Free Radic. Biol. Med. [JOURNAL]
Sun
200 papers
Targeting pyroptosis in tauopathies: A redox-driven axis of neuroinflammation and neurodegeneration.
Alonso-López E, Silva-Llanes I, Díez-Tejedor E … +1 more , Lastres-Becker I
Free Radic Biol Med · 2026 Aug · PMID 42000084 · Publisher ↗
Tauopathies encompass a diverse group of neurodegenerative disorders characterized by abnormal TAU accumulation, synaptic dysfunction, neuroinflammation, and progressive neuronal loss. Beyond its role as a pathological h...
Tauopathies encompass a diverse group of neurodegenerative disorders characterized by abnormal TAU accumulation, synaptic dysfunction, neuroinflammation, and progressive neuronal loss. Beyond its role as a pathological hallmark, increasing evidence indicates that TAU actively drives neurodegeneration by disrupting mitochondrial function, promoting oxidative stress, and triggering maladaptive innate immune responses. In this context, pyroptosis, a highly inflammatory form of programmed cell death mediated by inflammasome activation and GASDERMIN pore formation, has emerged as a critical mechanism linking TAU pathology to chronic neuroinflammation and neuronal damage. This review summarizes current advances on the molecular crosstalk between TAU pathology, redox imbalance, inflammasome signaling, and pyroptotic cell death across primary and secondary tauopathies, including Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD). We discuss how pathological TAU induces mitochondrial dysfunction and reactive oxygen species generation, providing key priming and activation signals for inflammasomes, particularly NLRP3, in microglia and other brain cells. Pyroptosis is highlighted as a downstream effector that amplifies neuroinflammation through the release of pro-inflammatory cytokines and danger-associated molecular patterns, thereby sustaining TAU propagation and neurodegeneration. Special attention is paid to the redox-sensitive transcription factor NRF2 as a central regulatory node capable of counteracting oxidative stress, inflammasome activation, and pyroptosis. Finally, we examine emerging therapeutic strategies targeting pyroptotic and redox pathways, discussing their translational potential and current limitations. Overall, this review positions pyroptosis-driven redox-immune dysregulation as a promising yet underexplored therapeutic target in TAU-driven neurodegenerative diseases.
Raddeanin A induces ferroptosis by targeting VEPH1 in a cisplatin-resistant epithelial ovarian cancer cell line.
Li H, Xing W, Dai Y … +6 more , Cao S, Yang X, Zhang Y, Zeng X, Liu H, Wu X
Free Radic Biol Med · 2026 Aug · PMID 41997548 · Publisher ↗
Ovarian cancer (OC) is a fatal female malignancy, and cisplatin resistance severely impacts the clinical management of epithelial ovarian cancer (EOC), the most prevalent histological subtype accounting for over 90% of c...
Ovarian cancer (OC) is a fatal female malignancy, and cisplatin resistance severely impacts the clinical management of epithelial ovarian cancer (EOC), the most prevalent histological subtype accounting for over 90% of cases. Exploration of novel effective targets and drugs for treatment of cisplatin-resistant EOC is urgently needed to address the tremendous challenge. In this study, we screened a Traditional Chinese Medicine (TCM) library including 978 monomers and found that Raddeanin A (RA) extracted from Anemone raddeana Regel displayed the powerful cytotoxic effect on cisplatin-resistant EOC cells. Further investigations revealed that RA had potential of inducing ferroptosis via binding to an evolutionarily conserved scaffold protein, VEPH1. Bioinformatics analysis combined with RA-sepharose pull-down assay and immunoprecipitation confirmed that RA interacted with two sites of VEPH1, site 1 (S1) at 212-217 aa and site 2 (S2) at 579-651 aa, and S1 was also involved in VEPH1 binding to and promoting lats1 activation. Moreover, RA bound to and enhanced VEPH1 degradation through the proteasome pathway, and meanwhile inhibited the interaction between VEPH1 and lats1, which in turn suppressed lats1 activation, promoted YAP nuclear translocation to up-regulate the expression of ferroptosis-driven proteins, TFRC and ACSL4, resulting in an imbalance of intracellular iron homeostasis, as well as promotion of lipid peroxidation, and thus inducement of ferroptosis in cisplatin-resistant EOC cells. Importantly, the in vivo results confirmed that RA induced ferroptosis and dramatically suppressed the growth of A2780/DDP transplanted tumours. Taken together, we revealed for the first time that VEPH1 is the direct target for RA, and ferroptosis contributes to RA-triggered anti-tumour effect on cisplatin-resistant EOC, which provides new insights into the therapeutic application of RA against EOC chemoresistance.
Inhibitory mechanism of thrombin (FIIa) by garlic-derived HS: persulfidation cleavage of the Cys42-Cys58 disulfide bond triggers FIIa cascade inactivation.
Du M, Zhou L, Lian Y … +3 more , Wang X, Wu Z, Bai B
Free Radic Biol Med · 2026 Aug · PMID 41991008 · Publisher ↗
Thrombin (FIIa) is a pivotal serine protease in the coagulation cascade. Its aberrant activation drives pathological thrombosis, myocardial infarction, and stroke. Although garlic-derived sulfur compounds are known for c...
