognosis. Either expression knockdown or pharmacological inhibition of DRP1 significantly reduced tumor cell mitophagy, leading to increased ROS production and consequently accelerating OSCC tumor cell death. The promoting effect of DRP1 on OSCC tumor growth, alongside its inhibitory effect on ROS production, was also confirmed in vivo. Furthermore, as a key nutrient stress sensor, AMP-activated protein kinase (AMPK) was activated upon glucose restriction. Pharmacological inhibition of AMPK was associated with reduced DRP1 mitochondrial translocation and diminished mitophagy. These findings collectively uncover that DRP1 contributes to mitophagy and allows OSCC cells to adapt to glucose limitation and overcome associated ROS stress, providing potential mechanistic insights for enhancing the efficiency of targeted therapies strategies.
A novel role for magnetotactic bacterium: Magnetospirillum magneticum AMB-1 prolonged healthy lifespan of Caenorhabditis elegans via regulating ferroptosis.
Ding Y, Huang X, Zhao Y … +7 more , Dong R, Zhou C, Wu Y, Du H, Wan J, Liu Y, Xu A
Free Radic Biol Med · 2026 Jun · PMID 42361992 · Publisher ↗
Magnetotactic bacteria (MTB), which contain special nano-magnetic particles within their cells, have been extensively studied for biomedical applications including drug delivery and cancer treatment. However, the practic...
Magnetotactic bacteria (MTB), which contain special nano-magnetic particles within their cells, have been extensively studied for biomedical applications including drug delivery and cancer treatment. However, the practical application of bacteria themselves remains relatively limited in current research. Magnetospirillum magneticum AMB-1 (AMB-1), an MTB capable of iron biomineralization and possessing potential antioxidant properties, was investigated in this study for its effects on lifespan and healthspan in Caenorhabditis elegans (C. elegans), as well as its underlying mechanisms. Our results showed that feeding with AMB-1 significantly extended the mean lifespan of C. elegans by 43.39 %, from 17.17 ± 1.25 to 24.62 ± 1.44 days. Moreover, AMB-1 improved neural function and preserved intestinal integrity in aged C. elegans, leading to a significant healthy lifespan extension. Further research found that AMB-1 treatment decreased Fe content by 34.11 % and lipid peroxide levels by 52.19 %, compared to the OP50-fed control. Notably, AMB-1 administration markedly attenuated aging-associated ferroptosis. Specifically, AMB-1 upregulated the expression of ftn-1, which encodes ferritin, and downregulated bli-3, the sole NADPH oxidase (NOX) homolog that promotes ferroptosis in C. elegans, leading to suppression of ferroptosis-related indicators. RNA interference (RNAi) experiments revealed that the ferroptosis-related gene ads-1, encoding alkylglycerophosphate synthase (AGPS), played a critical role in AMB-1-induced longevity. These findings demonstrated that AMB-1 promoted healthy aging in C. elegans by inhibiting ferroptosis, highlighting its potential as an effective anti-aging microbial agent.
CD200R protects against ulcerative colitis by regulating macrophage polarization and intestinal barrier function: evidence from human patients and mouse disease models.
Liu X, Hu Y, Wang J … +6 more , Ruan Q, Chen Y, Guo X, Peng L, Ke X, Guo Z
Free Radic Biol Med · 2026 Jun · PMID 42349804 · Publisher ↗
BACKGROUND AND OBJECTIVE: Ulcerative colitis (UC) is a chronic inflammatory disorder characterized by dysregulated mucosal immunity and impaired epithelial barrier function. CD200R is an inhibitory immune receptor involv...
BACKGROUND AND OBJECTIVE: Ulcerative colitis (UC) is a chronic inflammatory disorder characterized by dysregulated mucosal immunity and impaired epithelial barrier function. CD200R is an inhibitory immune receptor involved in immune homeostasis, but its cell-specific expression pattern and functional role in UC remain unclear. METHODS: We reanalyzed single-cell RNA sequencing (scRNA-seq) data from human UC colonic tissues to characterize CD200R expression at cellular resolution. CD200R expression was further validated in colonic biopsies from UC patients and non-IBD controls. Functional roles of CD200R were investigated using DSS-induced colitis models in global CD200R-deficient mice and AAV-mediated CD200R-overexpressing mice. In vitro RAW264.7 macrophage experiments and Caco-2 epithelial assays were performed to assess macrophage polarization, oxidative stress, epithelial barrier integrity, and downstream signaling pathways. RESULTS: scRNA-seq analysis revealed that CD200R expression was predominantly reduced in intestinal macrophages in UC, accompanied by activation of inflammatory signaling pathways. Consistently, CD200R expression was decreased in UC patient tissues and correlated with disease severity. In vivo, CD200R deficiency aggravated DSS-induced colitis, enhanced oxidative stress, promoted M1 macrophage polarization, and disrupted epithelial barrier integrity. In contrast, CD200R overexpression alleviated intestinal inflammation, promoted M2 polarization, and preserved barrier function. Transcriptomic and protein analyses further identified changes in AMPK/PPARγ and TLR4/NF-κB-related signaling associated with CD200R modulation. CONCLUSIONS: Reduced CD200R expression is associated with intestinal inflammation in UC. Integrated analyses of human tissues, single-cell transcriptomic data, and experimental models suggest that CD200R may contribute to the regulation of macrophage polarization, oxidative stress, and epithelial barrier function, supporting further investigation of CD200R as a candidate therapeutic axis in UC.
