Free Radic. Biol. Med. [JOURNAL]
Sun
200 papers
Mitoredox shifts in mitochondrial dysfunction.
Moos WH, Faller DV, Glavas IP … +9 more , Kanara I, Kodukula K, Pernokas J, Pernokas M, Pinkert CA, Powers WR, Sampani K, Steliou K, Vavvas DG
Free Radic Biol Med · 2026 May · PMID 42173175 · Publisher ↗
Mitochondrial dysfunction underlies a broad spectrum of primary and secondary disorders, yet current frameworks do not fully capture how diverse genetic, metabolic, and environmental stressors converge on shared patholog...
Mitochondrial dysfunction underlies a broad spectrum of primary and secondary disorders, yet current frameworks do not fully capture how diverse genetic, metabolic, and environmental stressors converge on shared pathological outcomes. Here, we propose that mitoredox shifts - bidirectional disruptions in mitochondrial redox homeostasis that alter mitochondrial quality control and genome-stability pathways - serve as a unifying axis linking oxidative stress, mitochondrial quality control failure, heteroplasmy dynamics, and regulated cell death. Both hyperactive and hypoactive mitochondrial states destabilize redox balance, altering PINK1/Parkin-dependent and receptor-mediated mitophagy, disrupting proteostasis, and reshaping mitochondrial network dynamics. These redox-driven perturbations influence the propagation of pathogenic mtDNA variants, modulate tissue-specific threshold effects, and bias cells toward apoptosis, ferroptosis, cuproptosis, and other regulated cell death pathways. We synthesize emerging evidence across mitochondrial genetics, bioenergetics, and redox signaling to outline how mitoredox shifts accelerate disease progression in both primary mitochondrial syndromes and secondary mitochondrial dysfunction. We further evaluate the expanding landscape of diagnostic biomarkers, including FGF21, GDF15, imaging-based oculomics, and high-throughput proteomic and genomic assays. In parallel, we highlight therapeutic strategies aimed at restoring redox balance, enhancing mitophagy, or shifting mitochondrial network composition by diluting dysfunctional organelles through mitochondrial transplantation. By emphasizing mitoredox imbalance as a recurrent feature of disease, this work synthesizes emerging diagnostic and therapeutic approaches across rare and common mitochondrial disorders.
The diving reflex elicits potent, non-electrophilic Nrf2 activation via trigeminal CGRP signaling.
Li C, Powell K, Wadolowski S … +4 more , Jacob A, LeDoux C, Brenner M, Wang P
Free Radic Biol Med · 2026 May · PMID 42167418 · Publisher ↗
Activation of nuclear factor erythroid 2-related factor 2 (Nrf2) is a powerful neuroprotective strategy, yet clinical translation to conditions of high stress remains limited by the paradoxical depletion of glutathione a...
Activation of nuclear factor erythroid 2-related factor 2 (Nrf2) is a powerful neuroprotective strategy, yet clinical translation to conditions of high stress remains limited by the paradoxical depletion of glutathione and increase of reactive oxygen species observed with conventional electrophilic activation. Here, we identify the diving reflex (DR) as a potent, non-electrophilic physiological activator of Nrf2 in the brain that circumvents this potential liability. Using a validated voluntary diving model in rats with acute (single session) and chronic (4-week) paradigms, we show that DR triggers calcitonin gene-related peptide (CGRP) release from trigeminal afferents, which engages parallel KEAP1-dependent (p62/Ser351-mediated autophagic degradation) and KEAP1-independent (AMPK/SIRT1/PI3K) signaling cascades to drive Nrf2 nuclear translocation and phosphorylation across multiple brain regions. Anti-CGRP antibody blockade abolished these effects, establishing CGRP as the essential upstream mediator. Unbiased proteomic profiling of 2388 brain proteins confirmed upregulation of Nrf2-regulated antioxidant enzymes with concurrent downregulation of oxidative stress markers. Critically, DR preserved cellular glutathione pools, elevated the GSH/GSSG ratio, and suppressed lipid peroxidation and protein nitration, a redox-sparing profile divergent from electrophilic activation. DR also exhibited a unique biphasic response: acute exposure produced rapid transcriptional upregulation of antioxidant genes, while chronic exposure generated a sustained extranuclear reserve of phosphorylated Nrf2, conferring long-term resilience. In a vascular dementia model of chronic cerebral hypoperfusion, chronic DR rescued hippocampal Nrf2 depletion, restored glutathione homeostasis, and preserved working memory. These findings establish the DR-CGRP-Nrf2 axis as a druggable, non-electrophilic pathway for neuroprotection that achieves pharmacological-level potency without redox compromise.
Mitochondrial dynamics and transfer in mesenchymal stromal cells: Redox regulation, therapeutic mechanisms, and engineering strategies.
Liu X, Wang X, Liu F
Free Radic Biol Med · 2026 May · PMID 42167417 · Publisher ↗
Mesenchymal stromal cells (MSCs) are metabolically active and redox-sensitive therapeutic cells, with their therapeutic potency tightly linked to mitochondrial integrity and function. Beyond paracrine and immunomodulator...
