Pub Date : 2026-01-23DOI: 10.1016/j.freeradbiomed.2026.01.030
Qi Yang , Shibing Zhao , Junxiu Zhao , Ying Shen , Yimei Hong , Jie Qiu , Ziqi Li , Fang Lin , Kexin Ma , Bei Hu , Yuelin Zhang , Xiaoting Liang
Background
Mitochondrial dysfunction plays an important role in the development of doxorubicin-induced cardiomyopathy (DIC). Mitochondrial transplantation (MT) exerts beneficial effects on multiple cardiovascular diseases.
Objective
This study aimed to determine whether transplantation of exogenous mitochondria derived from induced pluripotent stem cell-derived mesenchymal stem cells (iPSC-MSC-Mito) could protect against DIC in mice and explore the potential molecular mechanisms.
Methods
Mitochondria were isolated from iPSC-MSCs using ultracentrifugation, then characterized by transmission electron microscopy and Western blotting. The cellular senescence of neonatal mouse cardiomyocytes (NMCMs) was examined by senescence-associated-β-galactosidase assay. Mitochondrial function in doxorubicin (DOX)-treated NMCMs exposed to different treatments was evaluated by seahorse assay. A mouse model of DIC was induced by intraperitoneal injection of DOX followed by intraperitoneal injection of iPSC-MSC-Mito. Cardiac function, fibrosis and cardiomyocyte senescence in each group was examined.
Results
The isolated iPSC-MSC-Mito exhibited intact mitochondrial morphology and quality. In vitro, iPSC-MSC-Mito could be internalized by NMCMs under DOX challenge. Administration of iPSC-MSC-Mito improved the respiratory capacity of cardiomyocytes under DOX challenge, due to downregulated lactate level, leading to inhibition of cardiomyocyte senescence. This effect was partially abrogated by exogenous lactate. Utilizing molecular docking and site-directed mutation assays, we found that lactate regulated SIRT2 expression by binding to the ARG97 and HIS187 residues in the PH domain of SIRT2. In vivo, transplantation of iPSC-MSC-Mito functionally attenuated DIC, manifested as improved cardiac function and decreased cardiac fibrosis and cardiomyocyte senescence.
Conclusions
Transplantation of mitochondria isolated from iPSC-MSCs improved cardiac function in a mouse model of DIC by alleviating cardiomyocyte senescence via improved metabolic function. This may offer a novel therapeutic strategy for DIC.
{"title":"Transplantation of Mitochondria isolated from iPSC-MSCs mitigates doxorubicin-induced cardiomyopathy by inhibiting cardiomyocyte senescence","authors":"Qi Yang , Shibing Zhao , Junxiu Zhao , Ying Shen , Yimei Hong , Jie Qiu , Ziqi Li , Fang Lin , Kexin Ma , Bei Hu , Yuelin Zhang , Xiaoting Liang","doi":"10.1016/j.freeradbiomed.2026.01.030","DOIUrl":"10.1016/j.freeradbiomed.2026.01.030","url":null,"abstract":"<div><h3>Background</h3><div>Mitochondrial dysfunction plays an important role in the development of doxorubicin-induced cardiomyopathy (DIC). Mitochondrial transplantation (MT) exerts beneficial effects on multiple cardiovascular diseases.</div></div><div><h3>Objective</h3><div>This study aimed to determine whether transplantation of exogenous mitochondria derived from induced pluripotent stem cell-derived mesenchymal stem cells (iPSC-MSC-Mito) could protect against DIC in mice and explore the potential molecular mechanisms.</div></div><div><h3>Methods</h3><div>Mitochondria were isolated from iPSC-MSCs using ultracentrifugation, then characterized by transmission electron microscopy and Western blotting. The cellular senescence of neonatal mouse cardiomyocytes (NMCMs) was examined by senescence-associated-β-galactosidase assay. Mitochondrial function in doxorubicin (DOX)-treated NMCMs exposed to different treatments was evaluated by seahorse assay. A mouse model of DIC was induced by intraperitoneal injection of DOX followed by intraperitoneal injection of iPSC-MSC-Mito. Cardiac function, fibrosis and cardiomyocyte senescence in each group was examined.</div></div><div><h3>Results</h3><div>The isolated iPSC-MSC-Mito exhibited intact mitochondrial morphology and quality. <em>In vitro</em>, iPSC-MSC-Mito could be internalized by NMCMs under DOX challenge. Administration of iPSC-MSC-Mito improved the respiratory capacity of cardiomyocytes under DOX challenge, due to downregulated lactate level, leading to inhibition of cardiomyocyte senescence. This effect was partially abrogated by exogenous lactate. Utilizing molecular docking and site-directed mutation assays, we found that lactate regulated SIRT2 expression by binding to the ARG97 and HIS187 residues in the PH domain of SIRT2. <em>In vivo</em>, transplantation of iPSC-MSC-Mito functionally attenuated DIC, manifested as improved cardiac function and decreased cardiac fibrosis and cardiomyocyte senescence.</div></div><div><h3>Conclusions</h3><div>Transplantation of mitochondria isolated from iPSC-MSCs improved cardiac function in a mouse model of DIC by alleviating cardiomyocyte senescence via improved metabolic function. This may offer a novel therapeutic strategy for DIC.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 381-393"},"PeriodicalIF":8.2,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146046460","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}
Pub Date : 2026-01-23DOI: 10.1016/j.freeradbiomed.2026.01.035
Fuzheng Zou , Kaiming Zhang , Xianding Sun, Xingwang Cheng, Ting Wang, Biao Kuang, Lei Shi, Xudong Yao, Mao Nie
Background
Osteoarthritis (OA) is a degenerative joint disease. Recent studies have shown that ferroptosis plays a critical role in OA. Arachidonate-5-lipoxygenase (ALOX5), a pivotal enzyme regulating arachidonic acid metabolism, is involved in the synthesis of the pro-inflammatory leukotrienes. However, its role in ferroptosis and OA has not been elucidated.
