Pub Date : 2026-01-19DOI: 10.1016/j.redox.2026.104043
Jing Tong , Tao Han , Jun Deng , Yu Gan , Ruiwen Ruan , Wei Zhao , Chen Xiong , Quan Liao , Shiqi Chen , Huitong Bu , Jianping Xiong , Xiang Zhou , Qian Hao
In colorectal cancer (CRC), p53 can either suppress or potentiate tumor sensitivity to ferroptosis under oxidative stress conditions. However, it remains to be elucidated how p53 differentially regulates ferroptosis, and whether it can initiate ferroptosis. Our findings reveal that p53 induces ferroptosis in the presence of abundant polyunsaturated fatty acids (PUFAs). FBXO2, which is encoded by a p53-inducible target gene, interacts with FABP5 and promotes the lysosomal degradation of FABP5 through chaperone-mediated autophagy. This results in a decrease in the levels of PUFAs, thereby increasing resistance to ferroptosis in CRC. Notably, the supplementation of arachidonic acid not only reverses p53-mediated ferroptosis resistance, but also coordinates with p53 to initiate ferroptosis independently of additional oxidative stress, effectively suppressing the growth of CRC cells both in vitro and in vivo. Altogether, our study uncovers that the availability of PUFAs is crucial for p53 to exert a pro-ferroptotic function in CRC.
{"title":"p53 and fatty acids collaborate to trigger ferroptosis via the FBXO2-FABP5 axis in colorectal cancer","authors":"Jing Tong , Tao Han , Jun Deng , Yu Gan , Ruiwen Ruan , Wei Zhao , Chen Xiong , Quan Liao , Shiqi Chen , Huitong Bu , Jianping Xiong , Xiang Zhou , Qian Hao","doi":"10.1016/j.redox.2026.104043","DOIUrl":"10.1016/j.redox.2026.104043","url":null,"abstract":"<div><div>In colorectal cancer (CRC), p53 can either suppress or potentiate tumor sensitivity to ferroptosis under oxidative stress conditions. However, it remains to be elucidated how p53 differentially regulates ferroptosis, and whether it can initiate ferroptosis. Our findings reveal that p53 induces ferroptosis in the presence of abundant polyunsaturated fatty acids (PUFAs). FBXO2, which is encoded by a p53-inducible target gene, interacts with FABP5 and promotes the lysosomal degradation of FABP5 through chaperone-mediated autophagy. This results in a decrease in the levels of PUFAs, thereby increasing resistance to ferroptosis in CRC. Notably, the supplementation of arachidonic acid not only reverses p53-mediated ferroptosis resistance, but also coordinates with p53 to initiate ferroptosis independently of additional oxidative stress, effectively suppressing the growth of CRC cells both in vitro and in vivo. Altogether, our study uncovers that the availability of PUFAs is crucial for p53 to exert a pro-ferroptotic function in CRC.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"90 ","pages":"Article 104043"},"PeriodicalIF":11.9,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146000847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-17DOI: 10.1016/j.redox.2026.104029
Wenqi Cui , Tianlu Wang , Juan Feng
Parkinson's disease (PD), characterized by dopaminergic neuron loss, still lacks disease-modifying therapies due to incompletely understood mechanisms. Guanylate-binding proteins (GBPs) are well-known immune regulators, but their roles in PD are largely unknown. In this study, we identify GBP2 as a critical driver of PD pathogenesis by impairing mitophagy. We found that GBP2 was significantly upregulated in the substantia nigra of PD patients, and in both MPTP-induced and A53T transgenic mouse models, as well as in MPP+-treated or A53T α-synuclein-overexpressing SH-SY5Y cells. Both in vivo and in vitro, genetic knockdown of GBP2 robustly alleviated the MPTP/MPP+-induced motor deficits, dopaminergic neuron loss, and apoptosis. Mechanistically, PD-related stress promotes GBP2 geranylgeranylation, driving its mitochondrial accumulation. At mitochondria, GBP2 directly binds the mitophagy receptor NIX via its large GTPase domain and targets it for ubiquitin-proteasomal degradation, thereby suppressing NIX-mediated mitophagy. Accordingly, GBP2 knockdown enhanced mitophagy, improved mitochondrial homeostasis, and protected against neuronal apoptosis. The neuroprotective effects of GBP2 knockdown were abolished by either pharmacological inhibition of mitophagy or genetic knockdown of NIX, indicating a linear pathway. Importantly, therapeutically targeting geranylgeranylation with GGTI298 significantly attenuated MPTP-induced neurotoxicity. Our study unveils a novel, druggable axis in PD pathogenesis where GBP2 disrupts mitochondrial quality control. Targeting GBP2 geranylgeranylation with GGTI298 presents a promising therapeutic strategy.
