Free Radical Biology and Medicine最新文献

{"title":"Integrative analyses of dicarbonyls and advanced glycation end-products with multiomic profiles across tissue, plasma and stool samples reveal methylglyoxal accumulation in colon cancer","authors":"Giulio Ferrero ,&nbsp;Raffaella Mastrocola ,&nbsp;Sonia Tarallo ,&nbsp;Barbara Pardini ,&nbsp;Jean Scheijen ,&nbsp;Marjo van de Waarenburg ,&nbsp;Gaetano Gallo ,&nbsp;Anastasia Chrysovalantou Chatziioannou ,&nbsp;Nivonirina Robinot ,&nbsp;Pekka Keski-Rahkonen ,&nbsp;Gianmarco Piccinno ,&nbsp;Nicola Segata ,&nbsp;Elom K. Aglago ,&nbsp;David J. Hughes ,&nbsp;Mazda Jenab ,&nbsp;Casper G. Schalkwijk ,&nbsp;Alessio Naccarati","doi":"10.1016/j.freeradbiomed.2026.01.034","DOIUrl":"10.1016/j.freeradbiomed.2026.01.034","url":null,"abstract":"<div><div>Advanced Glycation Endproducts (AGEs) arise from the reaction of proteins with highly reactive dicarbonyl compounds such as methylglyoxal (MGO), glyoxal (GO) and 3-deoxyglucosone (3-DG), which have been implicated in inflammation and carcinogenesis. How dicarbonyls and AGEs are distributed across tumor tissue and surrogate specimens, and how they relate to systemic metabolism, AGE-related pathways, and alterations in gut microbiota in colon cancer, remains poorly understood.</div><div>An integrative multi-specimen analysis of MGO, GO, 3-DG and major AGEs was performed using targeted tandem mass spectrometry in matched tumor tissue, adjacent normal mucosa, plasma, and stool from 26 sporadic colon cancer patients. These measurements were combined with tumor RNA-sequencing, untargeted plasma metabolomics, and stool shotgun metagenomics generated from the same individuals.</div><div>A marked accumulation of MGO was observed in tumor tissue when compared with adjacent mucosa, accompanied by higher levels of the MGO-derived AGE Nδ-[5-hydro-5-methyl-4-imidazolon-2-yl]-ornithine (MG-H1). Tissue MG-H1 concentrations significantly correlated with corresponding plasma levels. Elevated tumor MGO levels were associated with up-regulation of <em>GLO1</em> (encoding for the detoxifying enzyme glyoxalase-1), <em>DDOST</em> (coding for the AGE-clearance receptor AGE-R1), and the glycolytic flux marker triose phosphate isomerase (TPI), alongside down-regulation of the AGE-scavenger receptor CD36. These findings suggest a candidate remodeling of dicarbonyl-handling pathways. The MGO/GO ratio in tumors was positively associated with the relative abundances of <em>Fusobacterium nucleatum</em> and <em>Parvimonas micra</em>, two bacterial species related to colorectal carcinogenesis, and with metagenomic signatures of oral-derived taxa colonizing the gut.</div><div>This pilot integrative analysis highlighted novel coherent associations among tissue, circulating, and stool levels of MGO-derived AGEs, the expression of AGE-related metabolic pathways, and microbial signatures in colon cancer. If confirmed in larger studies, these candidate molecular and microbial interactions may provide novel insights into the dicarbonyl stress involvement in tumor biology.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 518-530"},"PeriodicalIF":8.2,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146043942","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BMAL1 downregulation exacerbates age-related nonalcoholic steatohepatitis by promoting NLRP3 inflammasome activation via HIF-1ɑ-mediated glycolysis","authors":"Yujie Ren ,&nbsp;Dongying Lv ,&nbsp;Jiayan Chen ,&nbsp;Wenjing Chen ,&nbsp;Chu Chen ,&nbsp;Lizong Zhang ,&nbsp;Jue Tu ,&nbsp;Keyan Zhu ,&nbsp;Dejun Wang ,&nbsp;Zhaowei Cai","doi":"10.1016/j.freeradbiomed.2026.01.058","DOIUrl":"10.1016/j.freeradbiomed.2026.01.058","url":null,"abstract":"<div><h3>Introduction</h3><div>Epidemiological studies have demonstrated higher incidence and mortality rate of nonalcoholic steatohepatitis (NASH) in the elderly population than in younger groups. However, the mechanisms underlying this age-related exacerbation remain poorly understood.</div></div><div><h3>Objective</h3><div>This study aimed to elucidate the specific pathways through which aging exacerbates NASH progression, using an integrated <em>in vivo</em> and <em>in vitro</em> model.