Thrombin (FIIa) is a pivotal serine protease in the coagulation cascade. Its aberrant activation drives pathological thrombosis, myocardial infarction, and stroke. Although garlic-derived sulfur compounds are known for cardiovascular protection, their redox-dependent regulation of key coagulation proteases remains largely undefined. In this study, we used a multi-scale approach combining enzymatic assays, structural characterization, molecular dynamics, and functional validation to elucidate how garlic-derived hydrogen sulfide (HS) inhibits FIIa. Real-time activity assays demonstrated that garlic-derived HS donors, including glutathione (GSH)-activated diallyl trisulfide (DATS), diallylthiosulfinate (Allicin), and diallyl disulfide (DADS), inhibited FIIa in an HS-release-dependent manner, confirming HS as the key bioactive FIIa inhibitor. Structural analyses showed that HS binding induced global conformational rigidification of FIIa, with decreased β-sheet and increased α-helix contents. Mechanistically, direct evidence from matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS/MS) confirmed that HS cleaved the Cys42-Cys58 disulfide bond (S-S) and specifically persulfidated Cys42-SH to Cys42-SSH. Computational modeling suggested this S-S cleavage may arrest the catalytic canyon's "self-chewing" motion, disrupt the oxyanion hole, decouple Na-mediated allostery, and induce rigidity, potentially locking FIIa in an autoinhibited state. Functionally, in vivo assays verified the anticoagulant efficacy of garlic-derived HS. Based on experimental and computational data, we proposed two interconnected mechanisms: the modeling-derived "Na-coordination-gated allosteric catalytic canyon self-chewing cycle" governing FIIa-mediated fibrinogen cleavage, and the experimentally supported "FIIa cascade inactivation via S-S persulfidation cleavage" underlying HS-dependent FIIa inhibition. This work identified a potential novel paradigm for redox-dependent regulation of the coagulation cascade, advanced natural product-based enzyme inhibition mechanisms, and provided a foundation for developing next-generation redox-targeted anticoagulants.
Cleland immunoblotting quantifies cysteine proteoform ensembles.
Cobley JN, Noble A, Guille M
Free Radic Biol Med · 2026 Aug · PMID 41991007 · Publisher ↗
Cysteine oxidation generates biologically important proteoforms that are difficult to directly resolve using conventional immunoblot or peptide-based mass spectrometry workflows. For a protein containing R cysteine resid...
Cysteine oxidation generates biologically important proteoforms that are difficult to directly resolve using conventional immunoblot or peptide-based mass spectrometry workflows. For a protein containing R cysteine residues, the number of theoretical cysteine proteoforms expands exponentially (2^R), while aggregate oxidation measurements collapse this space into a single percentage value. Here, we present Cleland immunoblotting, a reversible mass-encoding strategy that resolves and quantifies intact cysteine proteoform ensembles by their oxidation integer. Each band contains co-migrating cysteine proteoforms with the same number of oxidised cysteines, and the degeneracy of each band follows the binomial theorem. Using the biotin-switch technique, reversibly oxidised cysteines are labelled with a 2-pyridyldithiol-functionalised polyethylene glycol (PEG) reagent to encode oxidation-dependent mobility shifts during gel electrophoresis. Following electrophoretic separation, the PEG-payload is reductively removed in-gel using Cleland's reagent (DTT) prior to membrane transfer, restoring antibody accessibility while preserving band resolution. Band structure follows binomial degeneracy, yielding r + 1 oxidation-graded ensembles that are experimentally distinguishable. Application to cdc20 in Xenopus laevis oocytes demonstrates resolution and quantification of discrete fully reduced and oxidised cysteine protoeforms. By resolving cysteine proteoform ensembles, Cleland immunoblotting can advance proteoform research.
Bisphenol A drives thyroid carcinogenesis through oxidative stress-lipid metabolic reprogramming via the PTEN/PI3K/AKT axis: Therapeutic reversal by a curcumin-modified quercetin nanomicelle system.
Liang J, Liu B, Sun M … +2 more , Yang X, Zhao Y
Free Radic Biol Med · 2026 Aug · PMID 41985638 · Publisher ↗
Bisphenol A (BPA), a pervasive endocrine-disrupting chemical, has been increasingly implicated in thyroid carcinogenesis, yet the links between redox imbalance and metabolic alterations remain incompletely defined. Here,...
