Free Radic. Biol. Med. [JOURNAL]
Sun
200 papers
Corrigendum to "Fatty acid oxidase Ehhadh mediates stem cell fate remodeling via mitophagy activation" [Free Radic. Biol. Med. 248 (2026) 109-126].
Zhou J, Zhang L, Liu T … +4 more , Sun J, Sun Y, Gao S, Shi K
Free Radic Biol Med · 2026 Jul · PMID 42401507 · Publisher ↗
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HDL/ApoA1 attenuates atherosclerosis by suppressing macrophage ferroptosis via NRF2-SLC7A11-GSH axis activation.
Yi Y, Luo Y, Deng Y … +6 more , Guo X, Liu W, Liu Y, Yu B, Zhao Y, Peng D
Free Radic Biol Med · 2026 Jul · PMID 42401351 · Publisher ↗
BACKGROUND: Macrophage death modalities critically determine atherosclerotic plaque stability and progression. While high-density lipoprotein (HDL) and its major component apolipoprotein A1 (ApoA1) are known for their ch...
BACKGROUND: Macrophage death modalities critically determine atherosclerotic plaque stability and progression. While high-density lipoprotein (HDL) and its major component apolipoprotein A1 (ApoA1) are known for their cholesterol reverse transport and atheroprotective effects, their role in regulating macrophage ferroptosis-an iron-dependent lipid peroxidation-driven cell death-is unexplored. OBJECTIVES: This study aims to explore whether HDL/ApoA1 confers atheroprotection through regulating macrophage ferroptosis. METHODS: The correlation between macrophage ferroptosis and plaque stability was first established using murine atherosclerosis models and human atherosclerotic specimens. The inhibitory effects of HDL/ApoA1 on macrophage ferroptosis were then validated using multiple pharmacological inducers. Integrated bioinformatic analysis combined with multi-level experimental approaches was employed to identify the underlying regulatory pathways. Finally, AAV-mediated overexpression and knockdown models in atherosclerotic mice were utilized for in vivo verification. RESULTS: Animal experiments showed that ferroptosis inhibitors improved plaque stability in ApoE/ mice. Analysis of human specimens revealed iron deposition, macrophage infiltration, and lipid peroxidation in atherosclerotic plaques, with strong spatial colocalization of these features, suggesting a potential contribution of macrophage ferroptosis to atherosclerosis progression. In vitro, HDL/ApoA1 effectively counteracted RSL3/FAC-induced macrophage ferroptosis, as indicated by reduced LDH release, decreased ROS levels, diminished ferrous iron content, and improved mitochondrial morphology. Mechanistically, HDL/ApoA1 inhibited NRF2 ubiquitination and degradation, promoted its nuclear translocation, upregulated SLC7A11 expression and restored intracellular GSH levels. In vivo, ApoA1 overexpression alleviated RSL3-aggravated atherosclerotic lesions, whereas macrophage-specific Nrf2 knockdown or SLC7A11 inhibition abolished the protective effects of ApoA1. CONCLUSION: This study demonstrates that HDL/ApoA1 inhibits macrophage ferroptosis via the NRF2-SLC7A11-GSH pathway, thereby attenuating atherosclerosis.
Salvianolic acid B mitigates neuronal ferroptosis after intracerebral hemorrhage in rats through a Piezo1-associated AMPK-mTOR pathway.
Zhang Z, Zhang L, Yuan Y … +8 more , Wu X, Chen J, Xie Y, Wang R, He S, Zheng H, Tao Y, Xie Z
Free Radic Biol Med · 2026 Jul · PMID 42401350 · Publisher ↗
Secondary brain injury (SBI) after intracerebral hemorrhage (ICH) is driven in part by iron-dependent oxidative damage and neuronal ferroptosis, but the molecular signals associated with ferroptotic vulnerability in the...
Secondary brain injury (SBI) after intracerebral hemorrhage (ICH) is driven in part by iron-dependent oxidative damage and neuronal ferroptosis, but the molecular signals associated with ferroptotic vulnerability in the hemorrhagic brain remain incompletely defined. Here, we investigated whether the mechanosensitive channel Piezo1 contributes to neuronal ferroptosis after ICH and whether Salvianolic acid B (Sal B) confers protection through a Piezo1-associated mechanism. In an autologous blood-induced rat ICH model and hemin-treated HT22 cells, Piezo1 expression was increased after ICH and was associated with indices of injury severity. Pharmacological activation of Piezo1 aggravated neurological deficits, lipid peroxidation, iron dysregulation, ferroptosis-related mitochondrial damage, and ferroptosis-associated protein changes, whereas Piezo1 inhibition produced the opposite effects. Sal B improved acute and long-term neurological outcomes, reduced brain edema and neuronal degeneration, and attenuated multiple hallmarks of ferroptosis. Combined in silico analysis and surface plasmon resonance (SPR) supported a direct interaction between Sal B and Piezo1. Mechanistically, the Piezo1 agonist Yoda1 largely abolished Sal B-mediated protection in vivo, while AMPK inhibition partly reversed the protective effects of Sal B in vivo and in vitro. Together, these findings suggest that Piezo1 is associated with ferroptosis-related oxidative injury after ICH and that Sal B mitigates SBI, at least in part, through a Piezo1-associated mechanism involving AMPK-mTOR signaling.