Metabolism of the antioxidant micronutrient ergothioneine as a plasma biomarker of cognitive resilience in older people with Alzheimer's disease amyloid pathology.
Chong JR, Cheah IK, Tang RM … +3 more , Halliwell B, Chen CP, Lai MKP
Free Radic Biol Med · 2026 Jun · PMID 42349803 · Publisher ↗
BACKGROUND: Associations between dietary micronutrients and cognitive resilience to Alzheimer's disease (AD) amyloid pathology is currently unknown. We investigated whether plasma levels of L-ergothioneine (ET), its meta...
BACKGROUND: Associations between dietary micronutrients and cognitive resilience to Alzheimer's disease (AD) amyloid pathology is currently unknown. We investigated whether plasma levels of L-ergothioneine (ET), its metabolite L-hercynine (HC), and their ratio (HC:ET, as an index of ET metabolism) affect known associations between biomarkers of amyloid pathology (p-Tau181 or p-Tau217) and cognitive decline. METHODS: 259 initially dementia-free participants recruited from memory clinics and the community in Singapore had baseline measurements of plasma p-Tau, ET, HC, as well as annual neuropsychological assessments for up to 5 years to derive cognitive trajectories based on Clinical Dementia Rating-Sum of Boxes (CDR-SB) slopes. RESULTS: High HC:ET attenuated the positive correlations between plasma p-Tau and CDR-SB slopes. Compared with participants with low amyloid burden, participants with high amyloid burden had higher risk of cognitive decline when HC:ET was low (Hazard ratio [HR] = 2.33, p = 0.002), but not when HC:ET was high (HR = 1.47, p = 0.32). CONCLUSION: The identification of ET metabolism as a novel biomarker of cognitive resilience supports further investigations into mechanisms underlying its neuroprotectant properties. ET should be further assessed as a potential candidate for countering amyloid pathology-associated cognitive decline.
Rosuvastatin ameliorates high-altitude cerebral edema by promoting blood-brain barrier integrity via the regulation of energy metabolism.
Jin H, Han B, He J … +4 more , Chen M, Guo J, Zhang L, Jia L
Free Radic Biol Med · 2026 Jun · PMID 42341957 · Publisher ↗
High-altitude cerebral edema (HACE) is a severe and potentially fatal neurological condition resulting from acute exposure to hypobaric hypoxia. This condition is characterized by the disruptions of endothelial tight jun...
High-altitude cerebral edema (HACE) is a severe and potentially fatal neurological condition resulting from acute exposure to hypobaric hypoxia. This condition is characterized by the disruptions of endothelial tight junctions, triggering blood-brain barrier (BBB) compromise and subsequent vasogenic edema. However, the effective protective strategies against HACE remain limited. The present research aimed to elucidate the protective effects of Rosuvastatin on HACE in rats and the underlying mechanisms. Rats were exposed to hypobaric hypoxia at an altitude equivalent to 6000 m for 24 h. Subsequently, analyses of brain structure, BBB integrity, and mitochondrial energy metabolism were performed to confirm the protective efficacy of Rosuvastatin against BBB disruption in HACE. The findings revealed that Rosuvastatin significantly maintained BBB integrity by promoting tight junctions in vascular endothelial cells of rats exposed to hypobaric hypoxia. Simultaneously, Rosuvastatin effectively mitigated hypobaric hypoxia-induced oxidative stress by reducing the formation of reactive oxygen species and malondialdehyde, while enhancing the activity of glutathione peroxidase and superoxide dismutase in brain tissue. Importantly, Rosuvastatin markedly attenuated mitochondrial function by enhancing oxidative phosphorylation. Collectively, our findings first demonstrated that Rosuvastatin mitigates HACE progression by modulating oxidative stress and mitochondrial energy metabolism.
Stabilization of Keap1 by alkannin triggers ferroptotic cell death in colorectal cancer via suppression of the Nrf2/GPX4 signaling.
Yu H, Liu J, Han R … +7 more , Shan K, Jiang R, Gao C, Chen J, Zhang R, Liu Z, Wu J
Free Radic Biol Med · 2026 Jun · PMID 42336003 · Publisher ↗
Colorectal cancer (CRC) is one of the most common and deadly types of cancer globally. Ferroptosis, a type of regulated cell death that relies on iron, has become a promising target for treating CRC. Alkannin, a natural...