Methods
Measuring the expression of ALOX5 and ferroptosis-related markers in human cartilage and synovial fluid. Constructed small interfering RNA or plasmids were used to knockdown or overexpress Alox5 to explore its role in chondrocyte. Transcription factors regulating Alox5 were predicted through database analysis, while RNA sequencing revealed signaling pathways modulated by Alox5. Subsequently, the role of ALOX5 in destabilization of medial meniscus (DMM) OA model was investigated by intra-articular injection of knockdown (AAV-ShAlox5) or overexpression (AAV-OEAlox5) adeno-associated virus. Finally, the therapeutic efficacy of ALOX5 inhibitor Zileuton, was verified in vivo and in vitro.
Results
We observed upregulated ALOX5 expression in human cartilage and Alox5 knockdown mitigated IL-1β- and FAC-induced chondrocyte damage by suppressing ferroptosis. Through database predictive analysis and experimental verification, ALOX5 was modulated by the JNK-p53 signaling axis. Through RNA-seq analysis, it was found that knockdown of Alox5 inhibited the activation of the JAK2-STAT3 signaling pathway, thereby delaying the process of ferroptosis and slowing down the wear of articular cartilage. In the mouse DMM model, intra-articular injection AAV-ShAlox5 delayed DMM-induced cartilage degeneration, whereas AAV-OEAlox5 exacerbated cartilage damage. Similarly, treatment with Zileuton alleviated ferroptosis and chondrocyte injury,demonstrating a protective effect in vivo and in vitro.
Conclusions
In summary, our study demonstrated knockdown of Alox5 inhibited the JAK2/STAT3 signaling, thereby suppressing ferroptosis and alleviating cartilage damage. Intra-articular injection of the ALOX5 inhibitor Zileuton or AAV-ShAlox5 in the knee joint alleviated cartilage damage in the mouse DMM model. Mechanistically, our study reveals that the JNK-p53-ALOX5 signaling axis alleviates OA by regulating ferroptosis in chondrocytes.
{"title":"Inhibiting Arachidonate-5-lipoxygenase expression ameliorates osteoarthritis progression by suppressing ferroptosis via the JAK2/STAT3 signaling pathway","authors":"Fuzheng Zou , Kaiming Zhang , Xianding Sun, Xingwang Cheng, Ting Wang, Biao Kuang, Lei Shi, Xudong Yao, Mao Nie","doi":"10.1016/j.freeradbiomed.2026.01.035","DOIUrl":"10.1016/j.freeradbiomed.2026.01.035","url":null,"abstract":"<div><h3>Background</h3><div>Osteoarthritis (OA) is a degenerative joint disease. Recent studies have shown that ferroptosis plays a critical role in OA. Arachidonate-5-lipoxygenase (ALOX5), a pivotal enzyme regulating arachidonic acid metabolism, is involved in the synthesis of the pro-inflammatory leukotrienes. However, its role in ferroptosis and OA has not been elucidated.</div></div><div><h3>Methods</h3><div>Measuring the expression of ALOX5 and ferroptosis-related markers in human cartilage and synovial fluid. Constructed small interfering RNA or plasmids were used to knockdown or overexpress <em>Alox5</em> to explore its role in chondrocyte. Transcription factors regulating <em>Alox5</em> were predicted through database analysis, while RNA sequencing revealed signaling pathways modulated by <em>Alox5</em>. Subsequently, the role of ALOX5 in destabilization of medial meniscus (DMM) OA model was investigated by intra-articular injection of knockdown (AAV-Sh<em>Alox5</em>) or overexpression (AAV-OE<em>Alox5</em>) adeno-associated virus. Finally, the therapeutic efficacy of ALOX5 inhibitor Zileuton, was verified in vivo and in vitro.</div></div><div><h3>Results</h3><div>We observed upregulated ALOX5 expression in human cartilage and <em>Alox5</em> knockdown mitigated IL-1β- and FAC-induced chondrocyte damage by suppressing ferroptosis. Through database predictive analysis and experimental verification, ALOX5 was modulated by the JNK-p53 signaling axis. Through RNA-seq analysis, it was found that knockdown of <em>Alox5</em> inhibited the activation of the JAK2-STAT3 signaling pathway, thereby delaying the process of ferroptosis and slowing down the wear of articular cartilage. In the mouse DMM model, intra-articular injection AAV-Sh<em>Alox5</em> delayed DMM-induced cartilage degeneration, whereas AAV-OE<em>Alox5</em> exacerbated cartilage damage. Similarly, treatment with Zileuton alleviated ferroptosis and chondrocyte injury,demonstrating a protective effect in vivo and in vitro.</div></div><div><h3>Conclusions</h3><div>In summary, our study demonstrated knockdown of <em>Alox5</em> inhibited the JAK2/STAT3 signaling, thereby suppressing ferroptosis and alleviating cartilage damage. Intra-articular injection of the ALOX5 inhibitor Zileuton or AAV-Sh<em>Alox5</em> in the knee joint alleviated cartilage damage in the mouse DMM model. Mechanistically, our study reveals that the JNK-p53-ALOX5 signaling axis alleviates OA by regulating ferroptosis in chondrocytes.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 334-349"},"PeriodicalIF":8.2,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146046410","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}