Myeloid specific knockout of Piezo1 alleviates ang Ⅱ-induced cardiac remodeling.
Liu J, Niu W, Xu P … +8 more , Guo H, Zhao Y, Hong T, Luo S, Wang P, Sun X, Chen X, Li J
Free Radic Biol Med · 2026 Jul · PMID 42398556 · Publisher ↗
INTRODUCTION: Cardiac remodeling in heart failure is closely associated with macrophage-mediated immune responses. The mechanosensitive ion channel Piezo1, which is abundantly expressed in macrophages, has been implicate...
INTRODUCTION: Cardiac remodeling in heart failure is closely associated with macrophage-mediated immune responses. The mechanosensitive ion channel Piezo1, which is abundantly expressed in macrophages, has been implicated in mechanically driven cardiovascular pathologies. However, the specific function of macrophage Piezo1 in pathological cardiac remodeling remains unclear. OBJECTIVE: Here, we aimed to investigate the potential regulation of heart failure by Piezo1 and delineate its underlying mechanosensitive signaling pathways. METHODS: We induced heart failure via chronic angiotensin Ⅱ (Ang Ⅱ) infusion in male Piezo1 and myeloid-specific Piezo1 knockout (Piezo1) mice. Cardiac function and pathological changes were assessed using echocardiography, histology and molecular assays. RESULTS: Piezo1 expression was markedly upregulated in mouse hearts following Ang Ⅱ infusion. Myeloid Piezo1 deficiency mitigated Ang Ⅱ-induced cardiac dysfunction, hypertrophy, fibrosis, and inflammation. Consistent with in vivo data, Piezo1 knockout reduced Ang Ⅱ-induced inflammatory responses and altered macrophage polarization in vitro. Mechanistically, Piezo1 aggravated disease progression by increasing Ca entry and activating CaMKⅡ, which drove cytoskeletal remodeling and promoted YAP/TAZ nuclear translocation in macrophages. Consequently, myeloid Piezo1 deficiency suppressed Ang Ⅱ-induced inflammatory responses and downstream intercellular crosstalk with cardiomyocytes and fibroblasts. CONCLUSION: Collectively, myeloid Piezo1 deficiency attenuates heart failure by restraining YAP/TAZ nuclear translocation in macrophages via a Ca/CaMKⅡ-dependent cytoskeletal remodeling pathway. This study suggests that Piezo1 may represent a promising therapeutic target for hypertension-associated heart failure.
Microglia-derived exosomal miR-31-5p promotes type 2 diabetic retinopathy by impairing physiological angiogenesis homeostasis.
Zhang J, Shangguan Y, Luo R … +5 more , Zhang X, Niu Y, Bi Y, Wang H, Li B
Free Radic Biol Med · 2026 Jul · PMID 42392284 · Publisher ↗
Diabetic retinopathy (DR) is characterized by disruption of the retinal physiological vasculature. Impairment of physiological angiogenesis profoundly destabilizes the retinal microenvironment and ultimately leads to vis...
Diabetic retinopathy (DR) is characterized by disruption of the retinal physiological vasculature. Impairment of physiological angiogenesis profoundly destabilizes the retinal microenvironment and ultimately leads to visual dysfunction. Current treatments, including anti-vascular endothelial growth factor (VEGF) and laser photocoagulation therapy, mainly slow disease progression by inhibiting pathological neovascularization. However, strategies to restore functional vascular networks and retinal homeostasis remain limited. Analysis of miRNA profiles in retinal tissue and plasma exosomes from DR patients revealed that miR-31-5p, enriched in microglia-derived exosomes, is markedly upregulated during DR progression and was closely associated with retinal microvascular injury and repair. In vitro experiments demonstrated that retinal microvascular endothelial cells efficiently internalize microglia-derived exosomes. Mechanistically, miR-31-5p disrupts vascular maturation and exacerbates microvascular dysfunction by suppressing flotillin-1 (FLOT1)/sphingosine kinase-1 (SPHK1)/sphingosine-1-phosphate (S1P)/VEGF/zona occludens-1 (ZO-1) signaling axis. Conversely, inhibition of miR-31-5p markedly restored physiological angiogenesis in retinal microvascular endothelial cells. In a DR mouse model, intravitreal injection of a miR-31-5p inhibitor similarly rescued FLOT1 expression in endothelial cells, promoted vascular regeneration, alleviated retinal inflammation and oxidative stress. This study clarifies a novel microglia-endothelial cell communication mechanism, in which microglia-derived exosomes deliver miR-31-5p to suppress the FLOT1/SPHK1/S1P/VEGF/ZO-1 signaling axis, thereby disrupting physiological retinal vascular remodeling. Targeting miR-31-5p may represent a potential therapeutic strategy to physiological angiogenesis homeostasis and slow DR progression.
GPX1 Drives Cuproptosis-Ferroptosis Resistance in Cold Tumors.