Bisphenol A (BPA), a pervasive endocrine-disrupting chemical, has been increasingly implicated in thyroid carcinogenesis, yet the links between redox imbalance and metabolic alterations remain incompletely defined. Here, we combined LC-MS/MS quantification of BPA and its major conjugates with in vitro and in vivo thyroid cancer models to examine oxidative stress markers and lipid indices assessed by targeted biochemical assays and to evaluate a curcumin-modified, quercetin-loaded chitosan nanomicelle system (Que@CSNPs-Cur). We observed BPA enrichment in tumor-bearing mice, accompanied by increased lipid indices (free fatty acids, triglycerides, and total cholesterol) and elevated oxidative stress markers (ROS, TOS, and MDA), as assessed by targeted enzymatic and colorimetric assays. At the molecular level, BPA exposure was associated with reduced PTEN expression and increased PI3K/AKT phosphorylation, consistent with enhanced proliferative and invasive phenotypes in papillary thyroid carcinoma cells. Que@CSNPs-Cur restored PTEN levels, reduced PI3K/AKT activation, attenuated redox and lipid indices, and promoted caspase-3-dependent apoptosis. In xenograft mice, Que@CSNPs-Cur suppressed tumor growth, decreased oxidative stress markers and lipid indices, and reduced tumor BPA residue. Collectively, these results suggest that BPA exposure is linked to PTEN/PI3K/AKT dysregulation, oxidative stress and lipid disturbances. Que@CSNPs-Cur is a promising redox-oriented nanotherapeutic strategy for BPA-associated thyroid cancer phenotypes. Notably, the present study does not determine whether oxidative stress is upstream or downstream of PTEN suppression.
CD36 serves as a potential drug-target to alleviate inflammation in atherosclerosis via leonurine-mediated blockade of its activation pocket.
Lin G, Chi AQ, Cai SY … +12 more , Zhang YM, Ren YC, Lu X, Sun C, Mu XP, Zhang IY, Weng JW, Li MY, Chen Y, Zhu YZ, Tao BB, Zhu YC
Free Radic Biol Med · 2026 Aug · PMID 41974278 · Publisher ↗
Scavenger receptor B3/differentiation cluster 36 (SCARB3/CD36) has been established as a fatty acid transporter and genetic deficiency of CD36 in mice models shows decreased uptake of oxidized low-density lipoprotein (ox...
Scavenger receptor B3/differentiation cluster 36 (SCARB3/CD36) has been established as a fatty acid transporter and genetic deficiency of CD36 in mice models shows decreased uptake of oxidized low-density lipoprotein (oxLDL) and reduced atherosclerosis. The present study proposes CD36 as a drug target inhibited by leonurine to alleviate inflammation and prohibit unstable atherosclerotic plaques. We showed that the anti-atherosclerotic effects of leonurine were dependent on CD36 in a mice model of arterial atherosclerosis induced by tandem stenosis surgery fed with Western diet (TS + WD) established in both wild type (WT) and Cd36 mice. In ApoE mice lethally irradiated and transplanted with bone marrow cells isolated from either Cd36 or WT mice with tandem stenosis and Western diet (BMT Cd36 or BMT WT, TS + WD), we further showed that the leonurine effects were dependent on CD36 in bone-marrow-derived inflammatory cells. Leonurine was found to inhibit the uptake of oxLDL in the macrophages and this effect was dependent on CD36. Direct interaction between leonurine and CD36 was validated using surface plasmon resonance (SPR) assay. Molecular dynamics (MD) simulations revealed a hydrophobic pocket in CD36 constituted by Y149, V154 and Y192 for leonurine targeting, which was blunted in cultured cells expressing mutant CD36 (V154H). In conclusion, CD36 serves as a drug target inhibited by leonurine to alleviate inflammation in atherosclerotic plaques. The hydrophobic pocket structure in CD36 for leonurine-binding is essential for future CD36-based drug design for new therapy against cardiovascular inflammation.
Heme oxygenase-1-enriched tolerogenic dendritic cell-derived exosomes attenuate lupus nephritis by restoring immune balance and iron homeostasis.
Xing Z, Yang J, Zhang H … +6 more , Xie Y, Yang Q, Wu M, Wang W, Gao S, Hua C
Free Radic Biol Med · 2026 Aug · PMID 41967722 · Publisher ↗
Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disorder characterized by chronic inflammation, oxidative stress, and multi-organ damage, with lupus nephritis (LN) constituting a major cause of morbidity...
Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disorder characterized by chronic inflammation, oxidative stress, and multi-organ damage, with lupus nephritis (LN) constituting a major cause of morbidity and mortality. Dysregulated iron metabolism and insufficient expression of heme oxygenase-1 (HO-1), a pivotal antioxidant enzyme regulating iron homeostasis and immune responses, have been implicated in LN pathogenesis. However, therapeutic strategies targeting HO-1 and iron dysregulation remain underexplored. Here, we demonstrate that HO-1 expression is markedly decreased in peripheral blood mononuclear cells from SLE patients, particularly those with LN, correlating inversely with disease activity and markers of iron homeostasis disruption. We established that IL-10 induces tolerogenic dendritic cells (tolDCs) through activation of the Nrf2-HO-1 pathway, concomitant with modulation of iron metabolism and oxidative stress genes. Leveraging this mechanism, we generated HO-1-enriched tolDC-derived exosomes (HO-1-tolDex) and characterized their immunomodulatory properties in vitro, showing effective suppression of pro-inflammatory cytokines and restoration of iron regulatory gene expression in recipient DCs. In vivo, HO-1-tolDex administered intravenously preferentially accumulated in kidneys of lupus-prone mice, exhibiting superior stability and targeting compared to parental tolDCs. Repeated dosing ameliorated renal pathology, concomitant with decreased DC activation and pathogenic autoantibody titers. Importantly, HO-1-tolDex reversed oxidative stress imbalances and normalized iron homeostasis markers, mitigating abnormal renal iron accumulation. These findings establish HO-1-tolDex as a potent, novel cell-free therapeutic agent that simultaneously modulates immune dysregulation, oxidative stress, and iron metabolism in SLE.