Mesenchymal stromal cells (MSCs) are metabolically active and redox-sensitive therapeutic cells, with their therapeutic potency tightly linked to mitochondrial integrity and function. Beyond paracrine and immunomodulatory actions, MSCs can transfer functional mitochondria to damaged cells, restoring bioenergetics, maintaining redox homeostasis via ROS regulation, and facilitating tissue repair and regeneration. This review summarizes recent progress in MSC mitochondrial biology, highlighting how metabolic reprogramming, mitochondrial biogenesis, fusion-fission dynamics and mitophagy coordinately regulate MSC stemness, differentiation, senescence and therapeutic capacity. It outlines core redox regulatory networks covering mitochondrial ROS production (ETC Complexes I/III and reverse electron transport), non-mitochondrial oxidases (NADPH oxidases), and canonical antioxidant signaling (Nrf2/Keap1, thioredoxin/peroxiredoxin and glutathione/glutaredoxin). Redox-dependent post-translational modifications governing mitochondrial transfer machinery are emphasized, including cysteine oxidation of connexin 43, redox-regulated Drp1 phosphorylation, and oxidative modulation of Miro1-mediated mitochondrial trafficking. Major intercellular mitochondrial transfer routes, such as tunneling nanotubes, connexin 43-based intercellular communication and extracellular vesicles, are discussed under inflammatory, hypoxic and metabolic stress conditions. Preclinical studies across pulmonary, cardiovascular, neurological, renal, hepatic and immune-mediated diseases validate that MSC-derived mitochondrial transfer preserves ATP production, mitigates oxidative injury and remodels recipient cell immunometabolic phenotypes. Emerging engineering strategies to improve mitochondrial delivery and therapeutic outcomes are also reviewed, alongside translational bottlenecks including cell source heterogeneity, mitochondrial quality control, in vivo tracking, dosage optimization and long-term biosafety. Overall, MSC mitochondrial dynamics and intercellular transfer bridge redox biology, metabolism and regenerative medicine, offering mechanistic insights for next-generation precision regenerative therapies.
ALDH2 alleviates diabetes-induced myocardial cell senescence and electrical remodeling by regulating SIRT1.
Wang L, Wang HH, Chen Q … +19 more , Luo SL, Fang S, Ling ZH, Tang WB, Wu YY, Ma FY, Liu MR, Sun ZY, Lu GQ, Tan X, Fan JL, Sun HY, Fu CW, Li XH, Tang B, Wang HJ, Gao Q, Wu SL, Kang PF
Free Radic Biol Med · 2026 Aug · PMID 42167416 · Publisher ↗
There is a significant association between cardiomyocyte senescence and cardiac insufficiency. Senescent myocardial cells increase the susceptibility to cardiomyopathy and arrhythmia, while diabetes accelerates myocardia...
There is a significant association between cardiomyocyte senescence and cardiac insufficiency. Senescent myocardial cells increase the susceptibility to cardiomyopathy and arrhythmia, while diabetes accelerates myocardial cell senescence. This study aims to explore whether ALDH2 can improve diabetes-induced myocardial cell senescence and electrical remodeling and reveal the underlying mechanism. In vivo, we found that ALDH2 overexpression effectively alleviated diabetes-induced cardiomyocyte senescence and the electrical remodeling of Nav1.5. Importantly, in vivo programmed electrical stimulation revealed that ALDH2 significantly reduced ventricular tachycardia (VT) susceptibility and duration in diabetic mice. In vitro, molecular docking confirmed the binding mode between ALDH2 and SIRT1. Using high glucose-induced H9C2 cardiomyocytes, we demonstrated that ALDH2 activation restored Nav1.5 protein expression and alleviated cellular senescence via SIRT1 upregulation. This protective mechanism is closely associated with SIRT1-mediated cellular ROS clearance and mitochondrial homeostasis. In conclusion, our study provides robust in vivo evidence that targeting the ALDH2/SIRT1 axis effectively prevents diabetic myocardial senescence and fatal electrical instability. These findings highlight a promising translational strategy to reduce the risk of malignant arrhythmias and improve cardiovascular health outcomes in diabetic patients.
8-oxo-7,8-dihydroguanosine (8-oxo-Guo) drives platelet inflammatory signaling pathways via toll-like receptors.
Pan JX, Li J, Li R … +10 more , Sheng G, Zeng LT, Gao XF, Huan R, Liu WS, Bu XX, Wang QE, Xi H, Qi RM, Cai JP
Free Radic Biol Med · 2026 May · PMID 42167415 · Publisher ↗
Beyond their pivotal role in hemostasis and thrombosis, the function of platelets in inflammation and immune regulation is increasingly recognized. 8-oxo-7,8-dihydroguanosine (8-oxo-Guo) is an endogenous nucleic acid oxi...