Colorectal cancer (CRC) is one of the most common and deadly types of cancer globally. Ferroptosis, a type of regulated cell death that relies on iron, has become a promising target for treating CRC. Alkannin, a natural compound from Lithospermum erythrorhizon, exhibits anti-tumor activity, yet its mechanism in CRC is unclear. This study investigated alkannin's role in regulating ferroptosis via the Keap1/Nrf2/GPX4 axis. Using network pharmacology and experimental validation in HCT116 and SW480 cells and a xenograft mouse model, we found that alkannin markedly inhibited the viability, proliferation, and migratory capacity of CRC cells, demonstrating significant anti-tumor activity. Network pharmacology revealed a primary association between alkannin's therapeutic effects and the induction of ferroptosis, along with the regulation of oxidative stress pathways, with a notable focus on the Keap1/Nrf2 axis. Experimental evidence confirmed that alkannin induced ferroptosis, as reflected by increased intracellular Fe levels and lipid peroxidation, along with reduced glutathione (GSH) content. These effects were reversed by ferroptosis inhibitors, which also attenuated alkannin-induced cytotoxicity. Mechanistically, alkannin enhanced Keap1 protein stability by suppressing its ubiquitination. It promoted the interaction between Keap1 and Nrf2, leading to decreased Nrf2 expression and inhibition of its nuclear translocation, thereby downregulating the expression of glutathione peroxidase 4 (GPX4), a key suppressor of ferroptosis. Genetic silencing of Keap1 significantly diminished alkannin-induced ferroptotic cell death. In vivo, alkannin effectively inhibited tumor growth in xenografted nude mice. Furthermore, it induced ferroptosis in tumor tissues, as evidenced by similar biochemical changes, which were counteracted by co-administration of a ferroptosis inhibitor. Consistently, alkannin upregulated Keap1 expression while reducing the protein levels of Nrf2 and GPX4 in tumor tissues. In conclusion, alkannin induces ferroptosis in CRC by stabilizing Keap1 to inhibit the Nrf2/GPX4 pathway, supporting its potential as a CRC therapeutic agent.
Gentamicin triggers fatty acid oxidation-dependent mitochondrial ROS, driving greater nephrotoxicity than apramycin and other aminoglycosides.
Liepinsh E, Krims-Dāvis K, Cirule H … +6 more , Pinkovskis K, Ozola M, Sevostjanovs E, Makrecka-Kuka M, Dambrova M, Hobbie SN
Free Radic Biol Med · 2026 Jun · PMID 42336002 · Publisher ↗
Apramycin has emerged as a promising antibacterial drug candidate that has demonstrated great preclinical efficacy and safety profile. In comparative studies, apramycin was found to be significantly less nephrotoxic than...
Apramycin has emerged as a promising antibacterial drug candidate that has demonstrated great preclinical efficacy and safety profile. In comparative studies, apramycin was found to be significantly less nephrotoxic than gentamicin; however, the underlying mechanisms have not been clarified. In the present study, we investigated whether different aminoglycoside antibiotics share the same toxicity mechanisms and whether cotreatment with the antioxidant N-acetyl-cysteine (NAC) can ensure even safer apramycin use. In addition, we investigated whether cilastatin decreases apramycin content in the kidneys and thus mitigates adverse effects. We found that NAC in combination with apramycin was not beneficial; a similar or even greater increase in nephrotoxicity markers was observed with this combination in rats and mice. Furthermore, we found that only gentamicin and, to a lesser extent, arbekacin and kanamycin induced a prominent increase in the mitochondrial fatty acid oxidation (FAO)-dependent production of HO. Apramycin, paromomycin, neomycin, dibekacin, geneticin, amikacin, tobramycin, and plazomicin stimulated neither FAO nor HO production in kidney mitochondria. We also found that gentamicin C1, which is one of the congeners in clinically used gentamicin, did not increase mitochondrial FAO or related HO production. In rats, treatment with cilastatin combined with apramycin partially prevented glomerular but not tubular kidney damage induced by a high dose of apramycin. In the same animals, we found that cilastatin did not affect apramycin content in the kidneys. In conclusion, gentamicin differs from other aminoglycoside antibiotics by coupling fatty-acid oxidation to mitochondrial reactive oxygen species (ROS) generation. Gentamicin congener C1, apramycin, and 10 other tested aminoglycosides do not stimulate mitochondrial ROS production, and the use of antioxidants to protect the kidneys against these aminoglycosides is not a reasonable strategy. Cilastatin protects against aminoglycoside-induced glomerular damage independent of the inhibition of aminoglycoside transport into kidney cells.
Impaired BCAA catabolism in macrophages exacerbates sepsis-induced lung injury by modulating mitochondrial AGE-RAGE and mtDNA release.
Hong Y, Xu Y, Luo K … +7 more , Wang H, Li Y, Liu J, Mao Y, Zhou L, Hu G, Jiang C
Free Radic Biol Med · 2026 Jun · PMID 42331302 · Publisher ↗
Although macrophage immunometabolism is a key contributor to the progression of sepsis-induced acute lung injury, the specific role of branched-chain amino acid (BCAA) catabolism in this process remains unclear. Here, we...