</div></div><div><h3>Methods</h3><div>Aged (18-month-old) and young (6-week-old) mice were fed a high-fat diet (HFD) for 16 weeks to induce NASH. A senescence-associated cellular model of NASH was established by co-treating murine hepatocyte AML-12 with H₂O₂ and free fatty acid (FFA). Gene expression profiling of liver tissue was performed using RNA sequencing to identify molecular signatures. Interventions were as follows: (1) <em>In vitro</em>, BMAL1 overexpression plasmids were transfected into AML-12 cells, followed by treatment with 2-deoxy-D-glucose (2-DG, a glycolysis inhibitor) and 2-methoxyestradiol (2-ME2, a HIF-1α inhibitor); (2) <em>in vivo</em>, hepatocyte-specific BMAL1 overexpression was achieved in aged HFD-fed mice through adeno-associated virus serotype 8 (AAV8) delivery. Mechanism validation was performed using biochemical assays, Western blot, cell staining, molecular docking, and Co-IP.</div></div><div><h3>Results</h3><div>Aged HFD-fed mice exhibited more severe NASH phenotypes than young mice. Transcriptomic analysis identified NLRP3-related signaling and circadian rhythm pathways as central contributors to age-specific NASH pathogenesis. These mice also exhibited elevated NLRP3 inflammasome activity, enhanced glycolysis, and reduced BMAL1 expression. In senescent NASH cells, BMAL1 overexpression along with 2-DG or 2-ME2 treatment significantly downregulated NLRP3 expression and attenuated lipid accumulation, inflammation, oxidative stress, and fibrosis. Mechanistically, BMAL1 directly bound to HIF-1α, thereby suppressing glycolysis. Hepatocyte-specific BMAL1 overexpression in aged HFD-fed mice markedly inhibited glycolysis and NLRP3 activation, resulting in an improvement in NASH-related pathologies.</div></div><div><h3>Conclusion</h3><div>This study revealed a novel mechanism in which BMAL1 downregulation under aging and HFD conditions promotes NASH progression by binding to HIF-1α and modulating the glycolysis-NLRP3 inflammasome axis.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 562-579"},"PeriodicalIF":8.2,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146100151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic traits and diet triggering the iron-induced hepatic model of the idiopathic disorder sporadic porphyria cutanea tarda","authors":"Susan Robinson ,&nbsp;Reginald Davies ,&nbsp;Viktoria Vagany ,&nbsp;Timothy W. Gant ,&nbsp;Andrew G. Smith","doi":"10.1016/j.freeradbiomed.2025.12.049","DOIUrl":"10.1016/j.freeradbiomed.2025.12.049","url":null,"abstract":"<div><div>Metabolic disorders can be the consequence of external factors and individual susceptibility. Sporadic porphyria cutanea tarda (sPCT) is an idiopathic disorder of liver heme synthesis exhibiting inhibition of uroporphyrinogen decarboxylase, characterised by dermal and hepatic deposition of uroporphyrins from oxidation of sensitive uroporphyrinogens (uroporphyria). sPCT is associated with alcohol, estrogenic drugs, HIV and hepatitis C, as well as a poorly understood influence of iron. Hexachlorobenzene (HCB) and reputably 2,3,7,8-tetrachlorodibenzo-<em>p</em>-dioxin (TCDD) cause a similar disorder. The hepatic aspects modelled in susceptible rodents in response to HCB and TCDD are potentiated by iron. Importantly, iron overload alone eventually causes hepatic uroporphyria in genetically susceptible mice. To determine whether this genetic susceptibility to iron toxicity is the consequence of a single genetic variant or is multigenic, a low power F2 intercross cross from sensitive SWR and resistant DBA/2 strains was used to detect chromosomal quantitative trait loci (QTL) associated with uroporphyria development enhanced by the heme precursor 5-aminolevulinic acid (5-ALA). Multiple QTL contributed to the development of uroporphyria. Differential gene expressions comparing mice of parent strains and the F2 extremes of resistance and susceptibility suggested possible contributions associated with QTL. Positions of QTL and the confidence regions were compared with those observed previously for uroporphyria induced more rapidly by TCDD in iron-loaded mice and showed overlapping but not identical loci. A difference in uroporphyric response to iron loading occurred with another sensitive strain, C57BL/10ScSn, whether maintained on one of two well-defined, but similar, same source commercial diets. Uroporphyria developed with a nutritionally enhanced diet rather than a lean maintenance diet. One common observation with uroporphyria was decreased expression of <em>Glul</em> for glutamine synthetase. The findings illustrate the interaction of polygenic factors, external factors and diet in models of idiopathic human disorders such as sPCT.