Beyond their pivotal role in hemostasis and thrombosis, the function of platelets in inflammation and immune regulation is increasingly recognized. 8-oxo-7,8-dihydroguanosine (8-oxo-Guo) is an endogenous nucleic acid oxidation product. Unclear is whether 8-oxo-Guo possesses the capacity to modulate the inflammatory status of circulating blood and platelet function. The present study investigated the influence of 8-oxo-Guo on platelet activation responses. An intravenous injection of 8-oxo-Guo in C57BL/6J mice enhanced platelet activity and increased levels of plasma inflammatory factors. To elucidate the underlying mechanism, human purified platelets were used. The results showed that 8-oxo-Guo treatment increased the expression of Toll-like receptor 2 (TLR2) and TLR4 on platelets. Integrated proteomic and phosphoproteomic analysis, combined with Western blot, demonstrated that 8-oxo-Guo activated multiple inflammation-related signaling pathways, including TLR2/TLR4-MyD88-associated signaling. Surface plasmon resonance analysis further demonstrated direct interactions between 8-oxo-Guo and TLR4/TLR2 with micromolar-range affinities, and pharmacological inhibition of TLR2 or TLR4 attenuated 8-oxo-Guo-induced inflammatory signaling. Consistent results were obtained from both in vivo and in vitro experiments. Our findings suggest that 8-oxo-Guo promotes platelet inflammatory activation at least partly through TLR2/TLR4-associated signaling, thereby expanding our understanding of platelet functions in oxidative stress-related immune regulation and identifying a potential therapeutic target for inflammatory diseases.
Nanoplastic exposure induces mitochondrial dysfunction-driven inflammation and senescence in renal tubular epithelial cells.
Kim BM, Yang SB, Ha S … +8 more , Kim MJ, Kim J, Park DE, Chung HY, Jung YS, Lee J, Lee H, Chung KW
Free Radic Biol Med · 2026 May · PMID 42162843 · Publisher ↗
Nanoplastic (NP) particles are emerging environmental contaminants with increasing concern regarding their potential impacts on human health; however, their effects on kidney function remain poorly understood. Here, we c...
Nanoplastic (NP) particles are emerging environmental contaminants with increasing concern regarding their potential impacts on human health; however, their effects on kidney function remain poorly understood. Here, we combined in vivo and in vitro approaches to investigate renal toxicity induced by chronic NP exposure. Oral administration of NPs (200 mg/kg/day) to mice for six weeks resulted in tubular-specific kidney injury accompanied by inflammatory and fibrotic responses. Transcriptomic profiling revealed coordinated downregulation of mitochondrial oxidative phosphorylation-related genes along with enrichment of inflammatory and fibrotic pathways in the kidney. Consistently, disrupted mitochondrial function in renal tubular epithelial cells, as evidenced by impaired oxidative phosphorylation, increased mitochondrial reactive oxygen species, and structural mitochondrial abnormalities. Mitochondrial damage was associated with activation of STING-dependent inflammatory signaling; pharmacological inhibition of STING attenuated inflammatory responses but did not suppress NP-induced cellular senescence, indicating mechanistic dissociation between inflammation and senescence. In contrast, prolonged NP exposure induced robust cellular senescence linked to sustained mitochondrial dysfunction. Activation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) restored mitochondrial function and suppressed both inflammatory signaling and cellular senescence in vitro. Importantly, pharmacological activation of PGC1α in NP-exposed mice mitigated mitochondrial damage, renal inflammation, senescence, and fibrotic remodeling in vivo. Collectively, these findings identify mitochondrial dysfunction as a central mechanism associated with NP-induced renal inflammation and senescence and provide mechanistic insight into the hazardous effects of NP exposure on the kidney.
Theaflavin-3,3'-digallate attenuates chondrocyte senescence via modulating FGF7 and KEAP1/NRF2 signaling pathway.
Kou H, Lu F, Li M … +8 more , Liu Y, Li S, Yin G, Chen J, Zhao G, Wang L, Wang Y, Xu C
Free Radic Biol Med · 2026 May · PMID 42162842 · Publisher ↗
Studies have demonstrated that chondrocyte senescence is involved in the pathological progression of osteoarthritis. This study aimed to investigate the effect of TF3 on chondrocyte senescence and its underlying molecula...
Studies have demonstrated that chondrocyte senescence is involved in the pathological progression of osteoarthritis. This study aimed to investigate the effect of TF3 on chondrocyte senescence and its underlying molecular mechanism. Primary chondrocytes were isolated from mice, and senescence-related markers, mitochondrial metabolism levels, and the expression of the FGF7/Keap1-NRF2-related pathway were examined using CCK-8 assay, Western blot, β-galactosidase staining, and fluorescence staining. RNA sequencing and molecular docking were further employed to explore the mechanisms by which TF3 inhibits chondrocyte senescence. A mouse model of destabilization of the medial meniscus (DMM) was established, and the anti-senescence and cartilage protective effects of TF3 were evaluated through H&E staining, immunohistochemistry, micro-CT, and Safranin O/Fast Green staining. The results showed that TF3 suppressed the expression of senescence-associated proteins, including p16, p21, IL-6, and MMP13, while promoting the expression of Coll2a1 in IL-1β induced cell senescence model. Additionally, TF3 reduced β-galactosidase activity and alleviated DNA damage. RNA sequencing and experimental findings revealed that the anti-senescence effect of TF3 might be related to the regulation of oxidative stress and mitochondrial metabolism. Furthermore, the FGF7 and Keap1/NRF2 pathway were involved in TF3-mediated inhibition of chondrocyte senescence. NRF2 knockdown and exogenous rFGF7 supplementation abrogated the protective effects of TF3 against chondrocyte senescence. Animal experiments further confirmed that TF3 exerted anti-senescence effects and delayed joint degeneration. This study reveals important molecular mechanisms by which TF3 inhibits chondrocyte senescence and retards OA progression, suggesting that TF3 may serve as a potential novel therapeutic strategy for OA.