Although macrophage immunometabolism is a key contributor to the progression of sepsis-induced acute lung injury, the specific role of branched-chain amino acid (BCAA) catabolism in this process remains unclear. Here, we hypothesized that defective BCAA catabolism in macrophages exacerbates lung injury through activation of the advanced glycation end products (AGEs)-RAGE axis and mitochondrial DNA (mtDNA)-mediated inflammation. We employed a myeloid-specific Pp2cm knockout mouse model to examine the impact of impaired BCAA catabolism on lung injury during sepsis. We found that Pp2cm deficiency upregulated AGEs and their receptor RAGE in macrophages, leading to mitochondrial damage and structural damage. This mitochondrial impairment increased mitochondrial reactive oxygen species production and promoted exosomal mtDNA release, ultimately resulting in aggravated lung injury and higher mortality in myeloid Pp2cm deficient mice subjected to polymicrobial sepsis. Therapeutically, adoptive transfer of bone marrow-derived macrophages from wild-type donors into myeloid Pp2cm deficient mice, restoration of BCAA catabolism using the branched-chain ketoacid dehydrogenase kinase inhibitor BT2 (3,6-dichlorobenzo[b]thiophene-2-carboxylic acid), inhibition of the AGE-RAGE axis with aminoguanidine, or blockade of exosome release with GW4869 all significantly attenuated lung injury and improved survival. Importantly, in septic patients, PP2Cm expression in peripheral blood mononuclear cells was inversely correlated with radiographic lung injury severity and oxygenation index. Together, these findings identify impaired macrophage BCAA catabolism as a critical driver of sepsis-induced lung injury and highlight the AGE-RAGE axis and mtDNA release as potential therapeutic targets.
Contribution of Lipids and Epilipids to the hallmarks of skin aging.
Gruber F, Bauer C, Kremslehner C
Free Radic Biol Med · 2026 Jun · PMID 42331301 · Publisher ↗
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Selenium nanoparticles alleviate ulcerative colitis by regulating macrophage mitochondrial dynamics.
Chang J, Zeng X, Zhang R … +3 more , Li T, Gao Q, Xu C
Free Radic Biol Med · 2026 Jun · PMID 42331300 · Publisher ↗
Ulcerative colitis (UC) progression is closely associated with aberrant macrophage polarization and mitochondrial dysfunction. Here, we explored how biogenic selenium nanoparticles (SeNPs) protect against experimental co...
Ulcerative colitis (UC) progression is closely associated with aberrant macrophage polarization and mitochondrial dysfunction. Here, we explored how biogenic selenium nanoparticles (SeNPs) protect against experimental colitis, using dextran sulfate sodium (DSS)-challenged mice, together with lipopolysaccharide (LPS)-activated THP-1-derived macrophages as complementary in vivo and in vitro models. We found that selenium deficiency markedly aggravated DSS-induced intestinal barrier disruption, mucosal injury, and mitochondrial damage, underscoring the critical role of selenium homeostasis in mucosal immunity. Compared with inorganic selenium (NaSeO), biogenic SeNPs showed superior efficacy in alleviating colitis severity, preserving intestinal barrier integrity, restoring the intestinal stem cell niche, and promoting epithelial regeneration. Mechanistically, SeNPs shifted macrophage polarization away from the pro-inflammatory M1 state toward a more restorative profile. Transcriptomic and molecular analyses further suggested that these immunometabolic benefits were associated with preserved selenoprotein expression and peroxidase (GPx)/thioredoxin reductase (TrxR) activities, particularly restoration of the endoplasmic reticulum (ER)-resident selenoproteins selenoprotein K (SELENOK) and selenoprotein T (SELENOT), together with modulation of inositol 1,4,5-trisphosphate receptor (IP3R)-voltage-dependent anion channel 1 (VDAC1)-mediated mitochondria-associated membrane (MAM) signaling. This stabilization of inter-organelle communication effectively blunted LPS-induced cytosolic calcium overload, thereby facilitating the molecular rebalancing of mitochondrial dynamics, as reflected by reduced dynamin-related protein 1 (DRP1) and increased mitofusin 2 (MFN2) expression, and was accompanied by attenuation of reactive oxygen species (ROS) overproduction and NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation. Furthermore, a Transwell co-culture system confirmed that SeNP-pretreated macrophages indirectly preserved NCM460 intestinal epithelial barrier integrity through paracrine mechanisms. Collectively, these results suggest that SeNPs may serve as a potential nanotherapeutic approach for UC by restoring intestinal homeostasis through modulation of macrophage mitochondrial dynamics and enhancement of immune-epithelial crosstalk.
HERC2 as a bidirectional iron metabolism switch: Synergistic NCOA4 stabilization and FBXL5 degradation drive ferroptosis-cascaded hepatotoxicity in NdO nanoparticles exposure.
Liu S, Du W, Sun C … +4 more , Liu Y, Xing D, Song Y, Liang Q
Free Radic Biol Med · 2026 Jun · PMID 42320848 · Publisher ↗
Neodymium oxide nanoparticles (NdNPs), pivotal materials in advanced manufacturing and frontier technologies, raise growing concerns due to their potential risk to environment and health risks. Epidemiological studies li...