Pub Date : 2026-01-22DOI: 10.1016/j.freeradbiomed.2025.12.059
Ying Liu, Chulong Fang, Changling Chen, Yuhang Yu, Jifen Wang, Lan Ye, Chunlin Zhang, Zhanhui Feng
<p><strong>Objective: </strong>Beyond neuroinflammation, oxidative stress is a key pathomechanism in epilepsy. This study investigated a novel SGLT2/NHE-1/NLRP3 signaling axis and evaluated its role in driving oxidative stress and neuroinflammation in epilepsy. We aimed to determine whether targeted inhibition of this axis could alleviate neuronal excitability and cognitive deficits by restoring redox balance and suppressing neuroinflammation.</p><p><strong>Methods: </strong>Network pharmacology predicted the primary anti-epileptic target of dapagliflozin. Bioinformatic analysis was performed on the GEO dataset GSE256068 from patients with temporal lobe epilepsy. A PTZ-kindled mouse model was established and treated with dapagliflozin (SGLT2 inhibitor), cariporide (NHE-1 inhibitor), or CY09 (NLRP3 inhibitor). Seizure behavior and EEG were recorded; cognitive function was assessed using the Morris water maze. Molecular analyses (RT-qPCR, Western blot, immunohistochemistry, ELISA, etc.) were conducted to evaluate neuroinflammation and oxidative stress. Complementary in vitro studies used HT22 hippocampal neuronal cells (a glia-free model) to validate the neuron-intrinsic operation of axis's role; Targeted inhibition of each component was performed using specific inhibitors, and molecular interactions were interrogated through overexpression, functional rescue experiments, molecular docking, and co-immunoprecipitation.</p><p><strong>Results: </strong>Bioinformatic and molecular analyses confirmed concerted upregulation of SGLT2, NHE-1, and NLRP3 in epileptic human and mouse hippocampi (p < 0.01), with significant enrichment in NOD-like receptor signaling pathway. All three inhibitors not only reduced seizure severity included seizure scores (mean seizure grade decreased from 4.88 to 3.12-3.48, p < 0.01), abnormal EEG discharges, and seizure duration (mean duration decreased from 42.32 min to 5.33-9.77 min, p < 0.01), but aslo improved spatial learning and memory abilities. In addition, inhibition of SGLT2/NHE-1/NLRP3 signaling axis mitigated oxidative damage by reducing ROS production and lipid peroxidation, while enhancing antioxidant defense (p < 0.05). Crucially, they suppressed NLRP3 inflammasome activation and neuroinflammation. In vitro studies defined a core unidirectional SGLT2→NHE-1→NLRP3 cascade functioning within neurons and revealed its operation within a self-amplifying regulatory network, demonstrating that inhibition at any node effectively attenuated both LPS-induced oxidative stress and inflammatory responses in the absence of glial cells. Direct protein interactions within the axis were identified, supporting the formation of a functional signaling complex. This integrated model positions oxidative stress as both a trigger and a sustained component coupled with neuroinflammation in a feed-forward loop.</p><p><strong>Conclusion: </strong>Our findings unveil the SGLT2/NHE-1/NLRP3 axis as a master regulator that integrates oxidative s
{"title":"Inhibition of the SGLT2/NHE-1/NLRP3 signaling axis attenuates neuroinflammation and oxidative stress to ameliorate seizures and cognitive impairment in epileptic mice.","authors":"Ying Liu, Chulong Fang, Changling Chen, Yuhang Yu, Jifen Wang, Lan Ye, Chunlin Zhang, Zhanhui Feng","doi":"10.1016/j.freeradbiomed.2025.12.059","DOIUrl":"10.1016/j.freeradbiomed.2025.12.059","url":null,"abstract":"<p><strong>Objective: </strong>Beyond neuroinflammation, oxidative stress is a key pathomechanism in epilepsy. This study investigated a novel SGLT2/NHE-1/NLRP3 signaling axis and evaluated its role in driving oxidative stress and neuroinflammation in epilepsy. We aimed to determine whether targeted inhibition of this axis could alleviate neuronal excitability and cognitive deficits by restoring redox balance and suppressing neuroinflammation.