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 126-139"},"PeriodicalIF":8.2,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145976042","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Distinct quaternary reaction behavior and stable charge-transfer complex formation in Schistosoma mansoni sulfide:quinone oxidoreductase","authors":"Augustin Tshibaka Kabongo ,&nbsp;Talaam Keith Kiplangat ,&nbsp;Yuki Tayama ,&nbsp;Acharjee Rajib ,&nbsp;Yuichi Matsuo ,&nbsp;Linh Manh Ha ,&nbsp;Samandram Sushilkumar Singh ,&nbsp;Tetsuo Yamashita ,&nbsp;Euki Yazaki ,&nbsp;Endah Dwi Hartuti ,&nbsp;Tetsuro Matsunaga ,&nbsp;Tomoaki Ida ,&nbsp;Tomoyoshi Nozaki ,&nbsp;Takaaki Akaike ,&nbsp;Tomoo Shiba ,&nbsp;Jun-Ichi Kishikawa ,&nbsp;Shinjiro Hamano ,&nbsp;Kiyoshi Kita ,&nbsp;Daniel Ken Inaoka","doi":"10.1016/j.freeradbiomed.2026.01.063","DOIUrl":"10.1016/j.freeradbiomed.2026.01.063","url":null,"abstract":"<div><div>Adults of <em>Schistosoma mansoni</em> reside in the mesenteric veins, where they are naturally exposed to high levels of hydrogen sulfide (H₂S). <em>S. mansoni</em> and other intestinal parasites have adapted to this sulfide-rich environment, but the evolved mechanisms to metabolize sulfide remain unelucidated. Here we reveal that the putative sulfide:quinone oxidoreductase (SQOR) encoded by <em>S. mansoni</em> is indeed an SQOR, catalyzing the first step of sulfide metabolism. We demonstrated that <em>S. mansoni</em> SQOR (SmSQOR) is expressed in eggs, cercaria and adult stages and localized in the mitochondria. The reaction catalyzed by SmSQOR was investigated using sulfane sulfur probe 4 (SSP4) and shown to require the co-presence of sulfide, quinone, and a sulfur acceptor, indicating a quaternary complex-mediated mechanism. Unlike human and bacterial SQORs, purified SmSQOR could not reduce quinones in the presence of sulfide alone unless sulfite, cyanide, or L-cysteine (but not coenzyme A or glutathione) was provided as the sulfur acceptor. In the presence of these sulfur acceptors, SmSQOR formed a long-lived charge-transfer (CT) complex, a transient electronically coupled association between electron donor and acceptor, as indicated by a broad band around 637–755 nm in the spectrum, which was associated with a partial loss of enzyme activity. Moreover, residues critical for CT complex formation and SQOR catalysis were identified. Using SSP4, we also demonstrated that SQOR was active in <em>S. mansoni</em> adult, egg, and cercaria stages. Taken together, these features suggest that metabolism of sulfide proceeds differently in <em>S. mansoni</em> than in humans.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 646-659"},"PeriodicalIF":8.2,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146118380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The interplay between the thioredoxin system and hypoxia-related factors in cancer.","authors":"Isabella Bramatti, Vasco Branco, Cristina Carvalho","doi":"10.1016/j.freeradbiomed.2026.03.040","DOIUrl":"10.1016/j.freeradbiomed.2026.03.040","url":null,"abstract":"<p><p>Hypoxia constitutes a common feature of tumor microenvironments, orchestrating cancer progression across various malignancies. Cancer growth and resistance to therapy are frequently associated with overexpression of antioxidant systems, such as the thioredoxin (Trx) system. This system is fundamental for cell survival and proliferation, playing a key role in maintaining redox homeostasis and regulating hypoxia-inducible factor-1alpha (HIF-1α) activity. This, in turn, regulates different genes involved in tumor progression, such as the vascular endothelial growth factor (VEGF), an indispensable factor for tumor invasiveness and microenvironment tumor maintenance. HIF-1α