Pub Date : 2026-04-01Epub Date: 2026-01-23DOI: 10.1016/j.freeradbiomed.2026.01.043
Zilin Li , Zhe Zhang , Xiaoqin Qian
Timosaponin AIII (Tim-AIII), a steroidal saponin derived from Anemarrhena asphodeloides, has emerged as a promising antitumor agent, yet its precise molecular targets and mechanisms in breast cancer remain poorly defined. Here, we identify fibroblast growth factor 2 (FGF2) as a direct binding target of Tim-AIII using a combination of network pharmacology, CETSA, and surface plasmon resonance assays. Mechanistically, Tim-AIII exhibits a dual therapeutic mode of action. First, it induces reactive oxygen species (ROS)-mediated endoplasmic reticulum (ER) stress, activating the eIF2α–ATF4–CHOP axis and initiating apoptosis. Second, it dampens the FGF2–FGFR1–PI3K/AKT signaling cascade, thereby inhibiting epithelial-mesenchymal transition (EMT) and suppressing cell migration and invasion. RNA sequencing and enrichment analyses confirm that Tim-AIII regulates critical oncogenic pathways, including ER stress, calcium signaling, and PI3K/AKT. In vivo evaluations demonstrate that Tim-AIII significantly reduces tumor growth without detectable systemic toxicity in breast cancer-bearing mice. This study not only elucidates the molecular basis of Tim-AIII's antitumor efficacy but also positions it as a potential targeted therapeutic for breast cancer, with dual action on ERS-induced apoptosis and EMT suppression.
{"title":"FGF2-targeted Timosaponin AIII provokes ER stress and dampens PI3KAKT signaling pathway in breast cancer","authors":"Zilin Li , Zhe Zhang , Xiaoqin Qian","doi":"10.1016/j.freeradbiomed.2026.01.043","DOIUrl":"10.1016/j.freeradbiomed.2026.01.043","url":null,"abstract":"<div><div>Timosaponin AIII (Tim-AIII), a steroidal saponin derived from <em>Anemarrhena asphodeloides</em>, has emerged as a promising antitumor agent, yet its precise molecular targets and mechanisms in breast cancer remain poorly defined. Here, we identify fibroblast growth factor 2 (FGF2) as a direct binding target of Tim-AIII using a combination of network pharmacology, CETSA, and surface plasmon resonance assays. Mechanistically, Tim-AIII exhibits a dual therapeutic mode of action. First, it induces reactive oxygen species (ROS)-mediated endoplasmic reticulum (ER) stress, activating the eIF2α–ATF4–CHOP axis and initiating apoptosis. Second, it dampens the FGF2–FGFR1–PI3K/AKT signaling cascade, thereby inhibiting epithelial-mesenchymal transition (EMT) and suppressing cell migration and invasion. RNA sequencing and enrichment analyses confirm that Tim-AIII regulates critical oncogenic pathways, including ER stress, calcium signaling, and PI3K/AKT. In vivo evaluations demonstrate that Tim-AIII significantly reduces tumor growth without detectable systemic toxicity in breast cancer-bearing mice. This study not only elucidates the molecular basis of Tim-AIII's antitumor efficacy but also positions it as a potential targeted therapeutic for breast cancer, with dual action on ERS-induced apoptosis and EMT suppression.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"247 ","pages":"Pages 95-106"},"PeriodicalIF":8.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146046406","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 : 2026-04-01Epub Date: 2026-02-04DOI: 10.1016/j.freeradbiomed.2026.01.062
Wang Zeying , Li Houyu , Yang Zhongbin , Tai Yu , He Qi , Hou Kun , He Qihang , Zhou Yingnan , Liu Zhi , Li Xiaojing , Zhang Xueming , Ma Qiang , Zhou Jingye , Shi Caixia , He Liran , Jin Jing , Su Yan
Background
D-ribose, a highly reducing pentose sugar, can be phosphorylated by ribokinase (RBKS) to form ribose-5-phosphate (R-5-P). Elevated urinary D-ribose levels have been reported in patients with type 2 diabetes mellitus (T2DM) and Alzheimer's disease, implicating its potential role in disease pathogenesis. Previous investigations into D-ribose cytotoxicity have primarily focused on its non-enzymatic glycation activity, while alternative mechanisms remain underexplored. Since hemoglobin is a major in vivo target of glycation, this study utilized K562 cells—which retain inducible hemoglobin expression—to explore additional cytotoxic mechanisms of D-ribose.