Yang S, Zhang C, Mei Z … +10 more , Ye Q, Guo G, Zhu G, Zheng X, Cui Y, Gu W, Zhou Y, Liu G, Wang G, Yang Z
Free Radic Biol Med · 2026 Jul · PMID 42392283 · Publisher ↗
Cold tumors, defined by an immunosuppressive microenvironment and metabolic stress, including glutamine deficiency, frequently exhibit resistance to therapeutic interventions. This study examined the role of glutathione...
Cold tumors, defined by an immunosuppressive microenvironment and metabolic stress, including glutamine deficiency, frequently exhibit resistance to therapeutic interventions. This study examined the role of glutathione peroxidase 1 (GPX1) in mediating resistance to cuproptosis and ferroptosis during glutamine deprivation. Through integrated multi-omics analyses, CRISPR-mediated gene editing, and functional assays in cold tumor cell lines, we identified GPX1 as a key regulator of redox homeostasis and a protector against cuproptosis. Upstream, glutamine deprivation induced the SLC7A11 upregulation, which enhanced GPX1-mediated resistance through the maintenance of pyrimidine metabolism. Downstream, GPX1 knockout mediated cross-sensitization to ferroptosis by altering the Fenton reaction, thereby exacerbating cell death. In vivo experiments confirmed that GPX1 knockout restored sensitivity to cuproptosis inducers and improved the efficacy of PD-L1 blockade. Collectively, these findings position GPX1 as a central metabolic checkpoint in cold tumors and highlight the SLC7A11-UMPs-GPX1 axis as a promising therapeutic target for overcoming treatment resistance and enhancing immunotherapy response.
Frataxin attenuates endothelial inflammation triggered by engulfment of senescent erythrocytes.
Cheng X, Cheng Y, Huang C … +4 more , Wei T, Guo Y, Gao J, Shen W
Free Radic Biol Med · 2026 Jul · PMID 42392282 · Publisher ↗
BACKGROUND: Hypertension is linked to a shortened erythrocyte lifespan, with endothelial cells acting as non-professional phagocytes to clear senescent erythrocytes. However, whether increased erythrophagocytosis contrib...
BACKGROUND: Hypertension is linked to a shortened erythrocyte lifespan, with endothelial cells acting as non-professional phagocytes to clear senescent erythrocytes. However, whether increased erythrophagocytosis contributes to endothelial inflammation remains unclear. Frataxin (FXN) plays a crucial role in controlling iron balance and metabolism. This study investigated the role of FXN-mediated iron engulfment in regulating endothelial pro-inflammatory phenotype. METHODS: Hypertensive models were established by infusing angiotensin II (Ang II) into endothelial cell-specific Fxn knockout mice for 14 days. Erythrocyte senescence was evaluated using scanning electron microscopy and metabolomics. Endothelial erythrophagocytosis and inflammation were assessed via immunofluorescence staining. Integrated proteomics along with surface plasmon resonance (SPR) analyses were employed to identify key proteins and protein-protein interactions during erythrophagocytosis. RESULTS: Erythrocytes from Ang II-infused mice displayed signs of senescence, including swelling and acanthocyte formation. Metabolomics revealed a progressive metabolic decline in erythrocytes. Endothelial cells efficiently cleared senescent erythrocytes, while proteomics identified decreased FXN and increased thioredoxin-interacting protein (TXNIP) protein levels. Although FXN function did not affect phagocytosis efficiency, its absence led to elevated mitochondrial iron overload, lipid peroxides and activation of the TXNIP/NLR family pyrin domain-containing 3 (NLRP3) inflammasome both in vivo and in vitro. Molecular docking showed FXN interacts with thioredoxin-2 (TRX2)/TXNIP redoxisome, forming a trimeric complex. FXN acetylation at Lys-192 (Fxn) caused TXNIP dissociation from oxidized TRX2, liberating TXNIP for NLRP3 activation. Furthermore, Fxn acetylation-deficient mice exhibited reduced endothelial oxidative stress and inflammation. CONCLUSIONS: Excessive endothelial erythrophagocytosis triggers NLRP3 inflammasome activation by destabilizing FXN/TRX2/TXNIP complex.
An enzyme kinetic model for quantitative interpretation of the role of nicotinamide nucleotide transhydrogenase (NNT) in cell physiology.
Gan Z, van der Stelt I, Grefte S … +3 more , Suarez Diez M, Koopman WJH, Keijer J
Free Radic Biol Med · 2026 Jul · PMID 42392281 · Publisher ↗
Nicotinamide Nucleotide Transhydrogenase (NNT) connects mitochondrial bioenergetics and redox homeostasis. It catalyzes a reversible reaction that couples proton transport across the mitochondrial inner membrane (MIM) to...
Nicotinamide Nucleotide Transhydrogenase (NNT) connects mitochondrial bioenergetics and redox homeostasis. It catalyzes a reversible reaction that couples proton transport across the mitochondrial inner membrane (MIM) to hydride transfer between mitochondrial NAD(H) and NADP(H). Understanding NNT kinetics is essential to decipher the link between NNT and mitochondrial functioning. Based on the protein structure and the molecular mechanism of NNT, we deduced that the kinetic mechanism of NNT can be described by a "ping-pong" mechanism. Integrated with its thermodynamic features, we established a mathematical model to describe its enzyme kinetics. The model successfully simulated experimental results obtained in submitochondrial particles. Further model analyses suggest that NNT operates in the forward mode under most physiological conditions, whereas reverse-mode action occurs under specific conditions, including mitochondrial membrane potential depolarization. Additionally, our analyses suggest that during physiological conditions, the NNT-mediated reaction is more sensitive to changes in redox homeostasis than changes in mitochondrial bioenergetics, as evidenced by a larger effect of the redox ratio of NADP(H) than that of NAD(H).