{"title":"Upregulated GBP2 exacerbates Parkinson's disease pathogenesis by impairing NIX-dependent mitophagy","authors":"Wenqi Cui , Tianlu Wang , Juan Feng","doi":"10.1016/j.redox.2026.104029","DOIUrl":"10.1016/j.redox.2026.104029","url":null,"abstract":"<div><div>Parkinson's disease (PD), characterized by dopaminergic neuron loss, still lacks disease-modifying therapies due to incompletely understood mechanisms. Guanylate-binding proteins (GBPs) are well-known immune regulators, but their roles in PD are largely unknown. In this study, we identify GBP2 as a critical driver of PD pathogenesis by impairing mitophagy. We found that GBP2 was significantly upregulated in the substantia nigra of PD patients, and in both MPTP-induced and A53T transgenic mouse models, as well as in MPP<sup>+</sup>-treated or A53T α-synuclein-overexpressing SH-SY5Y cells. Both in vivo and in vitro, genetic knockdown of GBP2 robustly alleviated the MPTP/MPP<sup>+</sup>-induced motor deficits, dopaminergic neuron loss, and apoptosis. Mechanistically, PD-related stress promotes GBP2 geranylgeranylation, driving its mitochondrial accumulation. At mitochondria, GBP2 directly binds the mitophagy receptor NIX via its large GTPase domain and targets it for ubiquitin-proteasomal degradation, thereby suppressing NIX-mediated mitophagy. Accordingly, GBP2 knockdown enhanced mitophagy, improved mitochondrial homeostasis, and protected against neuronal apoptosis. The neuroprotective effects of GBP2 knockdown were abolished by either pharmacological inhibition of mitophagy or genetic knockdown of NIX, indicating a linear pathway. Importantly, therapeutically targeting geranylgeranylation with GGTI298 significantly attenuated MPTP-induced neurotoxicity. Our study unveils a novel, druggable axis in PD pathogenesis where GBP2 disrupts mitochondrial quality control. Targeting GBP2 geranylgeranylation with GGTI298 presents a promising therapeutic strategy.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"90 ","pages":"Article 104029"},"PeriodicalIF":11.9,"publicationDate":"2026-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145995153","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-17DOI: 10.1016/j.redox.2026.104035
Jianxiong Han , Zhongkang Yan , Zhiran Sun , Wenyuan Dang , Bao Li , Shuangshuang Li , Xinru Lv , Lin Ni , Anyuan He , Pengying Gu , Feifei Wang , Lili Wang , Xingyuan Yang
Hepatic fibrosis is a major driver of mortality in metabolic dysfunction-associated steatotic liver disease (MASLD)—previously known as non-alcoholic fatty liver disease (NAFLD). While hepatic stellate cell (HSC) activation and myofibroblast accumulation are central to fibrogenesis, the regulatory mechanisms remain incompletely understood. Acetyl-CoA acyltransferase 2 (ACAA2), a pivotal enzyme in fatty acid oxidation, has been implicated in lipid metabolism but has not been investigated as a therapeutic target in MASLD. Here, we show that ACAA2 upregulation in HSCs exacerbates hepatic fibrosis by promoting ferroptosis-associated transcriptional programs, whereas ACAA2 inhibition attenuates both ferroptosis and fibrogenesis in preclinical models. Mechanistically, ACAA2 palmitoylation governs its subcellular localization and function, and blocking this modification suppresses HSC activation via AMPK pathway stimulation, thereby mitigating fibrosis. Our study establishes ACAA2 palmitoylation as a druggable node for antifibrotic therapy, offering novel insights into metabolic regulation of hepatic fibrosis.