Neodymium oxide nanoparticles (NdNPs), pivotal materials in advanced manufacturing and frontier technologies, raise growing concerns due to their potential risk to environment and health risks. Epidemiological studies linked neodymium exposure to liver dysfunction, but the underlying mechanisms remained unclear. Here, we demonstrated that respiratory exposure to NdNPs led to significant hepatic accumulation, second only to the lungs, and induced liver injury in mice, characterized by increased parenchymal echogenicity, histopathological and ultrastructural damage, and hepatocyte ferroptosis. In HepG2 cells, NdNPs triggered ferroptosis, as evidenced by reduced cell viability, mitochondrial membrane/cristae disruption, elevated redox-active iron, exacerbated lipid peroxidation, and impaired repair capacity. The ferroptosis inhibitors ferrostatin-1 (Fer-1) and deferoxamine (DFO) rescued NdNPs-induced cell death, confirming ferroptosis. Mechanistically, NdNPs dysregulated iron homeostasis through dual HERC2-mediated pathways: (i) weakening HERC2-NCOA4 binding stabilized NCOA4, enhancing ferritinophagy-mediated redox-active iron release; and (ii) strengthening HERC2-FBXL5 interaction promoted FBXL5 degradation, derepressing IRP2/TFR1-mediated redox-active iron uptake. Together, these actions synergistically expanded the labile iron pool, driving lethal lipid peroxidation and ferroptosis. Critically, NCOA4 knockout, inhibition of the HERC2-FBXL5 interaction, and FBXL5 overexpression each significantly alleviated NdNPs-induced elevation of redox-active iron, lipid peroxidation, impairment of lipid peroxidation repair capacity, and cell death. Our findings establish HERC2-mediated dual-axis iron dysregulation as a previously unrecognized driver of NdNPs hepatotoxicity.
ADORA2B/ador-1 is required for multi-system transcriptional adaptation to mild hypoxia and healthspan extension in C. elegans.
Capó X, Torrens-Mas M, Calvo-Navarrete G … +10 more , Gill F, Raimundo A, Saunter C, Carretero A, Navas-Enamorado C, de la Llave AM, Sánchez-Polo A, Masmiquel L, Weinkove D, Gonzalez-Freire M
Free Radic Biol Med · 2026 Jun · PMID 42320847 · Publisher ↗
BACKGROUND: Mild intermittent hypoxia is emerging as a promising strategy to enhance healthspan, but the molecular mechanisms remain poorly defined. ADORA2B, a hypoxia-inducible adenosine receptor, is known to regulate m...
BACKGROUND: Mild intermittent hypoxia is emerging as a promising strategy to enhance healthspan, but the molecular mechanisms remain poorly defined. ADORA2B, a hypoxia-inducible adenosine receptor, is known to regulate metabolism and stress responses, yet its role in functional aging is unclear. METHODS: Using Caenorhabditis elegans, we investigated the role of the ADORA2B ortholog ador-1 in mediating the healthspan effects of mild hypoxia. We exposed wild-type and ador-1 knockout worms to low-dose cobalt chloride (CoCl) and assessed movement, speed, and lifespan metrics through automated imaging. Transcriptomic analyses via 3' RNA-seq and Gene Set Enrichment Analysis (GSEA) were performed to characterize underlying molecular responses. RESULTS: Mild hypoxia significantly extended healthspan in wild-type C. elegans, increasing sustained locomotor activity and distance traveled throughout adulthood. This benefit was markedly attenuated in ador-1 mutants, which displayed reduced baseline healthspan and a substantially blunted transcriptional response to CoCl treatment. Transcriptomic analyses identified coordinated regulation of canonical hypoxia-responsive genes, including acs-2, icl-1, adh-1, ftn-1 and ftn-2, consistent with activation of hypoxia-responsive transcriptional programs. GSEA revealed activation of pathways related to neuronal plasticity, muscle function and mitochondrial adaptation, together with transcriptional downregulation of ROS-related pathways. In contrast, hypoxia-treated ador-1 mutants exhibited suppression of pathways associated with ciliary function, immune responses, protein synthesis and cellular homeostasis. CONCLUSIONS: ADORA2B is required for the coordinated transcriptional adaptation associated with hypoxia-induced healthspan extension in C. elegans. Loss of ador-1 is associated with impaired baseline healthspan and an attenuated response to hypoxic conditioning. These findings support a model in which successful hypoxic adaptation requires coordinated regulation of multiple biological systems.
SIRT5 desuccinylates ME2 to suppress oxidative stress in bovine mammary epithelial cells.
Sun S, Yang Q, Liu X … +7 more , Chen X, Luo S, Song L, Han Y, Liu Y, Li H, Wang Y
Free Radic Biol Med · 2026 Jun · PMID 42320846 · Publisher ↗
Excessive accumulation of reactive oxygen species (ROS) in mitochondria is a key factor in inducing cellular oxidative stress. NADPH serves as a critical reducing equivalent for maintaining glutathione (GSH) in its reduc...