Corrigendum to "The opposite role of lactate dehydrogenase a (LDHA) in cervical cancer under energy stress conditions" [Free Radic. Biol. Med. 214 (2024) 2-18].
Jia C, Wu Y, Gao F … +8 more , Liu W, Li N, Chen Y, Sun L, Wang S, Yu C, Bao Y, Song Z
Free Radic Biol Med · 2026 Jul · PMID 42386398 · Publisher ↗
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Complement C3a induces synaptic elimination in the hippocampus and neurobehavioral deficits in later life of septic neonatal rats triggered by lipopolysaccharide.
Huang P, Jiang S, Chen Z … +7 more , Liu N, Li H, Wang A, Luo L, Huang W, Chen S, Deng Y
Free Radic Biol Med · 2026 Jul · PMID 42385800 · Publisher ↗
Neonatal septic encephalopathy is a severe complication of sepsis, yet its underlying neuropathological mechanisms remain poorly understood. This study investigated the role of the complement component C3a in mediating s...
Neonatal septic encephalopathy is a severe complication of sepsis, yet its underlying neuropathological mechanisms remain poorly understood. This study investigated the role of the complement component C3a in mediating synaptic elimination and neurobehavioral deficits in later life of a lipopolysaccharide (LPS)-induced neonatal sepsis model. We found that activated hippocampal astrocytes upregulated C3a expression, while its receptor, C3aR, was elevated in both microglia and neurons. Blocking the C3a/C3aR axis with a C3a receptor antagonist (C3aRA) attenuated cognitive impairments, synaptic loss, and microglial engulfment of synapses. C3a led to downregulated expression of neurofilament medium (NF-M) and an increased accumulation of phosphorylated Tau (p-Tau) in primary neurons in vitro. Mechanistically, C3a activated the ERK signaling pathway in primary neurons. Inhibition of ERK with ASN007 mitigated C3a-induced synaptic elimination, neuronal damage, and behavioral deficits both in vivo and in vitro. Our results suggest that astrocyte-derived C3a may contributes to hippocampal synaptic elimination and cognitive deficits through C3a/C3aR/ERK pathway in later life of neonatal septic rats. These findings highlight the C3a/C3aR/ERK axis as a potential therapeutic target for preventing synaptic and cognitive deficits in neonatal septic encephalopathy.
Ultraviolet B-induced oxidative stress drives stromal remodeling and malignant transformation of actinic keratosis via a podoplanin-C-type lectin-like receptor 2 signaling axis.
Yao Z, Lu L, Song M … +9 more , Zhu J, Hu H, Xu Q, Gui Q, Yang K, Cui Y, Wang H, Jiang H, Ying J
Free Radic Biol Med · 2026 Jul · PMID 42385799 · Publisher ↗
Ultraviolet B (UVB) radiation induces oxidative stress and promotes photocarcinogenesis; however, the molecular mechanisms linking oxidative stress to the malignant transformation of actinic keratosis (AK) remain incompl...
Ultraviolet B (UVB) radiation induces oxidative stress and promotes photocarcinogenesis; however, the molecular mechanisms linking oxidative stress to the malignant transformation of actinic keratosis (AK) remain incompletely understood. Here, we performed an integrative multi-omics analysis of six independent cohorts combining bulk RNA sequencing, single-cell transcriptomics, functional experiments, and clinical validation. UVB irradiation induced oxidative stress and significantly increased podoplanin (PDPN) expression in keratinocytes in a dose-dependent manner. Mechanistically, keratinocyte-derived PDPN interacted with C-type lectin-like receptor 2 (CLEC-2) on fibroblasts through its platelet aggregation-stimulating (PLAG) domain, triggering fibroblast senescence and the senescence-associated secretory phenotype (SASP), characterized by enhanced secretion of matrix metalloproteinase-1 (MMP-1) and interleukin-6 (IL-6). Single-cell transcriptomic analysis identified 272 epithelial-specific hub genes converging on PDPN-centered regulatory networks, and a 12-gene signature demonstrated strong diagnostic performance and prognostic value. Functional studies showed that PDPN silencing markedly attenuated UVB-induced cell migration and SASP activation, whereas deletion of the PLAG domain abolished PDPN-CLEC-2 interaction. Analysis of human specimens further demonstrated progressive upregulation of PDPN and CLEC-2 expression during the transition from normal skin to AK and cutaneous squamous cell carcinoma (cSCC). Collectively, our findings identify a PDPN-CLEC-2-mediated stromal remodeling program that links UVB-induced oxidative stress to malignant transformation in AK and highlight this signaling axis as a potential therapeutic target for photochemoprevention.
Low-dose ionizing radiation drives thyroid carcinogenesis via VPS53 enhanced EGFR Re-recycling.