{"title":"Acetyl-CoA acyltransferase 2 palmitoylation drives liver fibrosis by inducing hepatic stellate cell ferroptosis","authors":"Jianxiong Han , Zhongkang Yan , Zhiran Sun , Wenyuan Dang , Bao Li , Shuangshuang Li , Xinru Lv , Lin Ni , Anyuan He , Pengying Gu , Feifei Wang , Lili Wang , Xingyuan Yang","doi":"10.1016/j.redox.2026.104035","DOIUrl":"10.1016/j.redox.2026.104035","url":null,"abstract":"<div><div>Hepatic fibrosis is a major driver of mortality in metabolic dysfunction-associated steatotic liver disease (MASLD)—previously known as non-alcoholic fatty liver disease (NAFLD). While hepatic stellate cell (HSC) activation and myofibroblast accumulation are central to fibrogenesis, the regulatory mechanisms remain incompletely understood. Acetyl-CoA acyltransferase 2 (ACAA2), a pivotal enzyme in fatty acid oxidation, has been implicated in lipid metabolism but has not been investigated as a therapeutic target in MASLD. Here, we show that ACAA2 upregulation in HSCs exacerbates hepatic fibrosis by promoting ferroptosis-associated transcriptional programs, whereas ACAA2 inhibition attenuates both ferroptosis and fibrogenesis in preclinical models. Mechanistically, ACAA2 palmitoylation governs its subcellular localization and function, and blocking this modification suppresses HSC activation via AMPK pathway stimulation, thereby mitigating fibrosis. Our study establishes ACAA2 palmitoylation as a druggable node for antifibrotic therapy, offering novel insights into metabolic regulation of hepatic fibrosis.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"90 ","pages":"Article 104035"},"PeriodicalIF":11.9,"publicationDate":"2026-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145995154","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Transfer RNA-derived small RNAs (tDRs) are emerging regulators of cellular stress response, yet their biogenesis and activities during mitochondrial dysfunction remain poorly understood. Here we profiled tDRs generated in HEK293T cells exposed to inhibitors of respiratory complexes I–V (rotenone, TTFA, antimycin A, KCN, oligomycin) or to arsenite and assessed the impact of CRISPR-mediated angiogenin (ANG) knockout, ANG over-expression and recombinant ANG supplementation on the stress response and tDRs production. tDR-seq revealed stress-specific, highly ordered tDR repertoires: rotenone and antimycin predominantly induced internal (i-tRF) and 3ʹ tRNA (tRF3) fragments, whereas arsenite induced anticodon-cleaved tRNA halves (tiRNAs). mito-tDRs were mostly internal fragments and antimycin induced the strongest mitochondrial tDRs expression. ANG deletion markedly impaired stress-induced tDR biogenesis and sensitized cells to antimycin and oligomycin stress, whereas its overexpression selectively enhanced tDR biogenesis and conferred protection against these mitochondrial stressor. Synthetic tDR mimics failed to rescue viability, implying that native modification patterns or cooperative tDR pools are required. tDR motif enrichment analysis identified YBX1-binding sites among antimycin-induced tDRs, and genetic perturbation of YBX1 phenocopied aspects of enhanced mitochondrial bioenergetics and stress resistance. Together, these findings demonstrate that context-specific, ANG-directed tDR biogenesis forms a crucial arm of the mitochondrial stress response.