</p><p><strong>Methods: </strong>Network pharmacology predicted the primary anti-epileptic target of dapagliflozin. Bioinformatic analysis was performed on the GEO dataset GSE256068 from patients with temporal lobe epilepsy. A PTZ-kindled mouse model was established and treated with dapagliflozin (SGLT2 inhibitor), cariporide (NHE-1 inhibitor), or CY09 (NLRP3 inhibitor). Seizure behavior and EEG were recorded; cognitive function was assessed using the Morris water maze. Molecular analyses (RT-qPCR, Western blot, immunohistochemistry, ELISA, etc.) were conducted to evaluate neuroinflammation and oxidative stress. Complementary in vitro studies used HT22 hippocampal neuronal cells (a glia-free model) to validate the neuron-intrinsic operation of axis's role; Targeted inhibition of each component was performed using specific inhibitors, and molecular interactions were interrogated through overexpression, functional rescue experiments, molecular docking, and co-immunoprecipitation.</p><p><strong>Results: </strong>Bioinformatic and molecular analyses confirmed concerted upregulation of SGLT2, NHE-1, and NLRP3 in epileptic human and mouse hippocampi (p < 0.01), with significant enrichment in NOD-like receptor signaling pathway. All three inhibitors not only reduced seizure severity included seizure scores (mean seizure grade decreased from 4.88 to 3.12-3.48, p < 0.01), abnormal EEG discharges, and seizure duration (mean duration decreased from 42.32 min to 5.33-9.77 min, p < 0.01), but aslo improved spatial learning and memory abilities. In addition, inhibition of SGLT2/NHE-1/NLRP3 signaling axis mitigated oxidative damage by reducing ROS production and lipid peroxidation, while enhancing antioxidant defense (p < 0.05). Crucially, they suppressed NLRP3 inflammasome activation and neuroinflammation. In vitro studies defined a core unidirectional SGLT2→NHE-1→NLRP3 cascade functioning within neurons and revealed its operation within a self-amplifying regulatory network, demonstrating that inhibition at any node effectively attenuated both LPS-induced oxidative stress and inflammatory responses in the absence of glial cells. Direct protein interactions within the axis were identified, supporting the formation of a functional signaling complex. This integrated model positions oxidative stress as both a trigger and a sustained component coupled with neuroinflammation in a feed-forward loop.</p><p><strong>Conclusion: </strong>Our findings unveil the SGLT2/NHE-1/NLRP3 axis as a master regulator that integrates oxidative s","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":"742-759"},"PeriodicalIF":8.2,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146044010","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}
Pub Date : 2026-01-22DOI: 10.1016/j.freeradbiomed.2026.01.026
Xiaoli Lv , Zhenyan Li , Qiliang Peng , Zhichao Fu , Chao Xu , Jian Wang , Songbing Qin , Jianping Cao , Lili Wang , Yang Jiao
Radioresistance in esophageal squamous cell carcinoma limits the benefit of radiotherapy. The role of N6 methyladenosine readers in this phenotype remains incompletely defined. We identify a YTHDF2 centered mechanism that links RNA modification to organelle redox control. Analyses of public transcriptomes and an immunohistochemistry cohort showed that higher YTHDF2 expression associates with unfavorable outcomes after radiotherapy, and ionizing radiation transiently increases YTHDF2 in cell models. Loss of YTHDF2 sensitized esophageal squamous cell carcinoma cells to irradiation, with more apoptosis, DNA damage, reactive oxygen species, and reduced clonogenic survival. YTHDF2 overexpression conferred protection in vitro and preserved tumor growth in xenografts after irradiation. Integrated MeRIP-seq and MeRIP-qPCR, together with reporter assays, indicated that YTHDF2 recognizes an m6A-modified site within the DHRS3 3′ untranslated region and is required to maintain DHRS3 protein expression after irradiation. DHRS3 depletion phenocopied radiosensitization, elevated reactive oxygen species, and disrupted redox balance with altered NADP+ to nicotinamide adenine dinucleotide phosphate (NADPH) ratios, and abrogated the radioprotective effects of YTHDF2 overexpression. Spatial imaging and perturbation analyses suggested that lecithin retinol acyltransferase (LRAT) enriches DHRS3 at endoplasmic-reticulum–lipid-droplet regions juxtaposed to mitochondria after irradiation. LRAT loss dispersed these interfaces, mislocalized DHRS3, and impaired retinoid and NADPH buffering, whereas enforced mitochondrial targeting of DHRS3 partially restored redox control. Collectively, these findings support a model in which an irradiation-responsive YTHDF2–DHRS3–LRAT axis assembles a retinoid-coupled NADPH module at endoplasmic reticulum (ER)–lipid-droplet (LD)–mitochondria interfaces to limit oxidative stress and contribute to radioresistance. Mechanistic experiments illustrate how this pathway buffers irradiation-induced oxidative stress across transcriptomic, biochemical, and imaging readouts, suggesting that targeting YTHDF2 or the DHRS3–LRAT node may offer a tractable strategy to improve radiotherapy in esophageal squamous cell carcinoma.