Dysregulation of arginase and arginine pathways in neurodegenerative diseases: Metabolic and cellular dysfunction and therapeutic implications.
Nalepa M, Skweres A, Węgrzynowicz M
Free Radic Biol Med · 2026 Aug · PMID 42156213 · Publisher ↗
Neurodegenerative diseases are increasingly recognized as disorders associated with metabolic dysfunction with arginine metabolism emerging as a significant contributor. Arginase, by regulating the balance between argini...
Neurodegenerative diseases are increasingly recognized as disorders associated with metabolic dysfunction with arginine metabolism emerging as a significant contributor. Arginase, by regulating the balance between arginine and ornithine, is positioned at the crossroads of multiple arginine metabolic pathways, thereby controlling a variety of cellular processes essential for proper brain homeostasis. Chronic disruption of these pathways may lead to dysfunction of neurons and glia ultimately resulting in the induction of neurodegenerative processes. In this review, based on data from patients and experimental models, we synthesize and critically evaluate evidence demonstrating alterations in arginase isoenzymes and associated metabolic pathways in Alzheimer's Parkinson's and Huntington's diseases, and amyotrophic lateral sclerosis. We discuss mechanisms through which dysregulation of arginase and arginine metabolism may contribute to neurodegeneration, including disturbances in nitrogen metabolism, oxidative and nitrosative stress, mitochondrial dysfunction, and neuroinflammation. Based on this body of evidence, we propose therapeutic strategies targeting arginase-related pathways, with the aim of preserving cellular metabolic homeostasis to ameliorate disease progression. Finally, we outline directions for future research, emphasizing that a proper understanding of the physiological roles of arginase isoenzymes and their disease-, stage-, and cell-specific dysregulation will be essential for the development of effective metabolically targeted therapies against neurodegenerative diseases.
MICU1 deficiency exacerbates cisplatin-induced acute kidney injury by tubular apoptosis and mitochondrial dysfunction.
Dong B, Bi H, Li Y … +8 more , Wang C, Wang J, Chen Z, Wang Y, Wang Y, Wang J, Lu C, Ding X
Free Radic Biol Med · 2026 May · PMID 42155615 · Publisher ↗
Cisplatin-induced acute kidney injury (AKI) is characterized by profound oxidative stress and mitochondrial dysfunction in proximal tubular cells. However, the upstream mechanisms governing this redox imbalance remain in...
Cisplatin-induced acute kidney injury (AKI) is characterized by profound oxidative stress and mitochondrial dysfunction in proximal tubular cells. However, the upstream mechanisms governing this redox imbalance remain incompletely defined. Here, we identify mitochondrial calcium uptake 1 (MICU1) as a critical regulator of tubular redox homeostasis. Using integrated multi-omics approaches, we found that MICU1 is markedly downregulated in injured proximal tubular subpopulations across various kidney diseases. Mechanistically, MICU1 deficiency disrupts mitochondrial calcium homeostasis, resulting in calcium overload and excessive mitochondrial reactive oxygen species (mtROS) generation. These changes trigger intrinsic apoptotic pathways, whereas MICU1 restoration alleviates such damage. Furthermore, we demonstrate that the ARNT/HIF-1α axis transcriptionally regulates MICU1. Under cisplatin stress, this axis is suppressed, thereby promoting mitochondrial dysfunction. Crucially, we found that MICU1-mediated mtROS control contributes to the preservation of epidermal growth factor receptor (EGFR) signaling, whereas excessive mtROS accumulation is associated with EGFR signaling impairment. Importantly, pharmacological targeting of mitochondrial calcium uptake using the small-molecule modulator MCU-i4 attenuates calcium overload, suppresses mtROS accumulation, and mitigates renal injury in vitro and in vivo. Collectively, our findings support a transcriptional-mitochondrial axis linking calcium dysregulation to oxidative stress and identify MICU1 as a potential therapeutic target for redox-driven kidney injury.
Selenium-GPX4 axis orchestrates intestinal arachidonic acid metabolic reprogramming to mitigate inflammation.
Tang C, Tian H, Lin L … +14 more , Li P, Fan S, Zhou L, Liu Y, Dong M, Feng X, Yang Y, Yu Y, Zhang H, Li Y, Luo Z, Zhao Q, Qin Y, Zhang J
Free Radic Biol Med · 2026 May · PMID 42155614 · Publisher ↗
Dietary westernization exacerbates polyunsaturated fatty acid-mediated intestinal inflammation, though the mechanistic links between arachidonic acid (AA)-induced gut metabolic dysregulation and glutathione peroxidase 4...