Heme oxygenase-1 attenuates sepsis-associated acute lung injury by suppressing the CREB3/ARF4 signaling pathway to mitigate Golgi stress in macrophages.
Kong C, Zhang Y, Li X … +9 more , Ren G, Guo C, Li M, Liu W, Zhang D, Li C, Shi J, Gong L, Yu J
Free Radic Biol Med · 2026 Aug · PMID 41967721 · Publisher ↗
Sepsis-associated acute lung injury (S-ALI) represents a significant clinical challenge due to its high incidence and mortality rates. Macrophages play a central and dual role in the pathogenesis of S-ALI, they serve as...
Sepsis-associated acute lung injury (S-ALI) represents a significant clinical challenge due to its high incidence and mortality rates. Macrophages play a central and dual role in the pathogenesis of S-ALI, they serve as a critical component of the innate immune defense against pathogen invasion, while simultaneously contributing to the propagation of excessive inflammatory responses and tissue damage. Consequently, modulation of macrophage function has emerged as a promising therapeutic strategy for S-ALI. Accumulating evidence indicates that heme oxygenase-1 (HO-1, encoded by HMOX1) exerts endogenous protective effects in S-ALI. Our prior studies demonstrated that HO-1 ameliorates S-ALI by modulating oxidative stress in macrophages. Furthermore, emerging reports suggest that HO-1 may also mitigate this pathological process through regulation of Golgi stress; however, the underlying molecular mechanisms remain poorly defined. In this study, using both in vivo and in vitro models of S-ALI, we demonstrate that HO-1 in alveolar macrophages directly interacts with the transcriptional activation domain (TAD) of CREB3, leading to the degradation of the CREB3/ARF4 signaling pathway. Moreover, activated CREB3 suppresses HO-1 gene transcription, establishing a negative feedback regulatory loop. This mechanism effectively restricts CREB3 trafficking from the endoplasmic reticulum to the Golgi apparatus and its subsequent nuclear translocation, thereby preventing excessive activation of CREB3-dependent signaling pathways during S-ALI and attenuating Golgi stress. Additionally, clinical analyzes reveal that the expression levels of HO-1, CREB3, and ARF4 in peripheral blood mononuclear cells (PBMCs) from sepsis patients are significantly elevated compared to those in non-septic controls and positively correlate with APACHE II and SOFA scores. These markers demonstrate significant positive associations with established severity indices, suggesting that HO-1, CREB3, and ARF4-either individually or in combination-may serve as potential novel biomarkers for the diagnosis of sepsis, the assessment of disease severity, and the prediction of clinical outcomes. Collectively, these findings indicate that HO-1 alleviates Golgi stress in macrophages by inhibiting the CREB3/ARF4 axis, thus improving cellular functional homeostasis, and highlight their potential as both a diagnostic biomarker and a therapeutic target in sepsis.
CuO-NPs suppress esophageal squamous cell carcinoma by altering oxidant-dependent energy metabolism, leading to mitophagy.
Liu Y, Yu X, Zhang X … +7 more , Zhang K, Li M, Jia S, Fu Y, Guo Y, Li X, Jiang W
Free Radic Biol Med · 2026 Aug · PMID 41966312 · Publisher ↗
Nanoparticles coupled with metals hold great promise for biomedical applications. While previous studies have shown the cytotoxic effects of copper oxide nanoparticles (CuO-NPs) on esophageal squamous cell carcinoma (ESC...
Nanoparticles coupled with metals hold great promise for biomedical applications. While previous studies have shown the cytotoxic effects of copper oxide nanoparticles (CuO-NPs) on esophageal squamous cell carcinoma (ESCC), the underlying mechanisms are unclear. Here, we demonstrate that CuO-NPs accumulate around mitochondria in esophageal cells, substantially inducing reactive oxygen species (ROS), which activates NRF2 in ESCC cells compared to normal esophageal keratinocytes. Transcriptomic analysis reveals that NRF2-downstream genes play crucial roles in both antioxidant activity and energy metabolism, which activate the protein kinase AMPK and inhibit AMPK downstream target mTORC1, ultimately leading to mitochondrial dysfunction and cell death in ESCC cells. We show that the critical mitophagy regulators, PINK1 and Parkin, are significantly upregulated in CuO-NP-treated ESCC cells. Since the transcription factor TFEB is a mTORC1 downstream target that has been shown to directly control PINK1/Parkin expression, we find that the mTORC1-TFEB-PINK1-Parkin (mTTPP) axis is involved in CuO-NP-induced cytotoxicity in ESCC cells. CuO-NPs inhibit mTORC1-mediated TFEB phosphorylation, thereby inducing TFEB nuclear translocation that increases PINK1/Parkin expression and activates the PINK1/Parkin-mediated mitophagy pathway. Ablation of the mTTPP axis by RNA interference attenuates the cytotoxicity induced by CuO-NPs in ESCC cells. The tumor-killing effects of CuO-NPs observed in vitro are also evident in the subcutaneous ESCC xenograft model in vivo. Taken together, our results suggest that CuO-NPs have potential for ESCC treatment and warrant further preclinical study.