can also be regulated by the signal transducer and activator of transcription 3 (STAT3), an oncogene stimulated by pro-inflammatory cytokines and growth factors. Targeting antioxidant systems, such as the Trx system, is an emerging strategy in cancer therapy, as tumor cells are more vulnerable to disruptions in redox homeostasis than normal cells. Even though there are some studies correlating the use of Trx inhibitors and the inhibition of hypoxia-related factors, the diverse pathways in which this occurs are still elusive. Therefore, in this review, we explore the multiple pathways through which the Trx system influences HIF-1α and highlight drugs that have been studied targeting hypoxia-related factors by inhibiting the Trx system. Given the link between oxidative stress and apoptosis in cancer cells, and the low overall survival rates for many cancers despite new therapies, understanding the Trx system's connection to hypoxia-related pathways could be crucial for advancing therapeutic approaches and tackling therapy resistance.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":"563-576"},"PeriodicalIF":8.2,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147480202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Non-surgical periodontal treatment improves mitochondrial bioenergetics in circulating immune cells of patients with chronic periodontitis","authors":"Jonathan Hermenejildo ,&nbsp;María Pelechá-Salvador ,&nbsp;Meylin Fernández-Reyes ,&nbsp;Laura Perea-Galera ,&nbsp;Jordi Mota-Plaza ,&nbsp;Javier Silvestre-Rangil ,&nbsp;Celia Bañuls ,&nbsp;Carlos Morillas ,&nbsp;Francisco Javier Silvestre ,&nbsp;Víctor M. Víctor ,&nbsp;Sandra López-Domènech ,&nbsp;Milagros Rocha","doi":"10.1016/j.freeradbiomed.2026.01.010","DOIUrl":"10.1016/j.freeradbiomed.2026.01.010","url":null,"abstract":"<div><h3>Introduction</h3><div>Chronic periodontitis (CP) is an inflammatory disease associated with local and systemic oxidative stress and leads to mitochondrial homeostasis disruption. Although non-surgical periodontal therapy (NSPT) has been proved to reduce the bacterial load and inflammation, the mechanisms underlying its effects on mitochondrial function and systemic redox balance remain poorly understood.</div></div><div><h3>Methods</h3><div>Eighty patients with CP underwent NSPT. Clinical, anthropometric, and biochemical parameters were evaluated at baseline and 12 weeks after therapy. Mitochondrial redox status, membrane potential, markers of mitochondrial biogenic signalling (PGC-1α), electron transport chain (ETC) complexes, and bioenergetic function were assessed in peripheral blood mononuclear cells (PBMCs). Correlation and multivariable analyses were performed to explore relationships between periodontal improvement and mitochondrial parameters.</div></div><div><h3>Results</h3><div>After NSPT, patients presented significant reductions in mitochondrial ROS and increased GPX1 expression. PBMCs also showed elevated PGC-1α and ETC I–IV protein levels, together with enhanced mitochondrial membrane potential, mass, and spare respiratory capacity. Baseline mitochondrial parameters were associated with the percentage of reduction of periodontal clinical parameters following NSPT.</div></div><div><h3>Conclusions</h3><div>NSPT not only ameliorates local periodontal inflammation but also modulates mitochondrial-related homeostasis and bioenergetic efficiency in circulating immune cells. The present findings support mitochondrial remodelling as a systemic mechanism underlying the benefits of periodontal therapy and a promising target for the treatment of inflammation-related comorbidities.