{"title":"YTHDF2–m6A regulation of DHRS3 at LRAT-organized organelle contacts orchestrates redox to drive radioresistance in esophageal squamous cell carcinoma","authors":"Xiaoli Lv , Zhenyan Li , Qiliang Peng , Zhichao Fu , Chao Xu , Jian Wang , Songbing Qin , Jianping Cao , Lili Wang , Yang Jiao","doi":"10.1016/j.freeradbiomed.2026.01.026","DOIUrl":"10.1016/j.freeradbiomed.2026.01.026","url":null,"abstract":"<div><div>Radioresistance in esophageal squamous cell carcinoma limits the benefit of radiotherapy. The role of N6 methyladenosine readers in this phenotype remains incompletely defined. We identify a YTHDF2 centered mechanism that links RNA modification to organelle redox control. Analyses of public transcriptomes and an immunohistochemistry cohort showed that higher YTHDF2 expression associates with unfavorable outcomes after radiotherapy, and ionizing radiation transiently increases YTHDF2 in cell models. Loss of YTHDF2 sensitized esophageal squamous cell carcinoma cells to irradiation, with more apoptosis, DNA damage, reactive oxygen species, and reduced clonogenic survival. YTHDF2 overexpression conferred protection <em>in vitro</em> and preserved tumor growth in xenografts after irradiation. Integrated MeRIP-seq and MeRIP-qPCR, together with reporter assays, indicated that YTHDF2 recognizes an m<sup>6</sup>A-modified site within the DHRS3 3′ untranslated region and is required to maintain DHRS3 protein expression after irradiation. DHRS3 depletion phenocopied radiosensitization, elevated reactive oxygen species, and disrupted redox balance with altered NADP<sup>+</sup> to nicotinamide adenine dinucleotide phosphate (NADPH) ratios, and abrogated the radioprotective effects of YTHDF2 overexpression. Spatial imaging and perturbation analyses suggested that lecithin retinol acyltransferase (LRAT) enriches DHRS3 at endoplasmic-reticulum–lipid-droplet regions juxtaposed to mitochondria after irradiation. LRAT loss dispersed these interfaces, mislocalized DHRS3, and impaired retinoid and NADPH buffering, whereas enforced mitochondrial targeting of DHRS3 partially restored redox control. Collectively, these findings support a model in which an irradiation-responsive YTHDF2–DHRS3–LRAT axis assembles a retinoid-coupled NADPH module at endoplasmic reticulum (ER)–lipid-droplet (LD)–mitochondria interfaces to limit oxidative stress and contribute to radioresistance. Mechanistic experiments illustrate how this pathway buffers irradiation-induced oxidative stress across transcriptomic, biochemical, and imaging readouts, suggesting that targeting YTHDF2 or the DHRS3–LRAT node may offer a tractable strategy to improve radiotherapy in esophageal squamous cell carcinoma.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 290-304"},"PeriodicalIF":8.2,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146024594","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}
Pub Date : 2026-01-22DOI: 10.1016/j.freeradbiomed.2026.01.014
Zhen Zhang , Hang Han , Liyang Ding, Hong Yang, Yu Deng, Yitong Shang, Tengjiao He, Xinru Cui, Bo Xu, Xufeng Fu
Di(2-ethylhexyl) phthalate (DEHP), a widely utilized plasticizer, impairs male reproductive function; however, the precise mechanisms underlying this effect have yet to be fully elucidated. This study investigates DEHP-induced spermatocyte toxicity and identifies therapeutic strategies. Integrated network toxicology and proteomics delineated testicular toxicity mechanisms through multi-dimensional analyses. We demonstrate that DEHP exposure induces spermatocyte ferroptosis via PINK1/Parkin-mediated mitophagy. Mechanistically, the bioactive metabolite MEHP promotes NRF2 degradation through the ubiquitin-proteasome pathway, inducing excessive mitochondrial clearance. This process mediates mitochondrial Fe2+ efflux, causing iron dysregulation and lipid peroxidation. Pharmacological inhibition of mitophagy by CsA attenuated ferroptosis and restored iron homeostasis, confirming ferroptosis dependence on mitophagic activation. Crucially, NRF2 activation concurrently suppresses both mitophagic flux and ferroptotic execution. MEHP-induced NRF2 degradation initiates pathological mitophagy and facilitates mitochondrial iron efflux, resulting in dysregulated iron metabolism within spermatocytes. This cascade culminates in spermatocyte ferroptosis mediated by Fe2+ accumulation and lipid peroxidation. This work provides definitive evidence linking environmental toxicant-induced mitophagy to germ cell ferroptosis, identifies NRF2 as a central regulator of this pathway, and proposes targeted mitophagy inhibition combined with NRF2 stabilization as therapeutic interventions.