Methods and results
CCK-8 assays demonstrated that D-ribose inhibited K562 cell proliferation in a concentration- and time-dependent manner, and this inhibitory effect was significantly enhanced in both hemin-induced differentiated and RBKS knockout K562 cells. Conversely, RBKS overexpression promoted proliferation and alleviated oxidative stress in K562 cells. Transcriptomic analysis revealed that differentially expressed genes in D-ribose-treated cells were enriched in mineral absorption and oxidative phosphorylation pathways (KEGG), as well as in biological processes related to copper ion homeostasis (GO). RT-qPCR confirmed that both D-ribose treatment and RBKS knockout downregulated key copper homeostasis genes (e.g., SLC31A1, MT1F, ATOX1) and mitochondrial respiratory chain genes (e.g., COX17, COX11, MTATP8, MTND6), and were accompanied by a significant reduction in intracellular free copper levels.
Conclusions
These findings reveal a novel cytotoxic mechanism mediated by the RBKS-copper-oxidative phosphorylation axis in D-ribose-treated K562 cells, providing key insights into the intracellular role of D-ribose.
{"title":"D-ribose-induced cytotoxicity in K562 cells: RBKS-dependent disruption of copper homeostasis and mitochondrial function","authors":"Wang Zeying , Li Houyu , Yang Zhongbin , Tai Yu , He Qi , Hou Kun , He Qihang , Zhou Yingnan , Liu Zhi , Li Xiaojing , Zhang Xueming , Ma Qiang , Zhou Jingye , Shi Caixia , He Liran , Jin Jing , Su Yan","doi":"10.1016/j.freeradbiomed.2026.01.062","DOIUrl":"10.1016/j.freeradbiomed.2026.01.062","url":null,"abstract":"<div><h3>Background</h3><div>D-ribose, a highly reducing pentose sugar, can be phosphorylated by ribokinase (RBKS) to form ribose-5-phosphate (R-5-P). Elevated urinary D-ribose levels have been reported in patients with type 2 diabetes mellitus (T2DM) and Alzheimer's disease, implicating its potential role in disease pathogenesis. Previous investigations into D-ribose cytotoxicity have primarily focused on its non-enzymatic glycation activity, while alternative mechanisms remain underexplored. Since hemoglobin is a major in vivo target of glycation, this study utilized K562 cells—which retain inducible hemoglobin expression—to explore additional cytotoxic mechanisms of D-ribose.</div></div><div><h3>Methods and results</h3><div>CCK-8 assays demonstrated that D-ribose inhibited K562 cell proliferation in a concentration- and time-dependent manner, and this inhibitory effect was significantly enhanced in both hemin-induced differentiated and <em>RBKS</em> knockout K562 cells. Conversely, <em>RBKS</em> overexpression promoted proliferation and alleviated oxidative stress in K562 cells. Transcriptomic analysis revealed that differentially expressed genes in D-ribose-treated cells were enriched in mineral absorption and oxidative phosphorylation pathways (KEGG), as well as in biological processes related to copper ion homeostasis (GO). RT-qPCR confirmed that both D-ribose treatment and <em>RBKS</em> knockout downregulated key copper homeostasis genes (e.g., <em>SLC31A1, MT1F, ATOX1</em>) and mitochondrial respiratory chain genes (e.g., <em>COX17, COX11, MTATP8, MTND6</em>), and were accompanied by a significant reduction in intracellular free copper levels.</div></div><div><h3>Conclusions</h3><div>These findings reveal a novel cytotoxic mechanism mediated by the RBKS-copper-oxidative phosphorylation axis in D-ribose-treated K562 cells, providing key insights into the intracellular role of D-ribose.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"247 ","pages":"Pages 240-250"},"PeriodicalIF":8.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146131740","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 : 2026-04-01Epub Date: 2026-02-04DOI: 10.1016/j.freeradbiomed.2026.01.065
Yukun Li , Sicheng Zheng , Haowen Zhuang , Ji Wu , Junyan Wang , Xing Chang
Objectives
Doxorubicin (Dox) is a potent chemotherapeutic agent whose clinical use is limited by severe cardiotoxicity. The underlying molecular mechanisms remain incompletely understood. This study aimed to investigate the role of the phosphoglycerate mutase 1 (PGAM1)/voltage-dependent anion channel 1 (VDAC1) axis in early-stage Dox-induced cardiotoxicity, focusing on its impact on mitochondrial quality control (MQC), endoplasmic reticulum (ER) stress, and the subsequent activation of innate immune signaling.