Excessive accumulation of reactive oxygen species (ROS) in mitochondria is a key factor in inducing cellular oxidative stress. NADPH serves as a critical reducing equivalent for maintaining glutathione (GSH) in its reduced state, which is essential for ROS scavenging and cellular protection. Here, we demonstrate that SIRT5 desuccinylates and activates malic enzyme 2 (ME2), thereby increasing intracellular NADPH and GSH levels. This enhanced antioxidant capacity effectively neutralizes excess ROS induced by lipoteichoic acid (LTA) in bovine mammary epithelial cells. Concomitantly, SIRT5-mediated ME2 activation improves mitochondrial membrane potential, ATP production, and the expression of mitochondrial biogenesis-related genes. Conversely, genetic ablation of SIRT5 or pharmacological inhibition of ME2 activity severely compromises cellular antioxidant defense and sensitizes cells to oxidative stress, indicating that ME2 is indispensable for the antioxidative function of SIRT5. Collectively, our study reveals a previously unrecognized mechanism in mammary epithelium whereby SIRT5 enhances antioxidant capacity and preserves mitochondrial function via ME2 desuccinylation. These findings highlight the SIRT5-ME2 axis as a potential therapeutic target for mitigating oxidative damage and preventing mastitis.
Multi-layered regulatory mechanisms and translational implications of mitochondrial redox imbalance in aging stem cells.
Ye Z, Chen S, Rui J … +3 more , Tang L, Wang T, Fan Q
Free Radic Biol Med · 2026 Jun · PMID 42314777 · Publisher ↗
Mitochondrial redox homeostasis is required for proper stem cell fate determination and tissue regeneration, and its dysregulation is a hallmark of aging-related stem cell dysfunction. This review systematically summariz...
Mitochondrial redox homeostasis is required for proper stem cell fate determination and tissue regeneration, and its dysregulation is a hallmark of aging-related stem cell dysfunction. This review systematically summarizes the multi-layered mechanisms by which aging-induced mitochondrial redox imbalance impairs stem cell identity, covering reactive oxygen species homeostasis, macromolecular metabolism, mitochondrial DNA integrity, mitochondrial dynamics, and the Sirtuin/forkhead box O (FoxO) signaling axis. We further highlight the context-specific metabolic features across different stem cell types and recent advances in targeted interventions to restore mitochondrial redox homeostasis, with a special focus on small molecule compounds with translational potential. This review further critically evaluates conflicting experimental evidence in current research, highlights major unresolved controversies and technical limitations in the field, providing a model that links mitochondrial redox status to epigenetic regulation for advancing both basic research and translational applications of mitochondrial redox-targeted interventions for stem cell aging.
An inulin-based fiber-rich diet alleviates doxorubicin cardiotoxicity via the fMet-KCNE2 axis to attenuate ferroptosis and oxidative stress.
Li J, He Y, Wu Y … +3 more , Tian H, Zhou Y, Xiao H
Free Radic Biol Med · 2026 Jun · PMID 42309360 · Publisher ↗
Doxorubicin (DOX)-induced cardiotoxicity remains a major complication of anticancer chemotherapy, and there is a substantial unmet need for safe and effective preventive and therapeutic strategies. This study investigate...
Doxorubicin (DOX)-induced cardiotoxicity remains a major complication of anticancer chemotherapy, and there is a substantial unmet need for safe and effective preventive and therapeutic strategies. This study investigated the potential mechanism of an inulin-based fiber-rich diet (FRD) in preventing DOX-induced cardiomyopathy (DIC). We found that FRD intervention significantly improved the survival of mice with DIC, protected cardiac function, and reduced myocardial injury and histopathological abnormalities. Mechanistically, transcriptomic profiling combined with pathway enrichment analyses indicated that suppression of ferroptosis constitutes a central component of FRD-mediated cardioprotection. Pharmacological validation further showed that the ferroptosis inducer erastin abolished the cardioprotective effects of FRD. Targeted metabolomics identified N-formylmethionine (fMet) as a key cardioprotective metabolite that was significantly upregulated following FRD intervention. fMet directly inhibited DOX-induced ferroptosis in cardiomyocytes, as evidenced by reduced lipid reactive oxygen species (ROS), malondialdehyde (MDA), and intracellular Fe levels, together with increased glutathione (GSH) levels and upregulated expression of glutathione peroxidase 4 (GPX4) and the cystine/glutamate antiporter (xCT) proteins. Further investigation revealed that the potassium channel auxiliary subunit KCNE2 is a critical target of fMet; KCNE2 knockdown abrogated the anti-ferroptotic effects of fMet in cardiomyocytes. Collectively, this study delineates a FRD-fMet-KCNE2 axis that suppresses cardiomyocyte ferroptosis and mitigates DIC, providing a mechanistic rationale for nutritional interventions to alleviate chemotherapy-associated cardiotoxicity.
RNF10 attenuates age-related muscle atrophy by promoting p53 degradation and alleviating oxidative stress.
Yang H, Zhang Y, Zhang L … +11 more , Dai X, Yu J, Zhao Y, Fu D, Shu Y, Zhou M, Cheng P, Wu Y, Xiang Y, Yang H, Xiao Q
Free Radic Biol Med · 2026 Jun · PMID 42309359 · Publisher ↗
Evidence identifies proteostasis imbalance and oxidative stress serve as fundamental pathological hallmarks of muscular atrophy, yet ring finger protein 10 (RNF10), a novel E3 ubiquitin ligase, in age-related muscular at...