Dietary westernization exacerbates polyunsaturated fatty acid-mediated intestinal inflammation, though the mechanistic links between arachidonic acid (AA)-induced gut metabolic dysregulation and glutathione peroxidase 4 (GPX4)-regulated inflammatory modulation require further elucidation. Employing both lipopolysaccharide (LPS)-induced and dietary AA-fed murine models, we revealed profound alterations in oxylipin profiles and catalytic enzyme expression, which were effectively alleviated by selenium (Se) supplementation via GPX4 upregulation. The LPS model was used to identify inflammation-associated alterations in AA metabolism, while the chronic dietary AA model was applied to further evaluate the pathological role of sustained AA metabolic activation in intestinal injury. Genetic approaches (Gpx4 and Gpx4) identified intestinal epithelial cells GPX4 as the central regulator orchestrating AA metabolic flux and inflammatory cascades. Single-cell RNA sequencing analysis demonstrated that while AA exposure alone induced moderate enterocyte reduction, concomitant IEC-Gpx4 knockdown markedly potentiated this depletion. Notably, ferrostatin-1 administration alleviated oxylipin dysregulation and inflammatory activation triggered by dietary AA treatment combined with IEC-Gpx4 knockout. IEC-macrophage co-culture experiments demonstrated that IEC-Gpx4 not only corrects AA-induced oxylipin disturbances but also suppresses chemokine/cytokine release and prevents Slamf7 pro-inflammatory macrophage polarization. Collectively, these findings establish the Se-GPX4-oxylipin axis as a fundamental regulatory circuit in intestinal inflammation, providing mechanistically grounded therapeutic strategies for inflammatory bowel diseases.
Corrigendum to "Cadmium induces ferroptosis in B cells via ATP6V0A1-upregulated lysosomal ferritinophagy: insights from murine transcriptomics and human cellular models" [Free Rad. Biol. Med. 242 (2026) 138-149].
Gu J, Ruan J, Li Z … +7 more , Fu H, Shi Q, Zhu J, Wu J, Gong X, Shi H, Jiang P
Free Radic Biol Med · 2026 Aug · PMID 42151026 · Publisher ↗
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Vanadium exposure promotes pulmonary fibrosis via crosstalk between cGAS-STING/NF-κB and Wnt signaling in ducks.
Chu X, Pan J, Yang Y … +7 more , Chen J, Chen H, Dai X, Xing C, Li H, Hu M, Yang F
Free Radic Biol Med · 2026 May · PMID 42144027 · Publisher ↗
Although trace vanadium occurs naturally in animal diets, environmental contamination cumulatively increases dietary exposure and bioaccumulation risks. The lung is highly susceptible to vanadium toxicity, and repeated e...
Although trace vanadium occurs naturally in animal diets, environmental contamination cumulatively increases dietary exposure and bioaccumulation risks. The lung is highly susceptible to vanadium toxicity, and repeated exposure can promote pulmonary inflammation and fibrotic remodeling. The mechanisms underlying vanadium-induced pulmonary fibrosis remain incompletely understood, particularly the role of cGAS-STING signaling and its interaction with the Wnt pathway. We established a vanadium exposure model in ducks and used network toxicology to assess pulmonary toxicity. KEGG and GO analyses showed enrichment in oxidative stress, NF-κB signaling, Wnt signaling, and processes related to mitochondrial and Golgi apparatus dysfunction. Vanadium exposure resulted in alveolar disruption, collagen accumulation, upregulation of fibrosis markers, mitochondrial and Golgi impairment, and persistent oxidative stress. Molecular analyses revealed time-dependent activation of the cGAS-STING, NF-κB, and Wnt pathways, accompanied by enhanced spatial associations among NF-κB, STING, and Wnt-3a. This study provides initial evidence that dietary vanadium exposure is associated with pulmonary fibrosis in ducks, accompanied by coordinated activation of the cGAS-STING/NF-κB axis and canonical Wnt signaling, and supports a potential inflammatory-to-fibrogenic signaling circuit.
Stabilization of β-catenin by 7,8-Dihydroxyflavone protects against osteoblast ferroptosis and bone loss in type 2 diabetic osteoporosis.
Lin BH, Ma RX, Weng WD … +4 more , Miao JS, Luo J, Jin C, Yang L
Free Radic Biol Med · 2026 Aug · PMID 42144026 · Publisher ↗
Type 2 diabetic osteoporosis (T2DOP) is characterized by a long-term imbalance in bone metabolism, where the diabetic environment heightens the risk of fragile fractures and reduces bone density. Emerging evidence highli...