{"title":"Di(2-ethylhexyl) phthalate induces male reproductive toxicity through mitophagy-dependent ferroptosis of spermatocytes in mice","authors":"Zhen Zhang , Hang Han , Liyang Ding, Hong Yang, Yu Deng, Yitong Shang, Tengjiao He, Xinru Cui, Bo Xu, Xufeng Fu","doi":"10.1016/j.freeradbiomed.2026.01.014","DOIUrl":"10.1016/j.freeradbiomed.2026.01.014","url":null,"abstract":"<div><div>Di(2-ethylhexyl) phthalate (DEHP), a widely utilized plasticizer, impairs male reproductive function; however, the precise mechanisms underlying this effect have yet to be fully elucidated. This study investigates DEHP-induced spermatocyte toxicity and identifies therapeutic strategies. Integrated network toxicology and proteomics delineated testicular toxicity mechanisms through multi-dimensional analyses. We demonstrate that DEHP exposure induces spermatocyte ferroptosis via PINK1/Parkin-mediated mitophagy. Mechanistically, the bioactive metabolite MEHP promotes NRF2 degradation through the ubiquitin-proteasome pathway, inducing excessive mitochondrial clearance. This process mediates mitochondrial Fe<sup>2+</sup> efflux, causing iron dysregulation and lipid peroxidation. Pharmacological inhibition of mitophagy by CsA attenuated ferroptosis and restored iron homeostasis, confirming ferroptosis dependence on mitophagic activation. Crucially, NRF2 activation concurrently suppresses both mitophagic flux and ferroptotic execution. MEHP-induced NRF2 degradation initiates pathological mitophagy and facilitates mitochondrial iron efflux, resulting in dysregulated iron metabolism within spermatocytes. This cascade culminates in spermatocyte ferroptosis mediated by Fe<sup>2+</sup> accumulation and lipid peroxidation. This work provides definitive evidence linking environmental toxicant-induced mitophagy to germ cell ferroptosis, identifies NRF2 as a central regulator of this pathway, and proposes targeted mitophagy inhibition combined with NRF2 stabilization as therapeutic interventions.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 252-268"},"PeriodicalIF":8.2,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146024671","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}
Pub Date : 2026-01-22DOI: 10.1016/j.freeradbiomed.2026.01.034
Giulio Ferrero, Raffaella Mastrocola, Sonia Tarallo, Barbara Pardini, Jean Scheijen, Marjo van de Waarenburg, Gaetano Gallo, Anastasia Chrysovalantou Chatziioannou, Nivonirina Robinot, Pekka Keski-Rahkonen, Gianmarco Piccinno, Nicola Segata, Elom K Aglago, David J Hughes, Mazda Jenab, Casper G Schalkwijk, Alessio Naccarati
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. 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. 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 GLO1 (encoding for the detoxifying enzyme glyoxalase-1), DDOST (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 Fusobacterium nucleatum and Parvimonas micra, two bacterial species related to colorectal carcinogenesis, and with metagenomic signatures of oral-derived taxa colonizing the gut. 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.
{"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, Raffaella Mastrocola, Sonia Tarallo, Barbara Pardini, Jean Scheijen, Marjo van de Waarenburg, Gaetano Gallo, Anastasia Chrysovalantou Chatziioannou, Nivonirina Robinot, Pekka Keski-Rahkonen, Gianmarco Piccinno, Nicola Segata, Elom K Aglago, David J Hughes, Mazda Jenab, Casper G Schalkwijk, Alessio Naccarati","doi":"10.1016/j.freeradbiomed.2026.01.034","DOIUrl":"10.1016/j.freeradbiomed.2026.01.034","url":null,"abstract":"<p><p>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. 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. 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 GLO1 (encoding for the detoxifying enzyme glyoxalase-1), DDOST (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 Fusobacterium nucleatum and Parvimonas micra, two bacterial species related to colorectal carcinogenesis, and with metagenomic signatures of oral-derived taxa colonizing the gut. 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.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":"518-530"},"PeriodicalIF":8.2,"publicationDate":"2026-01-22","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}
Glaucoma remains the leading cause of irreversible blindness worldwide. Trabecular meshwork (TM) dysfunction, particularly fibrosis, is a major driver of elevated intraocular pressure (IOP). Although steroid-induced glaucoma is well established, the impact of chronic stress-related endogenous steroids on TM pathology remains unclear. This study established a corticosterone induced chronic stress mouse model and a cortisol treated human TM cells (HTMCs) model that demonstrated that sustained steroid elevation promotes TM fibrosis and mitochondrial dysfunction. RNA sequencing of HTMCs after cortisol treatment revealed monoamine oxidase A (MAOA) upregulation and enrichment of profibrotic pathways. Cortisol increased mitochondrial elongation factor 1 (MIEF1) and dynamin-related protein 1 (DRP1) phosphorylation at Ser616 (p-DRP1Ser616), driving excessive fission. Knockdown of MAOA or MIEF1 reduced oxidative stress, mitochondrial fragmentation, and extracellular matrix remodeling, whereas overexpression of MAOA and MIEF1 produced the opposite effect. Molecular docking, molecular dynamics simulations, and co-immunoprecipitation confirmed that MAOA interacts with MIEF1 and enhances MIEF1–DRP1 coupling. This study identified the MIEF1–MAOA–DRP1 pathway as a mediator of stress-induced TM fibrosis. It provides new insight into the pathogenesis of glaucoma and identifies MAOA as a potential intervention target for treating glaucoma.