SESN2 suppresses ferroptosis in polycystic ovary syndrome by maintaining PRDX6 K209 lactylation.
Li YY, Xu N, Gu XY … +3 more , Yu B, Luan YY, Yin CH
Free Radic Biol Med · 2026 Aug · PMID 41966311 · Publisher ↗
Polycystic ovary syndrome (PCOS) is a prevalent and heterogeneous endocrine-metabolic disorder affecting women of reproductive age, characterized by elevated androgen levels, disrupted ovulation, and polycystic ovarian c...
Polycystic ovary syndrome (PCOS) is a prevalent and heterogeneous endocrine-metabolic disorder affecting women of reproductive age, characterized by elevated androgen levels, disrupted ovulation, and polycystic ovarian changes. Increasing evidence indicates that oxidative stress and ferroptosis contribute to granulosa cell dysfunction and ovarian impairment in PCOS. In this study, we identified sestrin 2 (SESN2), a stress-inducible metabolic regulator, as a protective factor against ferroptosis in PCOS. Using both in vitro and in vivo PCOS models, we demonstrate that SESN2 deficiency aggravates oxidative stress and ferroptosis in ovarian granulosa cells. Mechanistically, loss of SESN2 reduced the overall lactylation level of peroxiredoxin 6 (PRDX6) and was associated with decreased lactylation at the K209 site, a modification important for PRDX6-mediated redox homeostasis. Quantitative co-immunoprecipitation showed that PRDX6 interacted with GPX4, and this interaction was markedly weakened by K209R mutation. Consistently, re-expression of wild-type PRDX6, but not the K209R mutant, substantially attenuated SESN2 deficiency-induced oxidative stress and ferroptotic injury. Overall, these findings indicate that SESN2 suppresses ferroptosis in PCOS at least partly by maintaining PRDX6 K209 lactylation, highlighting the SESN2-PRDX6 pathway as a potential therapeutic target for PCOS.
The oxidative stress-triggered activation of the PKC-Nrf2-G6PD pathway drives Benz(a)pyrene-induced endometrial stromal cell proliferation.
Jiao F, Ma M, Peng L … +9 more , Luo X, Tong M, Yi T, Long F, Gao R, Han F, He J, Xu H, Chen X
Free Radic Biol Med · 2026 Aug · PMID 41966034 · Publisher ↗
Benzo(a)pyrene (BaP), a ubiquitous environmental pollutant, exerts reproductive toxicity by disrupting endometrial decidualization, yet the underlying mechanisms remain unclear. This study aimed to dissect the molecular...
Benzo(a)pyrene (BaP), a ubiquitous environmental pollutant, exerts reproductive toxicity by disrupting endometrial decidualization, yet the underlying mechanisms remain unclear. This study aimed to dissect the molecular cascade linking BaP-induced oxidative stress to abnormal endometrial stromal cell (ESC) proliferation and decidualization injury. Pregnant mice were gavaged with 0.2 mg kg·day BaP from gestational Day 1 to 7, and primary ESCs were treated with BaP, HO, NAC and different inhibitor/agonist in vitro. BaP exposure reduced embryo implantation sites, induced asymmetric embryo distribution in bilateral uterine horns, and down-regulated decidualization markers (FOXO1, BMP2, HOXA10) in vivo and in vitro. Concurrently, BaP up-regulated proliferation markers (PHH3, PCNA, Ki67) and EdU incorporation in ESCs. Mechanistically, BaP induced uterine oxidative stress by down-regulating antioxidant enzymes (GPx4, CAT, SOD2) and accumulating intracellular ROS. HO recapitulated BaP-induced phenotypes, while NAC reversed these effects. BaP-induced oxidative stress activated the PKCα/KEAP1 pathway, promoting Nrf2 phosphorylation and nuclear translocation. Inhibition of PKCα by PKC-IN-6 alleviated BaP-induced Nrf2 activation. Activated Nrf2 up-regulated transketolase (TKT) and glucose-6-phosphate dehydrogenase (G6PD), key enzymes of the pentose phosphate pathway (PPP), to drive abnormal ESC proliferation. ML385 inhibited Nrf2 to rescued BaP-induced ESC hyperproliferation and decidualization injury, while SFN activated Nrf2 mimicked BaP's toxic effects. Collectively, BaP induces oxidative stress in early pregnancy uteri, sequentially activating the PKCα/KEAP1/Nrf2 pathway and G6PD and TKT, leading to ESC proliferation-differentiation imbalance and decidualization impairment. This study uncovers a novel oxidative stress-mediated mechanism of BaP reproductive toxicity, identifying Nrf2 and PPP enzymes as potential therapeutic targets for pollutant-related pregnancy disorders.