Type 2 diabetic osteoporosis (T2DOP) is characterized by a long-term imbalance in bone metabolism, where the diabetic environment heightens the risk of fragile fractures and reduces bone density. Emerging evidence highlights ferroptosis as a key mechanism underlying glucolipotoxicity-induced osteoblast death. 7,8-Dihydroxyflavone (7,8-DHF), a plant-derived flavonoid with potent antioxidant and anti-ferroptotic properties, has not been thoroughly investigated in the context of T2DOP. First acknowledged in 1984 as a key type of secondary osteoporosis, T2DOP is distinguished by notable cortical porosity and increased bone fragility. Given its complex pathogenesis, further research is crucial. The progression of T2DOP could be significantly influenced by ferroptosis, a form of cell death that depends on iron. This investigation sought to understand the impact of 7,8-DHF on ferroptosis caused by high glucose and palmitic acid (HGPA) and its significance for T2DOP. Using BODIPY-C11 and FerroOrange staining, Western blotting, mitochondrial assays, immunoblotting, and immunofluorescence, we evaluated 7,8-DHF's protective effects on MC3T3-E1 cells. In vivo, micro-CT, H&E staining, calcein-alizarin red double labeling, and immunohistochemistry were employed in a murine T2DOP model. 7,8-DHF significantly inhibited HGPA-induced ferroptosis, reduced lipid peroxidation, lowered ROS levels, and restored osteogenic capacity. Moreover, bone density and GPX4 expression were elevated, and the Wnt/β-catenin pathway was activated. These effects were weakened by β-catenin knockdown., suggesting that 7,8-DHF mitigates T2DOP by modulating Wnt/β-catenin signaling to suppress ferroptosis.
Nitric oxide initiates early differentiation events in Leishmania infantum stage transition.
Villarubias T, Royo J, Pério P … +6 more , Monier M, Bourgeade-Delmas S, Gobart D, Valentin A, Terrisse AD, Reybier K
Free Radic Biol Med · 2026 May · PMID 42142814 · Publisher ↗
Leishmaniasis, caused by Leishmania parasites, remains a major global health burden. The promastigote-to-amastigote transition is critical for establishing infection within mammalian macrophages, where parasites encounte...
Leishmaniasis, caused by Leishmania parasites, remains a major global health burden. The promastigote-to-amastigote transition is critical for establishing infection within mammalian macrophages, where parasites encounter intense oxidative stress. While reactive oxygen species (ROS) are traditionally viewed as antimicrobial effectors, emerging evidence suggests they may also function as differentiation signals. We investigated the effects of three distinct ROS species, superoxide (via menadione), hydrogen peroxide (HO), and nitric oxide (via SNAP), on L. infantum differentiation. Following dose optimization, we assessed morphological changes, stage-specific gene expression, amastin protein accumulation, and redox homeostasis. Nitric oxide emerged as the most potent initiator of early differentiation events, inducing significant upregulation of ama34, a gene coding for the amastin protein, characteristic of the amastigote stage, and downregulation of par4, a gene coding for the parasite's flagellum, characteristic of the promastigote stage. These gene expressions are similar to those observed in axenic amastigotes. SNAP treatment also increased amastin protein levels and modulated genes involved in nuclear transport (ntf2), mitochondrial function (afg1), and trypanothione metabolism (tr). HO showed moderate effects, while menadione-derived superoxide had minimal impact. Notably, antioxidant enzyme genes remained largely unaffected by ROS treatments despite their upregulation in amastigotes. Our findings demonstrate that ROS, particularly nitric oxide, serve as environmental cues initiating early differentiation events in Leishmania. However, ROS exposure alone is insufficient for complete stage conversion, as evidenced by modest stress-response activation and incomplete antioxidant upregulation compared to fully differentiated amastigotes. Complete conversion requires integration of multiple signals including temperature shift, acidification, and prolonged host exposure. Our data support a model wherein NO acts as an early trigger rather than a comprehensive driver of full stage transition.
The joint anti-hepatocellular carcinoma mechanism of selenium and lenvatinib mediated by Nrf2-ferroptosis axis in M2 tumor associated macrophage.
Zhao Y, Wang Y, Zhao W … +6 more , Chen L, Chen H, Song Y, Tang Y, Li H, Yao P
Free Radic Biol Med · 2026 Aug · PMID 42140504 · Publisher ↗
BACKGROUND: Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with limited treatment options. Lenvatinib demonstrates efficacy but is associated with significant toxicity at standard doses. Tumor-associate...
BACKGROUND: Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with limited treatment options. Lenvatinib demonstrates efficacy but is associated with significant toxicity at standard doses. Tumor-associated macrophages (TAMs), especially the pro-tumor M2 phenotype, contribute to an immunosuppressive microenvironment in HCC by promoting immune evasion. Selenium (Se), an essential trace element with anticancer properties, can reduce M2-TAM infiltration; however, its potential synergy with low-dose lenvatinib (L-Len) to enhance antitumor efficacy while minimizing toxicity remains unexplored. METHODS: Subcutaneous HCC models were established to assess the therapeutic effects of Se combined with L-Len. Tumor growth, toxicity, and infiltration of M2-TAMs were evaluated. Mechanistic studies analyzed Nrf2 activation and downstream targets (GPx4/xCT) in TAMs to determine ferroptosis-inducing effects of combined treatment. RESULTS: Se + L-Len showed comparable antitumor efficacy to standard-dose lenvatinib but with reduced toxicity. The combination reduced M2-TAMs infiltration and induced ferroptosis by suppressing Nrf2 and GPx4/xCT. CONCLUSION: Se enhances L-Len's efficacy, and a key mechanism contributing to this synergy appears to be the targeting of Nrf2-mediated ferroptosis in M2-TAMs. This suggests a potential strategy to improve HCC treatment while minimizing toxicity, which warrants further investigation in more clinically relevant models.