{"title":"Context-specific Angiogenin-mediated tRNA fragments (tDRs) biogenesis shapes the mitochondrial stress response","authors":"Shadi Al-Mesitef , Daisuke Ando , Tomoya Saigasaki , Yuki Sakaguchi , Shunya Akagi , Abdulrahman Mousa , Sherif Rashad , Kuniyasu Niizuma","doi":"10.1016/j.redox.2026.104038","DOIUrl":"10.1016/j.redox.2026.104038","url":null,"abstract":"<div><div>Transfer RNA-derived small RNAs (tDRs) are emerging regulators of cellular stress response, yet their biogenesis and activities during mitochondrial dysfunction remain poorly understood. Here we profiled tDRs generated in HEK293T cells exposed to inhibitors of respiratory complexes I–V (rotenone, TTFA, antimycin A, KCN, oligomycin) or to arsenite and assessed the impact of CRISPR-mediated angiogenin (ANG) knockout, ANG over-expression and recombinant ANG supplementation on the stress response and tDRs production. tDR-seq revealed stress-specific, highly ordered tDR repertoires: rotenone and antimycin predominantly induced internal (i-tRF) and 3ʹ tRNA (tRF3) fragments, whereas arsenite induced anticodon-cleaved tRNA halves (tiRNAs). mito-tDRs were mostly internal fragments and antimycin induced the strongest mitochondrial tDRs expression. ANG deletion markedly impaired stress-induced tDR biogenesis and sensitized cells to antimycin and oligomycin stress, whereas its overexpression selectively enhanced tDR biogenesis and conferred protection against these mitochondrial stressor. Synthetic tDR mimics failed to rescue viability, implying that native modification patterns or cooperative tDR pools are required. tDR motif enrichment analysis identified YBX1-binding sites among antimycin-induced tDRs, and genetic perturbation of YBX1 phenocopied aspects of enhanced mitochondrial bioenergetics and stress resistance. Together, these findings demonstrate that context-specific, ANG-directed tDR biogenesis forms a crucial arm of the mitochondrial stress response.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"90 ","pages":"Article 104038"},"PeriodicalIF":11.9,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145995157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lactational mastitis threatens maternal-infant health and animal husbandry efficiency, with traditional antibiotics limited by milk residues and bacterial resistance. Selenium (Se) regulates inflammation via selenoproteins, but its core effector in mammary inflammation remains unclear. This study investigates the role and mechanism of Se and selenoprotein P (SeP) in LPS-induced mastitis. Tissue pathology, inflammation, apoptosis, and tight junctions (TJs) are assessed via H&E staining, qPCR, Western blot, etc., in mice with varying Se diets (deficient, basal, enriched) subjected to LPS-induced mastitis, and in mouse mammary epithelial cells (MMECs) with SeP silencing or enrichment. Se deficiency exacerbates LPS-induced acinar atrophy, inflammation, NF-κB activation, and release of pro-inflammatory factors (IL-6, IL-1β, TNF-α), while Se enrichment alleviates these effects. SeP, highly expressed in lactating mammary tissue and upregulated by Se, mediates protection through three pathways: inhibiting NF-κB to reduce inflammation, regulating the BAX/BCL2 balance and RIPK1/RIPK3/MLKL pathway to suppress apoptosis and necroptosis, and stabilizing TJ proteins (ZO-1, Occludin, Claudin-1) to repair the blood-milk barrier. In summary, SeP is a core effector of Se in regulating mammary inflammatory injury, maintaining lactational mammary homeostasis via anti-inflammatory, anti-apoptotic, and barrier-protective effects, and provides a new target for mastitis management.
{"title":"A positive effect of selenoprotein on mammary gland: Selenoprotein P stabilizes tight junctions by reducing cell death through inflammation mitigation in mice","authors":"Mengran Zhu, Tianchao Xu, Hongli Lv, Yuxi Zhang, Jilong Luo, Mengyao Guo","doi":"10.1016/j.redox.2026.104036","DOIUrl":"10.1016/j.redox.2026.104036","url":null,"abstract":"<div><div>Lactational mastitis threatens maternal-infant health and animal husbandry efficiency, with traditional antibiotics limited by milk residues and bacterial resistance. Selenium (Se) regulates inflammation via selenoproteins, but its core effector in mammary inflammation remains unclear. This study investigates the role and mechanism of Se and selenoprotein P (SeP) in LPS-induced mastitis. Tissue pathology, inflammation, apoptosis, and tight junctions (TJs) are assessed via H&E staining, qPCR, Western blot, etc., in mice with varying Se diets (deficient, basal, enriched) subjected to LPS-induced mastitis, and in mouse mammary epithelial cells (MMECs) with