Reaction-yield detected magnetic resonance spectroscopy of radical pairs in cryptochrome-4a: a computational study.
Alvarez PH, Gerhards L, Solov'yov IA … +1 more , Hore PJ
Free Radic Biol Med · 2026 Aug · PMID 41962602 · Publisher ↗
RYDMR (reaction-yield detected magnetic resonance) is a spectroscopic technique used to study transient radical pairs by measuring changes in the yields of their reaction products induced by a weak oscillating magnetic f...
RYDMR (reaction-yield detected magnetic resonance) is a spectroscopic technique used to study transient radical pairs by measuring changes in the yields of their reaction products induced by a weak oscillating magnetic field in the presence of a static magnetic field. Here we report spin dynamics simulations that explore the experimental conditions required for an in vivo RYDMR study of radical pairs in the cryptochrome proteins thought to be the receptors in the magnetic compass sense of migratory songbirds. The main conclusions are as follows. (a) RYDMR signals at the Larmor resonance condition would provide strong support for a magnetoreception mechanism based on radical pair chemistry. (b) The signals should be stronger when the static and time-dependent fields are mutually perpendicular than when they are parallel. (c) Assuming one component of the pair is a flavin radical, the width of the RYDMR spectrum should depend on the direction of the static field with respect to the tricyclic flavin ring system. (d) The spectra could allow one to distinguish radical pairs in which a flavin radical is combined with either a tryptophanyl radical, a tyrosyl radical, or a radical with very weak hyperfine interactions. (e) For the clearest insights into the mechanism of magnetic sensing, the frequency of the oscillating field should exceed ∼100 MHz. (f) Harmonic signals and spin-locking effects may provide additional information on the nature of the magnetoreceptor.
Echinacoside improves antioxidant responses and angiogenesis through Parkin-MFN2-mediated mitophagy to promote diabetic wound healing.
Li Z, Li Z, Li Q … +11 more , Miao R, Ma Y, Wei S, Mao J, Wang X, Zeng X, Zhou Y, Ye J, Xia W, Lin C, Mao C
Free Radic Biol Med · 2026 Jul · PMID 41962601 · Publisher ↗
Due to complex immune and metabolic dysfunctions, diabetic wounds commonly suffer from infection, oxidative stress, impaired angiogenesis, thereby leading to chronic non-healing lesions. Since current therapies remain in...
Due to complex immune and metabolic dysfunctions, diabetic wounds commonly suffer from infection, oxidative stress, impaired angiogenesis, thereby leading to chronic non-healing lesions. Since current therapies remain insufficient, increasing attention has been directed toward mitophagy, a key regulator of energy balance and stress responses, with mitochondrial dysfunction recognized as a critical driver of defective repair. In this study, we explored the therapeutic role of echinacoside (Ech), a phenylethanol glycoside from Echinacea, known for its potent antioxidant, anti-inflammatory, and pro-angiogenic properties, in promoting diabetic wound healing. Network pharmacology analysis was employed to identify the potential targets of Ech in diabetic condition. In vitro, under HO-induced oxidative stress, Ech mitigated the functional impairment of human umbilical vein endothelial cells (HUVECs), enhancing their proliferation, migration, angiogenesis, and antioxidant capacity. Mechanistically, Ech restored HUVECs function by activating Parkin-MFN2-mediated mitophagy through ubiquitination and concurrently upregulated USP35 expression, which mitigated excessive mitophagy. These effects were confirmed using the Parkin-dependent mitophagy inhibitor cyclosporin A (CsA) and USP35-specific siRNA (siUSP35). In a diabetic mouse full-thickness cutaneous wound model, Ech treatment significantly activated Parkin-dependent mitophagy, leading to enhanced neovascularization and collagen deposition at wound site, thereby accelerated the healing process of diabetic wounds. Collectively, these findings identify Ech as a promising therapeutic agent for diabetic wound repair and provide mechanistic insights into its regulation of mitophagy to improve antioxidant responses and angiogenesis, offering a foundation for the development of targeted treatment strategies.
Amentoflavone mitigates UVB-induced epidermal photoaging by antagonizing PAR2-driven PI3K/Akt/FoxO6 oxidative-stress signaling.
Li L, Li Z, Xiao S … +4 more , Li A, Tian F, Shu P, Gu W
Free Radic Biol Med · 2026 Aug · PMID 41962600 · Publisher ↗
Escalating surface ultraviolet-B (UVB) radiation accelerates skin photoaging and underscores the need for safe, plant-derived photoprotectants. Amentoflavone (AF), the principal biflavonoid of the resurrection plant Sela...