Liu Y, Zhou L, Zhu J … +9 more , Ao X, Wang P, Yan Z, Chen H, Zhang X, Ye M, Luan S, Gu Y, Zhou PK
Free Radic Biol Med · 2026 Jul · PMID 42385798 · Publisher ↗
Ionizing radiation is a confirmed independent environmental factor for thyroid cancer. Environmental and occupational exposure are exposed to low-dose ionizing radiation (LDR), which underscores the persistent need to de...
Ionizing radiation is a confirmed independent environmental factor for thyroid cancer. Environmental and occupational exposure are exposed to low-dose ionizing radiation (LDR), which underscores the persistent need to decipher the mechanisms of LDR induced thyroid carcinogenesis. In addition to the canonical driver mutations or chromosomal rearrangements, there remains a gap in understanding the key drivers of LDR-induced thyroid cancer that needs to be clarified. VPS53, a core subunit of the Golgi-associated retrograde protein (GARP) complex, mediates retrograde vesicular trafficking, but its role in LDR-induced thyroid tumorigenesis is uncharacterized. Here, we found that LDR induces an increase in VPS53 copy number in clones of thyroid follicular epithelial cell malignant transformation, leading to elevated expression levels, and high VPS53 expression is associated with poor prognosis in thyroid cancer patients. Functionally, VPS53 promotes the proliferation and clonal formation of thyroid cancer cells; meanwhile, xenograft tumor experiments in nude mice demonstrated that high expression of VPS53 facilitates tumor growth. Mechanistically, VPS53 directly interacts with EGFR, redirecting it from the lysosomal degradation pathway to the plasma membrane recycling pathway, thereby maintaining the sustained activation of the carcinogenesis signaling pathway. Moreover, VPS53 alters the direction of DNA double-strand break repair, favoring non-homologous end joining (NHEJ) over homologous recombination (HR), which exacerbates genomic instability. These mechanisms collectively promote the thyroid carcinogenesis. Collectively, we have confirmed a novel mechanism by which the VPS53-EGFR axis drives thyroid carcinogenesis induced by LDR, and provided new insights into thyroid tumor biology.
Myeloid HIF-1α Couples Glycolytic Energy Supply with NCF2-Dependent Oxidative Killing to Protect Against Klebsiella pneumoniae Pneumonia.
Guo Y, Meng B, Zhu R … +8 more , Dong S, Zhang S, Wang J, Li Y, Yang Y, Liu Y, Yu L, Li J
Free Radic Biol Med · 2026 Jul · PMID 42385797 · Publisher ↗
BACKGROUND: Hypervirulent Klebsiella pneumoniae (hvKp) induces severe pneumonia and sepsis. HIF-1α coordinates metabolic and immune responses in myeloid cells, but its role in hvKp-mediated pulmonary defense remains unde...
BACKGROUND: Hypervirulent Klebsiella pneumoniae (hvKp) induces severe pneumonia and sepsis. HIF-1α coordinates metabolic and immune responses in myeloid cells, but its role in hvKp-mediated pulmonary defense remains undefined. METHODS: Monocyte HIF-1α expression was assessed in patients with Klebsiella pneumoniae (K. pneumoniae) pneumonia. Myeloid-specific Hif-1α knockout mice and BMDMs were used to examine survival, bacterial burden, and macrophage function. RNA-seq, Seahorse flux analysis, and confocal microscopy were employed to investigate the regulatory effects of HIF-1α on phagocytosis and ROS production. The Hif-1α-NCF2-ROS signaling pathway was substantiated through the application of small interfering RNA (siRNA), JASPAR prediction tools, dual-luciferase reporter assays, chromatin immunoprecipitation followed by quantitative PCR (ChIP-qPCR), metabolic inhibitors, and dimethyloxalylglycine (DMOG), a prolyl hydroxylase inhibitor that stabilizes HIF-1α. RESULTS: Clinical data showed a negative correlation between monocyte HIF-1α levels and serum CRP, procalcitonin, ICU stay duration, and SOFA scores. In vivo, myeloid Hif-1α knockout mice demonstrated heightened susceptibility to hvKp, with markedly reduced survival and widespread bacterial dissemination. Mechanistically, Hif-1α-deficient macrophages displayed impaired phagocytosis, phagolysosomal maturation, and glycolytic reprogramming in response to infection. RNA-seq identified NCF2, encoding p67-phox, as a critical HIF-1α-dependent component of the NADPH oxidase complex. JASPAR prediction, dual-luciferase reporter assays, and ChIP-qPCR further demonstrated that NCF2 is directly transcriptionally regulated by HIF-1α. HIF-1α deficiency impaired both glycolytic ATP production and NCF2-mediated ROS generation, thereby compromising macrophage antibacterial activity. Inhibition of glycolysis or silencing NCF2 abolished HIF-1α-dependent defense, whereas pharmacological stabilization of HIF-1α using DMOG significantly enhanced host resistance. CONCLUSION: HIF-1α serves as a pivotal regulator of host defense in experimental hvKp pneumonia and is clinically associated with disease severity in K. pneumoniae pneumonia, linking glycolytic metabolism to the NCF2-ROS bactericidal pathway. These findings highlight the potential of targeting immunometabolic pathways to improve host defense against severe K. pneumoniae infections.