SeP silencing or enrichment. Se deficiency exacerbates LPS-induced acinar atrophy, inflammation, NF-κB activation, and release of pro-inflammatory factors (IL-6, IL-1β, TNF-α), while Se enrichment alleviates these effects. SeP, highly expressed in lactating mammary tissue and upregulated by Se, mediates protection through three pathways: inhibiting NF-κB to reduce inflammation, regulating the BAX/BCL2 balance and RIPK1/RIPK3/MLKL pathway to suppress apoptosis and necroptosis, and stabilizing TJ proteins (ZO-1, Occludin, Claudin-1) to repair the blood-milk barrier. In summary, SeP is a core effector of Se in regulating mammary inflammatory injury, maintaining lactational mammary homeostasis via anti-inflammatory, anti-apoptotic, and barrier-protective effects, and provides a new target for mastitis management.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"90 ","pages":"Article 104036"},"PeriodicalIF":11.9,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145995155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-15DOI: 10.1016/j.redox.2026.104034
Zhengquan Zhu , Yihan Wang , Xinye Yu , Tingyu Wang , Yin Li , Ruizhe Wang , Haiyun Chen , Binjia Ruan , Wangsen Cao , Gaojian Tao , Yong Wang , Daojuan Wang
Arrested follicular development and anovulation are hallmarks of polycystic ovary syndrome (PCOS), in which granulosa cell (GC) ferroptosis is emerging as a potential contributor. However, its precise role and regulation remain largely unknown. Here, we identify a methyl-CpG-binding domain protein 2 (MBD2)-driven ferroptotic program as a central pathogenic mechanism in PCOS. In a dehydroepiandrosterone (DHEA)-induced PCOS mouse model, GCs exhibited marked ferroptotic alterations and transcriptional suppression of glutathione peroxidase 4 (GPX4), a key anti-ferroptotic enzyme. GC-specific Gpx4 knockout exacerbated ferroptosis, impaired follicular maturation, reduced corpora lutea formation, and aggravated PCOS pathology. GPX4 repression was associated with increased DNA methyltransferases (DNMTs), elevated DNA Methyl-reading protein MBD2 and hypermethylation of the Gpx4 promoter. Pharmacological inhibition of MBD2 with KCC-07, or DNMT blockade with 5-Azacytidine, restored GPX4 expression, reduced lipid peroxidation and GC ferroptosis, and alleviated ovarian dysfunction. Integrative ATAC-seq and RNA-seq analyses revealed enhanced Gpx4 promoter accessibility in PCOS ovaries, where MBD2, MAZ, HDAC3 and NCoR assembled into a repressive complex that was interrupted by KCC-07 treatment. Importantly, pharmacologic GPX4 inhibition with RSL3 or GC-specific Gpx4 deletion abrogated the protective effects of MBD2 inhibition, establishing GPX4 repression as the critical downstream effector. Collectively, these findings uncover an MBD2-driven epigenetic program that silences GPX4, triggers GC ferroptosis, and promotes PCOS pathogenesis. Targeting MBD2 to restore epigenetic control of ferroptosis offers a promising therapeutic strategy for PCOS.
{"title":"Methylation reader MBD2-mediated GPX4 transcriptional repression drives ovarian granulosa cell ferroptosis in PCOS","authors":"Zhengquan Zhu , Yihan Wang , Xinye Yu , Tingyu Wang , Yin Li , Ruizhe Wang , Haiyun Chen , Binjia Ruan , Wangsen Cao , Gaojian Tao , Yong Wang , Daojuan Wang","doi":"10.1016/j.redox.2026.104034","DOIUrl":"10.1016/j.redox.2026.104034","url":null,"abstract":"<div><div>Arrested follicular development and anovulation are hallmarks of polycystic ovary syndrome (PCOS), in which granulosa cell (GC) ferroptosis is emerging as a potential contributor. However, its precise role and regulation remain largely unknown. Here, we identify a methyl-CpG-binding domain protein 2 (MBD2)-driven ferroptotic program as a central pathogenic mechanism in PCOS. In a dehydroepiandrosterone (DHEA)-induced PCOS mouse model, GCs exhibited marked ferroptotic alterations and transcriptional suppression of glutathione peroxidase 4 (GPX4), a key anti-ferroptotic enzyme. GC-specific Gpx4 knockout exacerbated ferroptosis, impaired follicular maturation, reduced corpora lutea formation, and aggravated PCOS pathology. GPX4 repression was associated with increased DNA methyltransferases (DNMTs), elevated DNA Methyl-reading protein MBD2 and hypermethylation of the <em>Gpx4</em> promoter. Pharmacological inhibition of MBD2 with KCC-07, or DNMT blockade with 5-Azacytidine, restored GPX4 expression, reduced lipid peroxidation and GC ferroptosis, and alleviated ovarian dysfunction. Integrative ATAC-seq and RNA-seq analyses revealed enhanced <em>Gpx4</em> promoter accessibility in PCOS ovaries, where MBD2, MAZ, HDAC3 and NCoR assembled into a repressive complex that was interrupted by KCC-07 treatment. Importantly, pharmacologic GPX4 inhibition with RSL3 or GC-specific Gpx4 deletion abrogated the protective effects of MBD2 inhibition, establishing GPX4 repression as the critical downstream effector. Collectively, these findings uncover an MBD2-driven epigenetic program that silences GPX4, triggers GC ferroptosis, and promotes PCOS pathogenesis. Targeting MBD2 to restore epigenetic control of ferroptosis offers a promising therapeutic strategy for PCOS.