Rescuing Prdx1-deficiency-mediated redox homeostasis disruption in bone marrow mesenchymal stem cells ameliorate radiation-induced bone loss.
Zhai Y, Bian Z, Wei J … +13 more , Wang S, Wang R, Cheng S, Li X, Cao L, Tang W, He Y, Ouyang J, Zeng Y, Zhang S, Zhao C, Liu M, Huang W
Free Radic Biol Med · 2026 Aug · PMID 42134626 · Publisher ↗
Ionizing radiation (IR) is a major cause of accelerated skeletal aging and severe bone loss, primarily by triggering oxidative stress and promoting premature senescence in bone marrow mesenchymal stem cells (BMSCs). This...
Ionizing radiation (IR) is a major cause of accelerated skeletal aging and severe bone loss, primarily by triggering oxidative stress and promoting premature senescence in bone marrow mesenchymal stem cells (BMSCs). This mechanism underscores a critical need for redox-based intervention. Peroxiredoxin 1 (Prdx1), a vital thiol peroxidase and redox sensor, is recognized for its potent anti-oxidative and anti-senescence capabilities. However, the precise function and underlying mechanism of Prdx1 in protecting BMSCs from IR-induced bone loss remain unexplored. Through Single-cell RNA-sequencing (scRNA-seq) and IR-induced bone loss mice model, we found that the Prdx1 expression in BMSCs exhibited a transient elevation in early stage after IR, while its expression was downregulated in late stage after IR. A prdx1-knockout mice (Prdx1) was constructed and exhibited aggravated bone loss after IR. Prdx1-derived primary BMSCs exhibited elevated oxidative stress and cellular senescence level, confirming a protective role for Prdx1. By high-throughput RNA-sequencing (RNA-seq), transcriptional factor prediction, molecular dynamic simulation, we verified that Prdx1 inhibited BMSCs oxidative stress injury via interacting with Pten and suppressing the Akt/FoxO signaling pathway. A BMSCs-specific E7 affinity peptide modified extracellular vesicle (EV) delivery system E7-EV was constructed to achieve targeted delivery of Prdx1 mRNA to BMSCs. E7-EV effectively suppressed IR-induced oxidative stress injury in vitro. Systemic administration of E7-EV effectively rescued IR-induced bone loss and demonstrated favourable biocompatibility in vivo. Our study identifies Prdx1 as a pivotal redox-regulated target in IR-induced BMSCs injury and introduces E7-EV as a novel, highly efficient, and safe gene therapy strategy for mitigating IR-induced bone loss.
CD36 inhibition promotes bone defect repair in spinal tuberculosis by regulating ferroptosis in bone marrow mesenchymal stem cells.
Que S, Zhang C, Wang Y … +15 more , Qiu Y, Tian B, Liu Q, Feng K, Chen J, Hou X, Li T, Yang G, Lian X, Liu Z, Zeng G, Fu H, Zhang R, Tang M, Gao Q
Free Radic Biol Med · 2026 Aug · PMID 42134625 · Publisher ↗
Spinal tuberculosis (STB) is commonly accompanied by progressive vertebral bone destruction and impaired bone repair. However, the key host mechanisms that limit bone regeneration in the tuberculous microenvironment rema...
Spinal tuberculosis (STB) is commonly accompanied by progressive vertebral bone destruction and impaired bone repair. However, the key host mechanisms that limit bone regeneration in the tuberculous microenvironment remain unclear. Here, we demonstrate that bone marrow mesenchymal stem cells (BMSCs) derived from vertebrae of patients with STB display impaired osteogenic differentiation. We further demonstrate at the cellular level that ferroptosis is one of the key pathways mediating BMSC injury in the STB-associated infectious microenvironment. Combined transcriptomic analysis and functional validation reveal that CD36 knockdown markedly reduces lipid peroxidation and reactive oxygen species (ROS) accumulation, while also ameliorating ultrastructural damage. Mechanistically, CD36 downregulation suppresses FYN phosphorylation and reduces tyrosine phosphorylation of NRF2, thereby promoting NRF2 stabilization and accumulation, and ultimately enhancing cellular resistance to ferroptosis. In a mouse model of STB, pharmacological inhibition of CD36, activation of NRF2, or direct blockade of ferroptosis each alleviates trabecular bone destruction and restores osteogenic phenotypes. Taken together, our study elucidates a molecular mechanism underlying Mtb-induced impairment of osteogenesis in the vertebrae and identifies CD36-targeted attenuation of ferroptosis in BMSCs as a potential therapeutic strategy for bone repair in STB.
BHLHE40 drives ferroptosis in Escherichia coli-induced endometrial injury by recruiting HDAC1 to repress CPT1B and impair NRF2 signaling.