Methods
We established a short-term cumulative Dox-induced cardiomyopathy model using wild-type and cardiomyocyte-specific PGAM1 knockout (PGAM1-CKO) mice. Cardiac function was assessed by echocardiography. In vitro experiments were performed on neonatal mouse cardiomyocytes (NMCMs) and HL-1 cells. Molecular techniques including Western blotting, immunofluorescence, co-immunoprecipitation, and quantitative PCR were used to dissect the signaling pathway. Key pathway components were validated using specific pharmacological inhibitors and activators.
Results
Dox treatment significantly upregulated PGAM1 expression in cardiomyocytes. PGAM1-CKO mice were protected from Dox-induced cardiac dysfunction, fibrosis, and inflammation. Mechanistically, Dox-induced PGAM1 promoted the pathological oligomerization of VDAC1. This PGAM1-VDAC1 interaction triggered the collapse of MQC and induced ER stress, leading to the leakage of mitochondrial DNA (mtDNA) into the cytosol. The released cytosolic mtDNA subsequently activated the cGAS-STING innate immune pathway, which we identified as a critical upstream driver of cardiomyocyte ferroptosis. Pharmacological induction of VDAC1 oligomerization or STING activation abolished the cardioprotective effects observed in PGAM1-CKO mice.
Conclusion
Our findings reveal a novel PGAM1/VDAC1 signaling axis that triggers early Dox-induced cardiotoxicity. This axis disrupts mitochondrial homeostasis, leading to mtDNA release, which activates the cGAS-STING pathway and ultimately culminates in cardiomyocyte ferroptosis. Targeting the PGAM1/VDAC1 interaction presents a promising therapeutic strategy to mitigate Dox-induced cardiac injury.
{"title":"PGAM1-dependent VDAC1 oligomerization disrupts mitochondrial quality control to drive doxorubicin cardiotoxicity via the cGAS-STING-ferroptosis axis","authors":"Yukun Li , Sicheng Zheng , Haowen Zhuang , Ji Wu , Junyan Wang , Xing Chang","doi":"10.1016/j.freeradbiomed.2026.01.065","DOIUrl":"10.1016/j.freeradbiomed.2026.01.065","url":null,"abstract":"<div><h3>Objectives</h3><div>Doxorubicin (Dox) is a potent chemotherapeutic agent whose clinical use is limited by severe cardiotoxicity. The underlying molecular mechanisms remain incompletely understood. This study aimed to investigate the role of the phosphoglycerate mutase 1 (PGAM1)/voltage-dependent anion channel 1 (VDAC1) axis in early-stage Dox-induced cardiotoxicity, focusing on its impact on mitochondrial quality control (MQC), endoplasmic reticulum (ER) stress, and the subsequent activation of innate immune signaling.</div></div><div><h3>Methods</h3><div>We established a short-term cumulative Dox-induced cardiomyopathy model using wild-type and cardiomyocyte-specific PGAM1 knockout (PGAM1-CKO) mice. Cardiac function was assessed by echocardiography. In vitro experiments were performed on neonatal mouse cardiomyocytes (NMCMs) and HL-1 cells. Molecular techniques including Western blotting, immunofluorescence, co-immunoprecipitation, and quantitative PCR were used to dissect the signaling pathway. Key pathway components were validated using specific pharmacological inhibitors and activators.