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"90 ","pages":"Article 104034"},"PeriodicalIF":11.9,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145995159","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chronic exposure to fine particulate matter (PM2.5) and insulin resistance (IR) are each linked to Alzheimer’s disease (AD), but IR has not been systematically positioned as a mechanistic conduit through which PM2.5 heightens AD vulnerability. Drawing on epidemiological, animal, and cellular studies, this review outlines converging pathways along a PM2.5-IR-AD axis: chronic neuroinflammation, oxidative stress and mitochondrial dysfunction, blood-brain barrier disruption, and impaired amyloid-β (Aβ) clearance. Across sections, study-specific limitations are comprehensively discussed. Positioning IR as a central node linking PM2.5 exposure to AD reframes air pollution as a modifiable metabolic-neurologic risk. Potential therapeutic and preventive avenues are also highlighted. Future work could prioritize longitudinal and interventional studies that directly interrogate the PM2.5-IR-AD triad and refine biomarkers to guide precision prevention.
慢性暴露于细颗粒物（PM2.5）和胰岛素抵抗（IR）都与阿尔茨海默病（AD）有关，但IR尚未被系统地定位为PM2.5增加AD易感性的机制管道。根据流行病学、动物和细胞研究，本综述概述了沿PM2.5-IR-AD轴的趋同途径：慢性神经炎症、氧化应激和线粒体功能障碍、血脑屏障破坏和淀粉样蛋白-β (a β)清除受损。在各个章节中，全面讨论了特定研究的局限性。将IR定位为PM2.5暴露与AD之间的中心节点，将空气污染重新定义为可改变的代谢神经风险。还强调了潜在的治疗和预防途径。未来的工作可以优先考虑直接询问PM2.5-IR-AD三元组的纵向和介入性研究，并完善生物标志物以指导精确预防。
{"title":"Smog, sugar, and synapses: Unraveling the PM2.5-insulin resistance-Alzheimer’s disease axis","authors":"Hsuan-Yu Huang , Yu-Yin Huang , Chia-Lin Wu , Wei-Chien Huang , Chih-Ho Lai","doi":"10.1016/j.redox.2026.104031","DOIUrl":"10.1016/j.redox.2026.104031","url":null,"abstract":"<div><div>Chronic exposure to fine particulate matter (PM2.5) and insulin resistance (IR) are each linked to Alzheimer’s disease (AD), but IR has not been systematically positioned as a mechanistic conduit through which PM2.5 heightens AD vulnerability. Drawing on epidemiological, animal, and cellular studies, this review outlines converging pathways along a PM2.5-IR-AD axis: chronic neuroinflammation, oxidative stress and mitochondrial dysfunction, blood-brain barrier disruption, and impaired amyloid-β (Aβ) clearance. Across sections, study-specific limitations are comprehensively discussed. Positioning IR as a central node linking PM2.5 exposure to AD reframes air pollution as a modifiable metabolic-neurologic risk. Potential therapeutic and preventive avenues are also highlighted. Future work could prioritize longitudinal and interventional studies that directly interrogate the PM2.5-IR-AD triad and refine biomarkers to guide precision prevention.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"90 ","pages":"Article 104031"},"PeriodicalIF":11.9,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145962518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-14DOI: 10.1016/j.redox.2026.104032
B. Chen , J.U. Mayer
Dendritic Cells are central players of our immune system, linking innate sensing to adaptive immunity through antigen presentation and T cell priming. Beyond transcriptional and cytokine-based regulation, mitochondria are emerging as potential regulators of Dendritic Cell biology. While still in its infancy, evidence is accumulating that mitochondrial pathways affect Dendritic Cell differentiation; that mitochondrial remodeling and bioenergetic rewiring underpin Dendritic Cell maturation and activation in response to pathogenic and inflammatory stimuli and that shifts in mitochondrial and redox dynamics, reactive oxygen species production and mitochondrial DNA release coincide with Dendritic Cell activation and co-stimulatory molecule expression. Mitochondria are furthermore involved in regulating Dendritic Cell migration by influencing cellular metabolism and cytoskeletal dynamics and support the antigen processing and presentation machinery, thereby dictating the quality of the initiated T cell response. Importantly, mitochondrial checkpoints also regulate Dendritic Cell survival, balancing immune activation with timely cell death to preserve immune homeostasis.