Escalating surface ultraviolet-B (UVB) radiation accelerates skin photoaging and underscores the need for safe, plant-derived photoprotectants. Amentoflavone (AF), the principal biflavonoid of the resurrection plant Selaginella tamariscina, has recognized anti-photoaging activity, yet its epidermal mechanism remains undefined. This study utilized animal and cellular models to investigate the therapeutic potential of AF (0.1-0.2 mg g) against photoaging. AF restored skin hydration and elasticity, reduced melanin deposition, and reversed UVB-induced epidermal hyperplasia and collagen/elastic-fiber disorganisation. AF decreased ROS and MDA while normalizing SOD, CAT and GSH-Px activities. Docking (LibDockScore = 125.596) and microscale thermophoresis (MST) revealed high-affinity AF-PAR2 interaction. Treatment with AF reduced PAR2 and Gαq levels, curtailed activation of PI3K, phosphorylated Akt, and phosphorylated FoxO6, and restored FoxO6 nuclear localization, which in turn enhanced MnSOD and CAT expression. In addition, AF suppressed UVB-induced upregulation of senescence-associated markers p16, p21, and GLB1 in both rat skin and HaCaT cells. However, administration of the PAR2 agonist SLIGRL-NH negated these benefits in both cellular and animal models. These findings position AF as a promising natural agent for anti-photoaging dermotherapy and provide a mechanistic basis for S. tamariscina-based product development.
O-GlcNAc modification orchestrates HUWE1-mediated ubiquitination of TfR1 to regulate ferroptosis and trophoblast syncytialization in preeclampsia.
Zhang H, Li M, Zhang J … +9 more , Sun Q, Jin X, Liu R, Li X, Chen X, Wang A, Luo Z, Shang Y, Kong Y
Free Radic Biol Med · 2026 Aug · PMID 41962599 · Publisher ↗
Trophoblast stress may be one of the etiologies of the pathology of the placenta in preeclampsia (PE). During pregnancy, females experience a substantial increase in iron requirements. Paradoxically, excessive iron intak...
Trophoblast stress may be one of the etiologies of the pathology of the placenta in preeclampsia (PE). During pregnancy, females experience a substantial increase in iron requirements. Paradoxically, excessive iron intake or elevated iron levels can pose risks to pregnancy and contribute to reproductive disorders. Labile iron, owing to its oxidative and toxic properties, triggers cellular oxidative stress and initiates ferroptosis. O-GlcNAc modification has been linked to ferroptosis in recent studies. However, its involvement in the pathophysiology of PE remains elusive. Our research identified abnormal ferroptosis in preeclamptic placentas, and was accompanied by reduced O-GlcNAc modification levels. Increasing O-GlcNAc modification rescued trophoblast syncytialization defects and oxidative stress damage induced by iron overload or ferroptosis. Through O-GlcNAc modification proteomics, we screened and validated the E3 ubiquitin ligase HUWE1 as a pivotal factor in trophoblast ferroptosis and syncytialization. Mechanistically, O-GlcNAc modification stabilizes HUWE1, facilitating the ubiquitination-mediated degradation of its substrate, transferrin receptor1 (TfR1). This process reduces iron uptake by trophoblasts, thereby inhibiting ferroptosis during syncytialization. Moreover, elevated O-GlcNAcylation ameliorates iron overload-induced preeclamptic phenotypes and mitigates adverse pregnancy outcomes. These findings highlight the unique role of O-GlcNAcylated HUWE1 in regulating TfR1 ubiquitination and suggest that targeting this pathway may offer a novel therapeutic strategy for PE.
Computational-experimental integration reveals PPARγ/Nrf2-GPX4 dual-targeting by combined selenomethionine-magnolol as a novel therapy for sarcopenic obesity.
Li Z, Liu B, Zhou L … +6 more , Chen N, Wang Y, Yang S, Fan X, Wang Y, Chen X
Free Radic Biol Med · 2026 Aug · PMID 41956327 · Publisher ↗
Sarcopenic obesity (SO), characterized by concurrent muscle loss and excessive adiposity, lacks effective interventions. This study investigated the enhanced effects of the selenomethionine (Se-Met) and magnolol (Mag) co...
Sarcopenic obesity (SO), characterized by concurrent muscle loss and excessive adiposity, lacks effective interventions. This study investigated the enhanced effects of the selenomethionine (Se-Met) and magnolol (Mag) combination against SO using an integrated computational-experimental approach. Network pharmacology and molecular docking predicted peroxisome proliferator-activated receptor γ (PPARγ) and the nuclear factor erythroid 2-related factor 2 - glutathione peroxidase 4 (Nrf2 - GPX4) axis as core targets, which was corroborated by single-cell transcriptomic data analysis showing their co-expression in muscle progenitor cells. In high-fat diet (HFD)-fed mice, the combined Se-Met and Mag treatment ameliorated metabolic dysregulation, reduced intramuscular lipid deposition, and improved muscle function more effectively than monotherapies. In C2C12 myotubes, the combination co-activated PPARγ to enhance lipid clearance and potentiated the Nrf2-GPX4 antioxidant axis. Notably, it modulated ferroptosis-related signaling by downregulating acyl-CoA synthetase long-chain family member 4 (ACSL4) and upregulating ferritin heavy chain 1 (FTH1) and heme oxygenase-1 (HO-1), an effect abolished by Nrf2 inhibition. Pharmacological inhibition of either PPARγ or Nrf2 reversed the protective benefits. Our findings reveal that Se-Met and Mag in combination target PPARγ and Nrf2-GPX4 pathways while regulating ferroptosis-related signaling to alleviate ferroptosis-associated markers, with phenotypic characteristics consistent with ferroptosis inhibition, thereby offering a novel nutraceutical strategy for SO.