Manoalide targets redox-mitochondrial vulnerability to induce bioenergetic failure and suppress angiogenic activity in glioblastoma.
Chen NF, Kuo HM, Yang SN … +6 more , Lo YH, Shih PC, Wang YJ, Jean YH, Wen ZH, Chen WF
Free Radic Biol Med · 2026 Jul · PMID 42385796 · Publisher ↗
Glioblastoma (GBM) displays pronounced metabolic adaptability and resistance to cell death, largely sustained by mitochondrial redox homeostasis. Targeting redox imbalance has emerged as a promising strategy; however, th...
Glioblastoma (GBM) displays pronounced metabolic adaptability and resistance to cell death, largely sustained by mitochondrial redox homeostasis. Targeting redox imbalance has emerged as a promising strategy; however, the relationship between phospholipase A2 (PLA2)-related signaling, mitochondrial dysfunction, and bioenergetic failure in GBM remains insufficiently defined. Bioinformatic analyses using TCGA and GTEx datasets revealed that phospholipase A2 group IVA (PLA2G4A) was upregulated in glioma and associated with unfavorable overall survival. PLA2G4A expression also showed modest but statistically significant correlations with selected redox and mitochondrial function-related genes, suggesting a possible association between PLA2-related signaling and the redox-mitochondrial state of glioma. Accordingly, we investigated whether manoalide, a marine-derived sesterterpenoid previously reported to inhibit PLA2 activity, could perturb mitochondrial redox equilibrium and promote oxidative stress-associated cytotoxicity in GBM cells. Manoalide induced intracellular and mitochondrial oxidant-associated fluorescence signals, accompanied by reduced antioxidant defenses and loss of mitochondrial membrane potential. Bioenergetic profiling revealed impaired oxidative phosphorylation, reduced oxygen consumption, and ATP depletion, indicating mitochondrial dysfunction. Antioxidant pretreatment with N-acetylcysteine attenuated oxidant-associated fluorescence signals, preserved mitochondrial membrane potential, and reduced apoptosis-associated signaling, suggesting that manoalide cytotoxicity is mediated at least in part through redox-associated mechanisms. Sustained oxidative stress was accompanied by autophagy-associated responses characterized by acidic vesicular organelle formation, LC3-II accumulation, and p62 elevation. These effects may be linked to the electrophilic α,β-unsaturated γ-lactone moiety of manoalide, which may contribute to its redox-modulating properties. In addition to tumor cell-intrinsic effects, manoalide suppressed endothelial migration, tube formation, and microvessel sprouting, suggesting anti-angiogenic activity in complementary endothelial and ex vivo angiogenesis models. Collectively, our findings integrate PLA2G4A-based transcriptomic evidence with functional analyses, suggesting manoalide-mediated disruption of mitochondrial redox homeostasis may represent a potential strategy to induce bioenergetic dysfunction, apoptosis-associated signaling, autophagy-associated stress responses, and anti-angiogenic activity in glioblastoma.
A Critical Role for Mitochondrial Dynamics in Cigarette Smoke Condensate-induced RPE Senescence.
Zhou Q, Zhang Z, Wu Y … +5 more , Dong C, Wu CC, Handa JT, Ma J, Wang S
Free Radic Biol Med · 2026 Jul · PMID 42385795 · Publisher ↗
Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly. Its pathogenesis remains incompletely understood, partly due to the complex interplay of genetic risk, aging, and environmental str...
Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly. Its pathogenesis remains incompletely understood, partly due to the complex interplay of genetic risk, aging, and environmental stressors. Cigarette smoking (CS) is a major modifiable risk factor for AMD, yet the mechanism linking CS to disease progression remains unclear. We hypothesize that CS accelerates AMD pathogenesis by exacerbating cellular senescence in the retinal pigment epithelium (RPE), thereby driving age-related RPE dysfunction and degeneration. In this study, differentiated ARPE-19 cells or mice were exposed to low-dose cigarette smoke condensate (CSC), and stress-induced senescence-like RPE phenotypes were induced, characterized by increased senescence markers, mitochondrial dysfunction, and retinal functional impairment. RPE senescence phenotypes were also confirmed in mice exposed to 6 months of CS in the smoking chamber. CSC-induced RPE senescence was associated with a biphasic alteration in mitochondrial morphology, progressing from early mitochondrial fragmentation to late mitochondrial hyperfusion, as well as impaired mitophagy flux, reduced mitochondrial turnover, and decreased mitochondrial biogenesis. Mechanistically, CSC increased dynamin-related protein 1 (DRP1) phosphorylation and promoted cleavage of the mitochondrial phosphatase PGAM5, mitochondrial remodeling associated with decreased DRP1 activities, elevated mitochondrial oxidative stress, and activation of mTOR signaling. Notably, overexpression of a DRP1 activity mutant (K38A) mimics the CSC-induced RPE senescence, while overexpression of the phosphodeficient DRP1-S637A mutant significantly attenuates both mTOR signaling and CSC-induced RPE senescence by restoring mitochondrial fission balance, improving mitochondrial quality-control responses, reducing mitochondrial oxidative stress. Collectively, these findings identify impaired DRP1-dependent mitochondrial remodeling as a key mechanism linking CSC exposure to RPE senescence. While we confirmed the RPE senescence phenotype in mice after 6 months of CS exposure, the specific mechanisms observed in this study require further validation in a chronic CS model. These findings encourage future research into mitochondrial dynamics and RPE senescence in AMD, suggesting that modulating RPE mitochondrial dynamics holds therapeutic potential for delaying AMD progression.