While the exact pathways of mitochondrial regulation are just beginning to be understood, disruptions in these programs can be far reaching. During aging, progressive mitochondrial dysfunction has been associated with impaired Dendritic Cell differentiation, diminished antigen presentation and impaired T cell responses. Similar defects have been observed in chronic diseases and cancer, leading us to hypothesize that genetic disorders linked to mitochondrial dysfunction also lead to defects in Dendritic Cell biology, impacting clinical symptoms such as immune dysregulation, heightened infection risk and inappropriate chronic inflammation.
Therefore, in this review we have summarized the emerging roles of mitochondrial regulation in Dendritic Cell biology and discuss therapeutic opportunities to restore immune competence by targeting mitochondrial and redox pathways in settings of Dendritic Cell dysfunction. These insights aim to encourage further research into these topics and propose targeted metabolic reprogramming as a new therapeutic strategy for healthy ageing and chronic disease management.
{"title":"Emerging frontiers in the mitochondrial regulation of dendritic cell biology","authors":"B. Chen , J.U. Mayer","doi":"10.1016/j.redox.2026.104032","DOIUrl":"10.1016/j.redox.2026.104032","url":null,"abstract":"<div><div>Dendritic Cells are central players of our immune system, linking innate sensing to adaptive immunity through antigen presentation and T cell priming. Beyond transcriptional and cytokine-based regulation, mitochondria are emerging as potential regulators of Dendritic Cell biology. While still in its infancy, evidence is accumulating that mitochondrial pathways affect Dendritic Cell differentiation; that mitochondrial remodeling and bioenergetic rewiring underpin Dendritic Cell maturation and activation in response to pathogenic and inflammatory stimuli and that shifts in mitochondrial and redox dynamics, reactive oxygen species production and mitochondrial DNA release coincide with Dendritic Cell activation and co-stimulatory molecule expression. Mitochondria are furthermore involved in regulating Dendritic Cell migration by influencing cellular metabolism and cytoskeletal dynamics and support the antigen processing and presentation machinery, thereby dictating the quality of the initiated T cell response. Importantly, mitochondrial checkpoints also regulate Dendritic Cell survival, balancing immune activation with timely cell death to preserve immune homeostasis.</div><div>While the exact pathways of mitochondrial regulation are just beginning to be understood, disruptions in these programs can be far reaching. During aging, progressive mitochondrial dysfunction has been associated with impaired Dendritic Cell differentiation, diminished antigen presentation and impaired T cell responses. Similar defects have been observed in chronic diseases and cancer, leading us to hypothesize that genetic disorders linked to mitochondrial dysfunction also lead to defects in Dendritic Cell biology, impacting clinical symptoms such as immune dysregulation, heightened infection risk and inappropriate chronic inflammation.</div><div>Therefore, in this review we have summarized the emerging roles of mitochondrial regulation in Dendritic Cell biology and discuss therapeutic opportunities to restore immune competence by targeting mitochondrial and redox pathways in settings of Dendritic Cell dysfunction. These insights aim to encourage further research into these topics and propose targeted metabolic reprogramming as a new therapeutic strategy for healthy ageing and chronic disease management.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"90 ","pages":"Article 104032"},"PeriodicalIF":11.9,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145995158","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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