Yuan C, Wang J, Wang Z … +12 more , Mao P, Dong P, Dong J, Guo L, Liu K, Cui L, Li J, Wang R, Zhang L, Tao H, Meng X, Wang H
Free Radic Biol Med · 2026 Aug · PMID 42128070 · Publisher ↗
Endometritis is a common disease of the reproductive system that leads to decreased fertility and potential miscarriage, resulting in substantial economic losses. Ferroptosis is an iron-dependent mode of cell death drive...
Endometritis is a common disease of the reproductive system that leads to decreased fertility and potential miscarriage, resulting in substantial economic losses. Ferroptosis is an iron-dependent mode of cell death driven by lipid peroxidation. Basic helix-loop-helix family member E40 (BHLHE40) has been developed as a molecular marker and a therapeutic target for bacterial infectious diseases. However, the underlying role of BHLHE40 needs to be further studied. This study investigated whether BHLHE40 drives Escherichia coli (E. coli) -induced endometrial ferroptosis by transcriptionally repressing carnitine palmitoyltransferase 1B (CPT1B) and attenuating the NRF2 signaling pathway, with the aim of elucidating the regulatory mechanism of the BHLHE40-CPT1B-NRF2 axis. In endometrial tissues from E. coli-infected cows (n = 8 per group, in vivo), the expression of BHLHE40 was increased by 3.6 times (p < 0.05), and its protein level positively correlated with the severity of tissue damage (Pearson r = 0.6722, p = 0.0034). Functionally, knockdown of BHLHE40 conferred significant protection against E. coli-induced cell death (decreased from 36% to 18%, p < 0.01), concurrently reversing the features of ferroptosis (p < 0.05), including reduced lipid peroxidation, decreased intracellular Fe concentration, and restored glutathione levels and the expression of anti-ferroptosis proteins. Integrated analysis of CUT&Tag and RNA-sequencing data revealed that BHLHE40 binds to the promoter region of CPT1B (enrichment increased by 5 times, p < 0.01) and transcriptionally represses its expression. Further investigation demonstrated that BHLHE40 mediates CPT1B repression by recruiting HDAC1 to the CPT1B promoter, a process reversible upon HDAC1 inhibition. Crucially, BHLHE40-mediated suppression of CPT1B led to functional impairment of the NRF2 signaling pathway. Overexpression of CPT1B inhibited ferroptosis by reactivating NRF2 and its downstream targets (p < 0.05), whereas inhibition of NRF2 abolished the protective effect (cell death increased from 16% to 27%, p < 0.01), confirming NRF2 as the critical downstream effector. This study elucidates the BHLHE40-CPT1B-NRF2-ferroptosis axis as a novel pathway and potential target for E. coli to cause endometrial epithelial injury.
Corrigendum to "AIM2-mediated senescence of gingival fibroblasts exacerbates inflammaging in periodontitis" [Free Radic. Biol. Med. 245 (2026) 71-83].
Hao C, Chen R, Fan Z … +1 more , Wang S
Free Radic Biol Med · 2026 Aug · PMID 42120252 · Publisher ↗
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Two birds with one stone: Targeting METTL3 ameliorates doxorubicin-induced endothelial premature senescence and atherosclerosis while potentiating its antitumor efficacy.
Tang H, Shen J, Yuan W … +14 more , Fan Q, Zhang W, Li R, Hu X, Ma X, Shi Y, Li Z, Han Y, Jiang W, Xing J, Qi D, Jian D, Cheng X, Jian L
Free Radic Biol Med · 2026 Aug · PMID 42119953 · Publisher ↗
Emerging evidence suggests that cancer survivors who have undergone anthracycline therapy frequently experience late-onset atherosclerosis. However, the mechanisms underlying this phenomenon and potential preventive stra...
Emerging evidence suggests that cancer survivors who have undergone anthracycline therapy frequently experience late-onset atherosclerosis. However, the mechanisms underlying this phenomenon and potential preventive strategies remain largely unexplored. In this study, we developed a mouse model to replicate doxorubicin (Dox)-induced atherosclerotic lesions. Given the established role of the RNA methyltransferase METTL3 in both atherogenesis and tumorigenesis, we conducted a comprehensive investigation to assess whether targeting METTL3 could mitigate Dox-induced atherosclerosis and enhance the efficacy of Dox in inhibiting tumor progression. Our findings reveal that Dox administration promotes vascular endothelial premature senescence and atherosclerosis, to a large extent by upregulating the expression of METTL3 and its substrate genes, particularly those encoding senescence-associated secreted proteins. To translate METTL3 as a therapeutic target, we developed and characterized an endothelium-targeted (achieved by coating with CD31 antibodies) nanoparticle loaded with the METTL3 inhibitor STM2457 (endothelium-targeted METTL3 nano-inhibitor, ETMN). As anticipated, ETMN effectively protects murine blood vessels against Dox-aggravated endothelial senescence and inflammation, as well as atheroma formation. Furthermore, ETMN, with enhanced enrichment in tumor allografts, significantly potentiates Dox's tumoricidal activity by attenuating METTL3 oncogenic signaling. In summary, our work offers a practical solution for addressing Dox therapy-related atherosclerosis, providing dual benefits and advancing the treatment and management of cancer patients undergoing anthracycline therapy.
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