Evidence identifies proteostasis imbalance and oxidative stress serve as fundamental pathological hallmarks of muscular atrophy, yet ring finger protein 10 (RNF10), a novel E3 ubiquitin ligase, in age-related muscular atrophy remains poorly characterized. Employing a natural aging mouse model and D-galactose-induced senescent C2C12 myotubes, we performed loss- and gain-of-function approaches for RNF10 with the aim of elucidating its downstream regulatory mechanisms. Aged mice showed significant declines in skeletal muscle mass and exercise capacity. Histological analysis revealed a significant reduction in gastrocnemius muscle (GAS) fiber cross-sectional area (CSA). Both in vivo and in vitro experiments showed elevated aging markers, increased inflammatory factors, decreased protein synthesis, enhanced proteolysis, and upregulated muscle atrophy indicators accompanied by nearly 50% reduction of RNF10 expression. AAV-mediated restoration of RNF10 in aged mice improved skeletal muscle mass and function, while reducing inflammatory levels and enhancing systemic antioxidant capacity. Mechanistically, RNF10 directly interacted with p53 to promote its ubiquitin-dependent degradation, which in turn reduced oxidative stress and improved mitochondrial function. In senescent myotubes, RNF10 deficiency elevated mitochondrial oxidative stress and disrupted proteostasis, effects that were rescued by p53 inhibition. TIGAR expression increased upon p53 degradation, and TIGAR silencing abolished the protective effects against myotube atrophy and oxidative stress, indicating that TIGAR is required for these beneficial outcomes. Our findings demonstrate that promoting RNF10-mediated p53 degradation represents a promising therapeutic strategy for sarcopenia intervention.
Comparison of the reactivity of hypochlorous acid (HOCl) and hyposelenocyanous acid (HOSeCN) with elastase: role of amino acid modification and structural changes in loss of activity.
Hemmling H, Webber OG, Guitart-Solanes A … +4 more , Fuentes-Lemus E, Hägglund P, Davies MJ, Hawkins CL
Free Radic Biol Med · 2026 Jun · PMID 42309358 · Publisher ↗
Elastase is a serine protease that plays a key role in intracellular and extracellular neutrophil-driven immune responses. There is a synergistic relationship between elastase and myeloperoxidase (MPO), which can boost p...
Elastase is a serine protease that plays a key role in intracellular and extracellular neutrophil-driven immune responses. There is a synergistic relationship between elastase and myeloperoxidase (MPO), which can boost pathogen killing and limit collateral proteolytic damage to host tissue. However, both proteins are strongly implicated in disease pathology, leading to interest in the design of therapeutic strategies to modulate their activity in vivo, particularly in chronic inflammatory settings. Here we examined whether the alternative MPO substrate selenocyanate (SeCN), can modulate elastase modification by hypochlorous acid (HOCl), via the formation of hyposelenocyanous acid (HOSeCN), as a potential therapeutic strategy. Exposure of elastase to HOCl results in significant loss of function, amino acid modification, fragmentation and aggregation. Trp and Tyr are readily modified, forming products including hydroxytryptophans, kynurenine and 3-chlorotyrosine. Loss of cystine, Met, His and Arg was also observed, together with N-chloramine formation, which did not appear to cause secondary oxidation. Inactivation of elastase was observed on exposure to HOSeCN, concomitant with protein unfolding. With HOSeCN, there was less extensive modification and loss of amino acid residues, with Trp and cystine residues shown to be the main targets. Fragmentation of elastase was observed, visualised on reducing gels, by the presence of specific low molecular mass bands. On non-reducing gels, a band at 50 kDa was detected, consistent with the formation of elastase dimers. Exposure of elastase to HOCl in the presence of sub-stoichiometric amounts of SeCN prevented enzyme inactivation and resulted in structural changes consistent with HOSeCN formation.
Shogaol triggers apoptosis and ferroptosis in Ewing sarcoma by targeting the polo-like kinase 1/nucleophosmin 1 axis.
Wu Z, Chen H, Zhou Y … +4 more , Zhang S, Li Z, Song Y, Hu J
Free Radic Biol Med · 2026 Jun · PMID 42303003 · Publisher ↗
Ewing sarcoma is an aggressive pediatric bone cancer with poor prognosis, highlighting the urgent need for novel therapeutics. This study demonstrates the potent anti-tumor activity of shogaol, a bioactive compound from...
Ewing sarcoma is an aggressive pediatric bone cancer with poor prognosis, highlighting the urgent need for novel therapeutics. This study demonstrates the potent anti-tumor activity of shogaol, a bioactive compound from ginger, against Ewing sarcoma, using both in vitro and in vivo model systems. In vitro, shogaol significantly inhibited cell proliferation and induced both apoptosis and ferroptosis in Ewing sarcoma cells, as evidenced by increased lipid reactive oxygen species, Malondialdehyde, and Fe levels, as well as altered expression of BAX, BCL2, GPX4, and SLC3A2. In vivo, shogaol significantly inhibited tumor cell growth in a subcutaneous xenograft mouse model using SKNMC cells. Using transcriptome sequencing and proteomics, we found that shogaol targeted the PLK1/NPM1 axis: it downregulated polo-like kinase 1 (PLK1), leading to reduced phosphorylation of NPM1 at Thr199. This facilitated the increased interaction between the E3 ligase TRIM28 and NPM1, leading to its ubiquitination and subsequent degradation, which in turn inhibited the MAPK signaling pathway. Key findings were validated by CETSA, isothermal dose-response fingerprinting, co-immunoprecipitation, and ubiquitination assays. These results demonstrate that shogaol exerts dual cytotoxic effects through the PLK1/NPM1 axis, presenting a potential natural therapeutic approach for Ewing sarcoma.