{"title":"Chronic stress-induced steroids mediate mitochondrial fission and fibrosis in the trabecular meshwork via the MIEF1-MAOA complex","authors":"Yilin Sun, Yingjian Sun, Mingxuan Wang, Zhibo Si, Zhaoying Zhang, Yajuan Zheng","doi":"10.1016/j.freeradbiomed.2026.01.037","DOIUrl":"10.1016/j.freeradbiomed.2026.01.037","url":null,"abstract":"<div><div>Glaucoma remains the leading cause of irreversible blindness worldwide. Trabecular meshwork (TM) dysfunction, particularly fibrosis, is a major driver of elevated intraocular pressure (IOP). Although steroid-induced glaucoma is well established, the impact of chronic stress-related endogenous steroids on TM pathology remains unclear. This study established a corticosterone induced chronic stress mouse model and a cortisol treated human TM cells (HTMCs) model that demonstrated that sustained steroid elevation promotes TM fibrosis and mitochondrial dysfunction. RNA sequencing of HTMCs after cortisol treatment revealed monoamine oxidase A (MAOA) upregulation and enrichment of profibrotic pathways. Cortisol increased mitochondrial elongation factor 1 (MIEF1) and dynamin-related protein 1 (DRP1) phosphorylation at Ser616 (p-DRP1<sup>Ser616</sup>), driving excessive fission. Knockdown of MAOA or MIEF1 reduced oxidative stress, mitochondrial fragmentation, and extracellular matrix remodeling, whereas overexpression of MAOA and MIEF1 produced the opposite effect. Molecular docking, molecular dynamics simulations, and co-immunoprecipitation confirmed that MAOA interacts with MIEF1 and enhances MIEF1–DRP1 coupling. This study identified the MIEF1–MAOA–DRP1 pathway as a mediator of stress-induced TM fibrosis. It provides new insight into the pathogenesis of glaucoma and identifies MAOA as a potential intervention target for treating glaucoma.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 316-333"},"PeriodicalIF":8.2,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146043974","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}
Pub Date : 2026-01-21DOI: 10.1016/j.freeradbiomed.2026.01.022
Lin Yang , Jinlian Wang , Xuhui Wang , Bianli Li , Di Zhao , Chunyi Li , Changzhi Li , Yuanbing Cui , Qiuyuan Chen , Yong Yang , Jinhai Gu , Shaozhang Hou , Lianxiang Zhang , Yuanyuan Qiang
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.
{"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 , Jinlian Wang , Xuhui Wang , Bianli Li , Di Zhao , Chunyi Li , Changzhi Li , Yuanbing Cui , Qiuyuan Chen , Yong Yang , Jinhai Gu , Shaozhang Hou , Lianxiang Zhang , 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, Fe<sup>2+</sup> 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":"2026-01-21","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}
Pub Date : 2026-01-20DOI: 10.1016/j.freeradbiomed.2026.01.033
Jinfen Guo , Changku Shi , Chunyu Yu , Yu Wang , Maotao He
Background
Alzheimer's disease (AD), Parkinson's disease (PD) and other neurodegenerative diseases have complex pathogenic mechanisms. Traditional theories (e.g., free radical damage/oxidative stress, inflammatory responses) have laid a foundation for understanding these pathological processes. However, single mechanisms cannot fully explain their complexity. In recent years, post-translational modifications (PTMs)—especially redox-related types such as S-sulfhydration—have emerged as key complementary regulators of nervous system homeostasis and disease progression. It is mediated by the endogenous gas signaling molecule hydrogen sulfide (H2S) and has unique regulatory effects.
Aim of review
This review systematically summarizes the molecular mechanisms and therapeutic targets of S-sulfhydration in AD and PD. It discusses the potential of S-sulfhydration in disease intervention and treatment. It also looks into H2S-based therapeutic strategies and their clinical application prospects. This review aims to provide a theoretical basis for understanding the role of PTMs in neurological diseases.
Key scientific concepts of review
This review summarizes clearly: in AD and PD, S-sulfhydration interacts with protein modifications like phosphorylation, S-nitrosylation and succinylation. It regulates key pathogenic proteins such as Tau, Aβ and Parkin. It also takes part in regulating energy metabolism, resisting oxidative stress and inhibiting inflammatory responses. These effects influence neuronal survival and functional homeostasis. This indicates that S-sulfhydration plays an important regulatory role in AD and PD progression. It is part of the complex network of pathological mechanisms. Its modification mechanisms and interaction pathways offer promising complementary molecular targets and intervention strategies for treating AD, PD, and other potential neurodegenerative diseases.
{"title":"Protein S-sulfhydration: Mechanisms and therapeutic implications in Alzheimer's disease and Parkinson's disease","authors":"Jinfen Guo , Changku Shi , Chunyu Yu , Yu Wang , Maotao He","doi":"10.1016/j.freeradbiomed.2026.01.033","DOIUrl":"10.1016/j.freeradbiomed.2026.01.033","url":null,"abstract":"<div><h3>Background</h3><div>Alzheimer's disease (AD), Parkinson's disease (PD) and other neurodegenerative diseases have complex pathogenic mechanisms. Traditional theories (e.g., free radical damage/oxidative stress, inflammatory responses) have laid a foundation for understanding these pathological processes. However, single mechanisms cannot fully explain their complexity. In recent years, post-translational modifications (PTMs)—especially redox-related types such as S-sulfhydration—have emerged as key complementary regulators of nervous system homeostasis and disease progression. It is mediated by the endogenous gas signaling molecule hydrogen sulfide (H<sub>2</sub>S) and has unique regulatory effects.</div></div><div><h3>Aim of review</h3><div>This review systematically summarizes the molecular mechanisms and therapeutic targets of S-sulfhydration in AD and PD. It discusses the potential of S-sulfhydration in disease intervention and treatment. It also looks into H<sub>2</sub>S-based therapeutic strategies and their clinical application prospects. This review aims to provide a theoretical basis for understanding the role of PTMs in neurological diseases.