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 159-168"},"PeriodicalIF":8.2,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145948772","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ketogenic diet improves cognitive impairment in rats with temporal lobe epilepsy by activating the Nrf2/HO-1/GPX4 signaling axis to inhibit ferroptosis","authors":"Lin Yang ,&nbsp;Jinlian Wang ,&nbsp;Xuhui Wang ,&nbsp;Bianli Li ,&nbsp;Di Zhao ,&nbsp;Chunyi Li ,&nbsp;Changzhi Li ,&nbsp;Yuanbing Cui ,&nbsp;Qiuyuan Chen ,&nbsp;Yong Yang ,&nbsp;Jinhai Gu ,&nbsp;Shaozhang Hou ,&nbsp;Lianxiang Zhang ,&nbsp;Yuanyuan Qiang","doi":"10.1016/j.freeradbiomed.2026.01.022","DOIUrl":"10.1016/j.freeradbiomed.2026.01.022","url":null,"abstract":"<div><div>A ketogenic diet (KD) has demonstrated significant therapeutic efficacy in drug-resistant epilepsy. The molecular mechanisms through which KDs exert therapeutic effects on temporal lobe epilepsy (TLE) are not yet fully understood. Recent studies suggest that ferroptosis, a cell death pathway driven by iron-dependent lipid peroxidation, plays a role in the pathophysiological progression of epilepsy. This research revealed that lithium-pilocarpine (LI-PILO)-induced status epilepticus in TLE models triggered pronounced ferroptosis in the rat hippocampus and that KDs inhibited neuronal ferroptosis in the hippocampus, as evidenced by elevated levels of the antioxidant factors, glutathione (GSH) and catalase (CAT), and decreased levels of 4-HNE, Fe²⁺ and the lipid peroxidation product malondialdehyde (MDA). We also observed ferroptosis-related mitochondrial abnormalities, including reduced mitochondrial volume, disrupted cristae, and the outright disappearance of cristae, in the epilepsy model group. These morphological alterations were markedly attenuated following KD intervention. Furthermore, KDs alleviated both neuronal loss and cognitive impairment in TLE rats. However, the neuroprotective effects of KDs were completely abolished by the ferroptosis inducer erastin. In addition, treatment with the ferroptosis inhibitor ferrostatin-1 (Fer-1) not only reduced hippocampal neuronal damage, as confirmed by Nissl staining and immunofluorescence but also improved cognitive performance in TLE rats, as evidenced by better outcomes in the Morris water maze and novel object recognition tests. With respect to the underlying mechanism, multiomics analysis revealed that KDs alter circulating metabolite profiles. Notably, we revealed that deoxycholyl-L-dopa may be a key metabolite for targeting Keap1, xCT and HO-1. Western blot and qPCR results revealed that KDs activated the Nrf2/HO-1/GPX4 signaling axis and upregulated the expressions of Nrf2, HO-1, FTH1, xCT and GPX4. Our findings identify ferroptosis inhibition as a mechanism underlying the efficacy of KDs in epilepsy.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 223-238"},"PeriodicalIF":8.2,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146024670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NRF2 at the crossroads of Parkinson’s disease and aging: Mechanistic insights and translational perspectives","authors":"A.J. García-Yagüe ,&nbsp;N Esteras ,&nbsp;A.T. Dinkova-Kostova ,&nbsp;A.I. Rojo ,&nbsp;P.G. Shiels ,&nbsp;A Dinnyes ,&nbsp;V Tamas ,&nbsp;H. van Goor ,&nbsp;I. Lastres-Becker","doi":"10.1016/j.freeradbiomed.2026.01.023","DOIUrl":"10.1016/j.freeradbiomed.2026.01.023","url":null,"abstract":"<div><div>Parkinson's disease (PD) is a multifactorial neurodegenerative disorder characterized by dopaminergic neuronal loss, α-SYNUCLEIN aggregation, mitochondrial dysfunction, oxidative stress, and neuroinflammation. The transcription factor NRF2 (nuclear factor erythroid 2–related factor 2) orchestrates cellular defense mechanisms by controlling genes involved in antioxidant responses, detoxification, and proteostasis. Impaired NRF2 signaling in PD amplifies oxidative damage, protein misfolding, and inflammatory cascades, whereas NRF2 activation confers broad neuroprotection. This review summarizes evidence from cellular, animal, and human studies delineating NRF2 regulatory roles in redox homeostasis, mitochondrial integrity, and microglial activation. In preclinical models, NRF2 deficiency accelerates neurodegeneration, while pharmacological activation with agents such as dimethyl fumarate, sulforaphane, and synthetic triterpenoids mitigates dopaminergic loss and neuroinflammation. Human studies reveal altered NRF2 pathway components in PD brain and peripheral tissues, and genetic variants in <em>NFE2L2</em> influence disease susceptibility and progression. Aging, PD's strongest risk factor, reduces NRF2 responsiveness through epigenetic and post-translational changes, promoting oxidative vulnerability and inflammaging. Environmental exposures, including pesticides and pollutants, further modulate NRF2 activity, compounding risk via cumulative “exposome” effects. Understanding NRF2 regulation provides mechanistic insight into PD pathogenesis and positions NRF2 activation as a promising therapeutic strategy for disease modification and healthy brain aging.