Genetic modifiers of Friedreich's ataxia pathophysiology in Drosophila melanogaster - A systematic review and meta-analysis.
Yadav RK, Swarup V, Ahuja A … +5 more , Talukdar D, Garg D, Aski M, Srivastava AK, Yadav P
Free Radic Biol Med · 2026 Jun · PMID 42303002 · Publisher ↗
Friedreich's ataxia (FRDA) is a rare autosomal recessive neurodegenerative disorder caused by reduced frataxin protein levels. Depleted frataxin leads to mitochondrial dysfunction, elevated oxidative stress and progressi...
Friedreich's ataxia (FRDA) is a rare autosomal recessive neurodegenerative disorder caused by reduced frataxin protein levels. Depleted frataxin leads to mitochondrial dysfunction, elevated oxidative stress and progressive neurodegeneration. The molecular mechanisms that regulate the severity of disease are still poorly understood. Genetic modifiers have proved to be important determinants of the disease pathophysiology and in uncovering novel therapeutic targets. This systematic review and meta-analysis was conducted to compare the effectiveness of different genetic modifiers of the pathophysiology of the FRDA in Drosophila model. Articles were screened as per PICO criteria and included articles were assessed for methodological quality using SYRCLE tool and plotted using robvis tool. Genetic modifiers improved survival (effect size (ES) 0.2082), brain vacuolization, Electroretinogram (ERG) (ES 0.6373), locomotion (ES 0.3356), and aconitase activity (ES 0.2087), of Drosophila FRDA models while the heterogeneity was high across different studies for all phenotypes. Genetic modifiers were compared on the basis of efficacy, reproducibility, mechanistic relevance, safety, therapeutic plausibility and graded for their effectiveness on disease pathogenicity. Ferritins overexpression, Miro inhibition, and catalase overexpression, converging pathways iron homeostasis, mitochondrial dynamics and oxidative stress management, were found to be the top ranked modifiers for their beneficial effects on FRDA pathophysiology and were suggested for further studies as therapeutic targets. Based on the limitations identified in this systematic review and meta-analysis, we recommend that subsequent research studies adopt standardized reporting practices, multiple phenotype validation, supporting behavioural outcomes with biochemical and cellular readouts, using genetically precise models and systematic sharing of raw data to enhance reproducibility and research value.
Cytosolic phospholipase A2α (PLA2G4A) promotes oxidative stress-mediated endothelial ferroptosis in sepsis-induced acute lung injury.
Wang L, Chen M, Meng X … +6 more , Wang R, Ma Y, Zhang A, Wei D, Wang R, Xie H
Free Radic Biol Med · 2026 Jun · PMID 42297195 · Publisher ↗
Sepsis-induced acute lung injury (ALI) is a life-threatening syndrome characterized by the disruption of the pulmonary vascular endothelial barrier; however, the upstream lipid metabolic networks orchestrating endothelia...
Sepsis-induced acute lung injury (ALI) is a life-threatening syndrome characterized by the disruption of the pulmonary vascular endothelial barrier; however, the upstream lipid metabolic networks orchestrating endothelial cell death remain incompletely understood. In this study, we investigated the role of cytosolic phospholipase A2α(PLA2G4A) in driving oxidative stress-mediated endothelial ferroptosis during sepsis. Through transcriptomic analysis of clinical datasets, we identified PLA2G4A as a significantly upregulated gene in the septic endothelium. Using lipopolysaccharide (LPS)-induced human endothelial cell models and a cecal ligation and puncture (CLP)-induced murine sepsis model, we demonstrated that PLA2G4A activation acts as a critical molecular switch that disrupts intracellular redox homeostasis. Specifically, aberrant PLA2G4A activity fueled the accumulation of lethal lipid peroxidation products malondialdehyde (MDA) while depleting antioxidant defenses, including glutathione (GSH) and GPX4 activity. This oxidative stress-dependent ferroptotic cascade directly compromised endothelial barrier integrity, evidenced by the degradation of key junctional proteins (ZO-1 and VE-Cadherin) and increased vascular permeability. Conversely, genetic silencing of PLA2G4A or pharmacological inhibition with CAY10650 effectively restored redox balance, suppressed endothelial ferroptosis, preserved pulmonary vascular integrity, and significantly improved survival in septic mice. Collectively, our findings define a novel "PLA2G4A-oxidative stress-endothelial ferroptosis" axis as a key driver of endothelial dysfunction, suggesting that targeting PLA2G4A represents a promising therapeutic strategy to mitigate oxidative injury in sepsis-induced ALI.
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