</div></div><div><h3>Key scientific concepts of review</h3><div>This review summarizes clearly: in AD and PD, S-sulfhydration interacts with protein modifications like phosphorylation, S-nitrosylation and succinylation. It regulates key pathogenic proteins such as Tau, Aβ and Parkin. It also takes part in regulating energy metabolism, resisting oxidative stress and inhibiting inflammatory responses. These effects influence neuronal survival and functional homeostasis. This indicates that S-sulfhydration plays an important regulatory role in AD and PD progression. It is part of the complex network of pathological mechanisms. Its modification mechanisms and interaction pathways offer promising complementary molecular targets and intervention strategies for treating AD, PD, and other potential neurodegenerative diseases.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 431-441"},"PeriodicalIF":8.2,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146029073","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}
Thyroid disorders profoundly disrupt metabolism, development, growth, pubertal timing, and fertility in domestic animals. Gonadotropin-inhibitory hormone (GnIH), a key inhibitory neuropeptide regulating reproductive function, has been implicated in metabolic dysfunction-associated infertility as well as thyroid dysfunction–related pubertal abnormalities. These observations suggest potential crosstalk between GnIH and thyroid hormones (THs), positioning GnIH as a possible integrative regulator linking the hypothalamic-pituitary-thyroid (HPT) and hypothalamic-pituitary-gonadal (HPG) axes. However, the role of GnIH in the modulation of thyroid function remains poorly defined. Using the pig as a translationally relevant model for neuroendocrine research, we investigated the peripheral effects of GnIH on TH synthesis and elucidated the underlying mechanisms in female piglets. Untargeted metabolomic analysis revealed a significant reduction in serum thyroxine levels following chronic intraperitoneal administration of GnIH compared with vehicle-treated controls. Furthermore, colocalization and pharmacological analyses demonstrated that peripheral GnIH directly suppresses TH synthesis in the thyroid gland, leading to decreased circulating TH levels and activation of the negative feedback regulation within the HPT axis. These results suggest that the thyroid gland is a primary peripheral target for GnIH-induced hypothyroidism. Subsequent in vivo and in vitro studies confirmed that peripheral GnIH disrupts mitochondrial function, inducing apoptosis and oxidative stress in thyroid follicular epithelial cells and ultimately causing hypothyroidism, while its effects on proliferation followed an opposite trend. These results establish that GnIH directly inhibits TH synthesis through mitochondrial dysfunction and follicular epithelial cell apoptosis, thereby contributing to hypothyroidism pathogenesis. Our study identifies GnIH as a novel neuroendocrine regulator of thyroid function and suggests that GnIH agonists or antagonists may offer therapeutic potential for thyroid disorders and related conditions.
{"title":"GnIH-induced mitochondrial dysfunction lead to oxidative stress and apoptosis in thyroid follicular cells, causing hypothyroidism","authors":"Ke Peng , Chengcheng Liu , Hongyu Zhu , Xingxing Song, Jiani Zhang, Bingqian Shen, Yuanyuan Xin, Wenqi Wang, Wantong Ji, Lingyuan Zhang, Meijun Lu, Guihao Tang, Junjie Ma, Jiapeng Li, Jiang Li, Yixian Wei, Jiaming Zheng, Xiaoye Wang, Chuanhuo Hu, Xun Li","doi":"10.1016/j.freeradbiomed.2026.01.032","DOIUrl":"10.1016/j.freeradbiomed.2026.01.032","url":null,"abstract":"<div><div>Thyroid disorders profoundly disrupt metabolism, development, growth, pubertal timing, and fertility in domestic animals. Gonadotropin-inhibitory hormone (GnIH), a key inhibitory neuropeptide regulating reproductive function, has been implicated in metabolic dysfunction-associated infertility as well as thyroid dysfunction–related pubertal abnormalities. These observations suggest potential crosstalk between GnIH and thyroid hormones (THs), positioning GnIH as a possible integrative regulator linking the hypothalamic-pituitary-thyroid (HPT) and hypothalamic-pituitary-gonadal (HPG) axes. However, the role of GnIH in the modulation of thyroid function remains poorly defined. Using the pig as a translationally relevant model for neuroendocrine research, we investigated the peripheral effects of GnIH on TH synthesis and elucidated the underlying mechanisms in female piglets. Untargeted metabolomic analysis revealed a significant reduction in serum thyroxine levels following chronic intraperitoneal administration of GnIH compared with vehicle-treated controls. Furthermore, colocalization and pharmacological analyses demonstrated that peripheral GnIH directly suppresses TH synthesis in the thyroid gland, leading to decreased circulating TH levels and activation of the negative feedback regulation within the HPT axis. These results suggest that the thyroid gland is a primary peripheral target for GnIH-induced hypothyroidism. Subsequent <em>in vivo</em> and <em>in vitro</em> studies confirmed that peripheral GnIH disrupts mitochondrial function, inducing apoptosis and oxidative stress in thyroid follicular epithelial cells and ultimately causing hypothyroidism, while its effects on proliferation followed an opposite trend. These results establish that GnIH directly inhibits TH synthesis through mitochondrial dysfunction and follicular epithelial cell apoptosis, thereby contributing to hypothyroidism pathogenesis. Our study identifies GnIH as a novel neuroendocrine regulator of thyroid function and suggests that GnIH agonists or antagonists may offer therapeutic potential for thyroid disorders and related conditions.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"246 ","pages":"Pages 350-367"},"PeriodicalIF":8.2,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146029075","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}
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