</div></div><div><h3>Results</h3><div>Dox treatment significantly upregulated PGAM1 expression in cardiomyocytes. PGAM1-CKO mice were protected from Dox-induced cardiac dysfunction, fibrosis, and inflammation. Mechanistically, Dox-induced PGAM1 promoted the pathological oligomerization of VDAC1. This PGAM1-VDAC1 interaction triggered the collapse of MQC and induced ER stress, leading to the leakage of mitochondrial DNA (mtDNA) into the cytosol. The released cytosolic mtDNA subsequently activated the cGAS-STING innate immune pathway, which we identified as a critical upstream driver of cardiomyocyte ferroptosis. Pharmacological induction of VDAC1 oligomerization or STING activation abolished the cardioprotective effects observed in PGAM1-CKO mice.</div></div><div><h3>Conclusion</h3><div>Our findings reveal a novel PGAM1/VDAC1 signaling axis that triggers early Dox-induced cardiotoxicity. This axis disrupts mitochondrial homeostasis, leading to mtDNA release, which activates the cGAS-STING pathway and ultimately culminates in cardiomyocyte ferroptosis. Targeting the PGAM1/VDAC1 interaction presents a promising therapeutic strategy to mitigate Dox-induced cardiac injury.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"247 ","pages":"Pages 71-94"},"PeriodicalIF":8.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146131872","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 : 2026-04-01Epub Date: 2026-02-02DOI: 10.1016/j.freeradbiomed.2026.02.001
Jiawei Zhao , Xuefeng Zhang , Yanqing Zhou , Dongsheng Bai , Jiaying Du , Chen Zhou , Chunyang Gu , Yuxiang Wang , Yuan Gao , Na Lu , Yue Zhao
Small cell lung cancer (SCLC) is an aggressive malignancy characterized by limited therapeutic options. In this study, we identified GL-V9 as a potent anti-SCLC agent that induces apoptosis through oxidative stress. GL-V9 significantly reduced SCLC cell viability in a dose-dependent manner and triggered apoptosis both in vitro and in xenograft models. Mechanistically, GL-V9 increased reactive oxygen species (ROS) levels and lipid peroxidation while impairing mitochondrial function, suggesting that its cytotoxic effects are mediated by oxidative stress. Drug-target interaction analyses revealed that GL-V9 directly binds to STEAP3, a key regulator of iron metabolism, and promotes its degradation via the ubiquitin-proteasome pathway. The loss of STEAP3 disrupted iron homeostasis and exacerbated oxidative stress. In contrast, STEAP3 overexpression attenuated ROS accumulation, mitochondrial damage, and apoptosis both in vitro and in vivo. Further investigation demonstrated that STEAP3 degradation decreased the stability of CISD2, a [2Fe-2S] cluster-containing mitochondrial protein essential for redox balance. GL-V9 downregulated CISD2 in a STEAP3-dependent manner, and restoring CISD2 expression significantly rescued cells from GL-V9-induced oxidative stress and apoptosis. Clinically, both STEAP3 and CISD2 are upregulated in SCLC tumors, and their elevated expression correlates with poor patient survival. Co-expression analysis associated these proteins with pathways involved in oxidative stress and mitochondrial dysfunction. Overall, these findings suggest that GL-V9 induces apoptosis in SCLC by targeting STEAP3 for proteasomal degradation, thereby disrupting the STEAP3-CISD2 axis and promoting oxidative stress-driven cell death. This study identifies a previously unrecognized redox regulatory pathway in SCLC and proposes a potential therapeutic strategy centered on selective induction of oxidative stress.