Retraction notice to "Leonurine (SCM-198) attenuates myocardial fibrotic response via inhibition of NADPH oxidase 4" [Free Radical Biol. Med. 54 (2013) 93-104].
Liu XH, Pan LL, Deng HY … +5 more , Xiong QH, Wu D, Huang GY, Gong QH, Zhu YZ
Free Radic Biol Med · 2026 Jun · PMID 42379980 · Publisher ↗
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Iron chaperones and RNA-binding proteins, PCBP1 and PCBP2, maintain hepatic iron balance and protect against ferroptosis.
Protchenko O, Tietgens AJ, Messager E … +5 more , Jadhav S, Kleiner DE, Grounds S, Shakoury-Elizeh M, Philpott CC
Free Radic Biol Med · 2026 Jun · PMID 42379276 · Publisher ↗
Poly rC binding proteins (PCBPs) 1 and 2 bind iron and ssDNA/RNA, acting as iron chaperones for enzyme metalation, ferritin storage, and iron toxicity prevention. Previously, we demonstrated that liver-specific PCBP1 del...
Poly rC binding proteins (PCBPs) 1 and 2 bind iron and ssDNA/RNA, acting as iron chaperones for enzyme metalation, ferritin storage, and iron toxicity prevention. Previously, we demonstrated that liver-specific PCBP1 deletion in mice increased unchaperoned iron, causing hepatic oxidative damage and steatosis. Little is known about the functions of PCBP2 in vivo. To define the roles of PCBP1 and PCBP2 in murine hepatic iron metabolism, we generated conditional (Alb-Cre) and vector-mediated (AAV8-TBG-iCre) deletion as models of chronic and acute PCBP deficiency, respectively. Conditional deletion in hepatocytes and cholangiocytes caused chronic, severe hepatic injury, with steatosis, necrosis, ductular reaction, increased plasma ALT and ALP, and Nrf2-dependent antioxidant gene activation. Vector-mediated PCBP1/PCBP2 double deletion in adult mice led to acute liver injury with periportal inflammation, apoptosis, and DNA damage, followed by compensatory hepatocyte proliferation. In contrast, single deletions caused mild or no acute liver abnormalities, suggesting a functional redundancy. Loss of both chaperones caused oxidative and ferroptosis-like injury, indicated by increased lipid peroxidation, 8-oxoguanine-modifcations of nucleic acids, and Nrf2 target gene expression. Dietary iron restriction, but not vitamin E, markedly improved liver pathology, normalized plasma markers, and reduced oxidative stress, demonstrating that iron toxicity, not general lipid peroxyl radicals, drives hepatocellular injury. Rescue experiments with PCBP1 variants demonstrated that wild-type PCBP1 restored normal hepatic function, while iron-binding-deficient (ΔFe) and RNA/DNA-binding-deficient (ΔRNA) variants failed. PCBP1ΔFe expression did not prevent liver damage or suppress ALT levels. PCBP1ΔRNA expression was, surprisingly, toxic to hepatocytes and caused more rapid cell death than transduction with no PCBP1 at all, suggesting that unbalanced iron- and RNA/DNA-binding activities are toxic to hepatocytes. These results establish PCBP1 and PCBP2 as essential, cooperative hepatic iron regulators whose loss causes ferroptosis-like injury through dysregulated iron and RNA/DNA homeostasis.
Irisin acts as an exercise mimetic to alleviate sedentary-induced osteoporosis by reprogramming macrophage-mediated inflammation via the HSP90-MAPK signaling axis.
Xiang X, Ruan Y, Feng S … +9 more , Bin W, Lan B, Daud DMA, Pare R, Palasuberniam P, Huang J, Liu H, Jiang W, He L
Free Radic Biol Med · 2026 Jun · PMID 42379275 · Publisher ↗
Sedentary behavior induces bone loss partly through chronic low-grade inflammation, presenting a critical need for novel pharmacological interventions. Irisin, a cleaved product of Fibronectin type III domain-containing...