Corrigendum to "Ghrelin attenuates oxidative stress and neuronal apoptosis via GHSR-1α/AMPK/Sirt1/PGC-1α/UCP2 pathway in a rat model of neonatal HIE" [Free Radic. Biol. Med. 141 (2019) 322-337].
Huang J, Liu W, Doycheva DM … +4 more , Gamdzyk M, Lu W, Tang J, Zhang JH
Free Radic Biol Med · 2026 Aug · PMID 41951530 · Full text
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Corrigendum to "Pituitary adenylate cyclase-activating polypeptide attenuates mitochondria-mediated oxidative stress and neuronal apoptosis after subarachnoid hemorrhage in rats" [Free Radic. Biol. Med. 174 (2021) 236-248].
Fang Y, Shi H, Huang L … +12 more , Ren R, Lenahan C, Xiao J, Liu Y, Liu R, Sanghavi R, Li C, Chen S, Tang J, Yu J, Zhang JH, Zhang J
Free Radic Biol Med · 2026 Aug · PMID 41951529 · Full text
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Role of glutamine metabolism reprogramming in ferroptosis of lens epithelial cells under high-glucose conditions.
Jiang C, Xu Z, Lu Y … +1 more , Du L
Free Radic Biol Med · 2026 Jul · PMID 41951018 · Publisher ↗
The actual pathways through which glucose elevation fosters the growth of diabetic cataracts (DC) are poorly comprehended. This paper demonstrates the active role played by re-programming of glutamine metabolism in facil...
The actual pathways through which glucose elevation fosters the growth of diabetic cataracts (DC) are poorly comprehended. This paper demonstrates the active role played by re-programming of glutamine metabolism in facilitating ferroptosis in lens epithelial cells (LECs). Glutaminase 2 (GLS2) was found as a core in the bioinformatics analysis of diabetes and cataract -related datasets. In in-vitro tests, it was proven that high - glucose (HG) conditions trigger ferroptosis in LECs. The ferroptosis process shows features such as the loss of glutathione, over-accumulation of iron, lipid peroxidation, and mitochondrial impairment. From a mechanical point of view, HG was reported to aid in ferroptosis in LECs through a synergistic elevation of the metabolic pathway which contains glutamine transporter solute carrier family 1 member 5 (SLC1A5), GLS2, and glutamic-oxaloacetic transaminase 1 (GOT1). Genetic or pharmacological inhibition of SLC1A5, GLS2 or GOT1 was effective in preventing glutamine degradation, glutamate production and ferroptosis induced by the high-glucose-level. Connection between inhibitors and target proteins in molecular docking experiments was proven to be stable. This same metabolic response was also observed in diabetic rat lenses and showed both ferroptosis markers and epithelial destruction. This paper shows that the stimulation of ferroptosis in lens epithelial cells is triggered by high glucose through the mediation of glutamine catabolic pathway SLC1A5/GLS2/GOT1, establishing a new pathogenic pathway and a new therapeutic omission.
Mitochondria transplantation preserves retinal ganglion cells and promotes CNS axonal regeneration.
Ashok A, Cho KS, Tai WL … +8 more , Huang L, Kam HT, Chaudhary S, Chang K, Pooranawattanakul S, Chen J, Lennikov A, Chen DF
Free Radic Biol Med · 2026 Aug · PMID 41951017 · Full text
Mitochondrial dysfunction is a central driver of retinal ganglion cell (RGC) loss in glaucoma and other forms of optic neuropathies, leading to irreversible blindness. Here, we demonstrate that replenishing the mitochond...
Mitochondrial dysfunction is a central driver of retinal ganglion cell (RGC) loss in glaucoma and other forms of optic neuropathies, leading to irreversible blindness. Here, we demonstrate that replenishing the mitochondrial pool through exogenous mitochondrial transplantation ("mitotherapy") in adult mice not only preserves neuronal survival but also promotes regenerative competence in the central nervous system (CNS). In aging or injured RGCs, we identified profound deficits in mitochondrial biogenesis, fission-fusion balance, and mitophagy. Transplantation of functional mitochondria in in vitro models of trophic deprivation and glutamate excitotoxicity restored mitochondrial homeostasis, improved energy production, reduced reactive oxygen species, enhanced RGC survival, and drove robust neurite outgrowth, with transplanted mitochondria actively trafficking to growth cones. This effect was dampened following inhibition of mitochondrial fusion, indicating a pivotal role of fusion-dependent functional integration of exogenous mitochondria. Strikingly, intravitreal delivery of mitochondria in an optic nerve crush model of adult mice enabled their integration into RGCs, improved survival and electrophysiological responses, and supported axonal regeneration across the lesion site. These findings indicate that mitochondrial transplantation strategy rescues bioenergetic failure and supports a pro-regenerative activity of neurons, highlighting the potential of mitotherapy as a transformative approach for neurodegenerative eye diseases and CNS injuries.
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