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 760-779"},"PeriodicalIF":8.2,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145988977","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insulin-like growth factor 2 mRNA-binding Protein 2 regulates PINK1 expression through m6A pathway to promote mitophagy in BMSCs alleviating postmenopausal osteoporosis","authors":"Yu Ji ,&nbsp;Yajun Cui ,&nbsp;Lingshuang Li ,&nbsp;Tianyu Cao ,&nbsp;Hongrui Liu ,&nbsp;Minqi Li","doi":"10.1016/j.freeradbiomed.2026.01.038","DOIUrl":"10.1016/j.freeradbiomed.2026.01.038","url":null,"abstract":"<div><div>The senescence and altered differentiation potential of bone marrow mesenchymal stem cells (BMSCs) contribute to the pathogenesis of postmenopausal osteoporosis (PMOP). Insulin-like growth factor 2 mRNA-binding protein 2 (IMP2) has been demonstrated to regulate BMSCs. However, its specific mechanistic actions remain unclear, particularly due to the lack of concrete evidence within the ovariectomy (OVX) <em>in vivo</em> microenvironment. In this study, we utilized Cre-LoxP technology to achieve BMSC-specific IMP2 knockout. This approach conclusively demonstrated <em>in vivo</em> that IMP2 deficiency induces BMSC senescence, suppresses osteogenic differentiation capacity, and leads to significant bone mass reduction in mice. Under OVX condition, IMP2 knockout also aggravates bone loss. Mechanistically, we argued that IMP2 stabilizes PINK1 mRNA via the N6-methyladenosine (m⁶A) pathway; upon IMP2 silencing, reduced PINK1 protein expression attenuates mitophagy in BMSCs, ultimately culminating in accelerated cellular senescence and diminished osteogenic potential, with the postmenopausal environment further aggravating this cascade.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 400-414"},"PeriodicalIF":8.2,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146046486","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HIF-1α translation mediated by PKCδ facilitates RSV-induced production of innate inflammatory cytokines in vitro and in vivo","authors":"Lifeng Chen ,&nbsp;Jiayi Chen ,&nbsp;Chuyi Liao ,&nbsp;Bin Chen ,&nbsp;Jiahua Zou ,&nbsp;Yujun Tang ,&nbsp;Si Xiong ,&nbsp;Zhong Liu ,&nbsp;Manmei Li","doi":"10.1016/j.freeradbiomed.2026.01.049","DOIUrl":"10.1016/j.freeradbiomed.2026.01.049","url":null,"abstract":"<div><div>A cytokine storm caused by respiratory syncytial virus (RSV) significantly influences the progression of pneumonia and bronchiolitis. It is essential to comprehend the underlying mechanism of the RSV-triggered cytokine storm to effectively manage RSV. Hypoxia-inducible factor-1 Alpha (HIF-1α) plays a pivotal role in innate immunity. It is known that RSV enhances HIF-1α expression, but the molecular mechanism of RSV-induced HIF-1α expression and its role in the production of innate inflammatory cytokines during RSV infection are not fully understood. Our research demonstrates that RSV infection increases HIF-1α expression both <em>in vitro</em> and <em>in vivo</em>. Further investigation into the mechanism of RSV-induced HIF-1α expression indicates that PKCδ regulates RSV-induced HIF-1α translation through the PI3K/Akt/mTOR signaling pathway. Additionally, HIF-1α expression, mediated by PKCδ/PI3K/Akt/mTOR signaling, stimulates the production of innate inflammatory cytokines by activating the NLRP3-inflammasome during RSV infection. Inhibition of HIF-1α or PKCδ markedly suppresses RSV-induced inflammation <em>in vitro</em> and <em>in vivo</em>. In summary, these findings elucidate the molecular mechanism of RSV-induced HIF-1α expression and identify HIF-1α as a novel target for anti-RSV drug development.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 614-626"},"PeriodicalIF":8.2,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146085127","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}