Sedentary behavior induces bone loss partly through chronic low-grade inflammation, presenting a critical need for novel pharmacological interventions. Irisin, a cleaved product of Fibronectin type III domain-containing protein 5 (FNDC5), has emerged as a potential exercise mimetic, yet its therapeutic efficacy and precise molecular targets in osteoimmunology remain elusive. Here, we investigate the pharmacological potential of irisin in mitigating sedentary-induced osteoporosis by modulating macrophage-mediated inflammation. Population-based analyses first established systemic inflammation as a key mediator between physical inactivity and osteoporosis. Crucially, FNDC5 knockout mice failed to exhibit exercise-induced skeletal benefits, confirming the indispensable role of endogenous irisin in bone homeostasis. Mechanistically, in vitro assays revealed that exogenous irisin administration potently suppresses Tumor necrosis factor-alpha (TNF-α) production in Lipopolysaccharide (LPS)-stimulated macrophages by directly downregulating Heat shock protein 90 (HSP90) and subsequently inhibiting the Mitogen-activated protein kinase (MAPK) signaling cascade. Furthermore, conditioned media from irisin-treated or HSP90-silenced macrophages effectively reversed LPS-induced osteoclastogenesis and restored osteoblast differentiation-therapeutic effects that were completely abolished by HSP90 overexpression. In vivo, pharmacological administration of irisin in sedentary mice successfully improved bone microarchitecture, attenuated systemic inflammation, and rebalanced bone remodeling via the HSP90/MAPK axis, exhibiting comparable efficacy to physical exercise without detectable organ toxicity. Collectively, these findings identify the irisin-HSP90-MAPK axis as a novel therapeutic target, establishing irisin as a viable pharmacological exercise mimetic against inflammation-driven bone loss.
Proteome-wide quantitative analysis of redox cysteine in porcine uterus reveals deoxynivalenol induced oxidative stress via protein hyperoxidation.
Fan S, Tian F, Wang Q … +7 more , Guan J, Lu S, Ding Y, Zheng X, Li Y, Yin Z, Zhang X
Free Radic Biol Med · 2026 Jun · PMID 42364855 · Publisher ↗
Deoxynivalenol (DON), a mycotoxin produced by fungi of the genus Fusarium, is ubiquitously distributed in feed and poses a substantial threat to human and animal health. Pigs exhibit particular sensitivity to DON, which...
Deoxynivalenol (DON), a mycotoxin produced by fungi of the genus Fusarium, is ubiquitously distributed in feed and poses a substantial threat to human and animal health. Pigs exhibit particular sensitivity to DON, which can induce reproductive impairment. While the ovarian toxicity of DON has been extensively investigated, its effects on the uterus remain largely understudied. We established a DON-exposed piglet model and observed severe oxidative damage in the uterus. Reactive oxygen species (ROS) regulate protein function by catalyzing cysteine modifications in vivo. Employing mass spectrometry-based redox proteomics, we identified 17,882 cysteine thiol oxidation sites across 7147 DON-affected proteins, among which 150 sites on 130 proteins displayed significant alterations following DON exposure. Notably, multiple key members of antioxidant protein families, such as GPXs and PRDXs, underwent extensive oxidation themselves-a phenomenon that may be associated with reduced enzymatic activity, as validated by experimental results on glutathione reductase (GSR). Finally, in vitro experiments demonstrated that tea polyphenols, a natural antioxidant present in tea, can mitigate DON-induced damage to endometrial cell lines by alleviating protein hyperoxidation. Our study provides novel insights into the uterine toxicity of DON and the pervasive nature of redox modifications, while also identifying potential therapeutic targets.
Ginsenoside Rk1 suppresses osteosarcoma progression by coordinately activating ferritinophagy and disrupting antioxidant defense to induce ferroptosis.
Lin R, Wu J, Fang R … +3 more , Suo Y, Lu H, Liu Q
Free Radic Biol Med · 2026 Jun · PMID 42364854 · Publisher ↗
Osteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents. Despite advances in multimodal therapy, the prognosis of metastatic or recurrent OS remains poor due to chemoresistance and l...
Osteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents. Despite advances in multimodal therapy, the prognosis of metastatic or recurrent OS remains poor due to chemoresistance and limited therapeutic options. In this study, we systematically investigated the antitumor efficacy and molecular mechanisms of ginsenoside Rk1 (GRk1), a rare saponin derived from Panax ginseng, in OS models. GRk1 markedly suppressed cell viability, clonogenic growth, migration, and epithelial-mesenchymal transition (EMT), while promoting tumor cell death in a dose- and time-dependent manner. Mechanistically, GRk1 disrupted cellular redox homeostasis by decreasing mitochondrial membrane potential and promoting ROS accumulation. Integrated transcriptomic and biochemical analyses demonstrated that GRk1 induced ferroptosis through coordinated regulation of iron metabolism and antioxidant defense pathways. GRk1 activated AMPK while suppressing mTOR signaling, leading to NCOA4-dependent ferritinophagy, ferritin degradation, and intracellular iron accumulation. Simultaneously, GRk1 inhibited Nrf2 nuclear translocation, thereby promoting autophagic degradation of SLC7A11 and suppressing the SLC7A11/GSH/GPX4 antioxidant axis, ultimately exacerbating lipid peroxidation. Pharmacological rescue experiments using dorsomorphin and TBHQ confirmed the involvement of the AMPK/mTOR/NCOA4 and Nrf2/SLC7A11/GPX4 pathways, respectively. Furthermore, GRk1 synergistically potentiated the cytotoxic effects of cisplatin. In a xenograft mouse model, GRk1 effectively inhibited tumor growth without inducing significant systemic toxicity. Collectively, these findings identify GRk1 as a potent natural ferroptosis inducer and support its potential development as a promising adjuvant therapeutic strategy for OS.
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