{"title":"The flavonoid GL-V9 induces oxidative stress mediated apoptosis in small cell lung cancer by promoting STEAP3 degradation","authors":"Jiawei Zhao , Xuefeng Zhang , Yanqing Zhou , Dongsheng Bai , Jiaying Du , Chen Zhou , Chunyang Gu , Yuxiang Wang , Yuan Gao , Na Lu , Yue Zhao","doi":"10.1016/j.freeradbiomed.2026.02.001","DOIUrl":"10.1016/j.freeradbiomed.2026.02.001","url":null,"abstract":"<div><div>Small cell lung cancer (SCLC) is an aggressive malignancy characterized by limited therapeutic options. In this study, we identified GL-V9 as a potent anti-SCLC agent that induces apoptosis through oxidative stress. GL-V9 significantly reduced SCLC cell viability in a dose-dependent manner and triggered apoptosis both <em>in vitro</em> and in xenograft models. Mechanistically, GL-V9 increased reactive oxygen species (ROS) levels and lipid peroxidation while impairing mitochondrial function, suggesting that its cytotoxic effects are mediated by oxidative stress. Drug-target interaction analyses revealed that GL-V9 directly binds to STEAP3, a key regulator of iron metabolism, and promotes its degradation via the ubiquitin-proteasome pathway. The loss of STEAP3 disrupted iron homeostasis and exacerbated oxidative stress. In contrast, STEAP3 overexpression attenuated ROS accumulation, mitochondrial damage, and apoptosis both <em>in vitro</em> and <em>in vivo</em>. Further investigation demonstrated that STEAP3 degradation decreased the stability of CISD2, a [2Fe-2S] cluster-containing mitochondrial protein essential for redox balance. GL-V9 downregulated CISD2 in a STEAP3-dependent manner, and restoring CISD2 expression significantly rescued cells from GL-V9-induced oxidative stress and apoptosis. Clinically, both STEAP3 and CISD2 are upregulated in SCLC tumors, and their elevated expression correlates with poor patient survival. Co-expression analysis associated these proteins with pathways involved in oxidative stress and mitochondrial dysfunction. Overall, these findings suggest that GL-V9 induces apoptosis in SCLC by targeting STEAP3 for proteasomal degradation, thereby disrupting the STEAP3-CISD2 axis and promoting oxidative stress-driven cell death. This study identifies a previously unrecognized redox regulatory pathway in SCLC and proposes a potential therapeutic strategy centered on selective induction of oxidative stress.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"247 ","pages":"Pages 1-14"},"PeriodicalIF":8.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146118409","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 : 2026-04-01Epub Date: 2026-02-11DOI: 10.1016/j.freeradbiomed.2026.02.025
Vasanthi Rajasekaran , Shubham Dubey , Teshi Kaushik , Annalese G. Neuenschwander , Namakkal-Soorappan Rajasekaran , Dan E. Berkowitz , Praveen K. Dubey
Preeclampsia (PE) is a pregnancy disorder characterized by high blood pressure and proteinuria after the 20th week. In this condition, reduced blood flow to the placenta leads to placental ischemia and oxidative stress, resulting in mitochondrial DNA damage and dysfunction. In this case of preeclampsia, a unique feature is observed: the presence of mitochondrial heterogeneity and heteroplasmy in the preeclamptic placenta, but not in circulating plasma. We found a single nucleotide addition (m.310C) in the MT-D-loop region and a heteroplasmic mutation (m.7681C < T) in the Cytochrome C Oxidase Subunit II (MT-COX2) gene. This heteroplasmic mutation causes a phenylalanine (F) to serine (S) substitution in the MT-COX2 protein. A cost-effective Tetra ARMS PCR assay was developed to screen this heteroplasmic variation, producing distinctive 269-bp, 197-bp (T), and 132-bp (C) bands. Additionally, mitochondrial mutational burden measurement in placental tissue indicated a higher number of mutant mitochondria than in WT, suggesting a significant mutational burden. Ultrastructural examination of the patient's placenta via electron microscopy demonstrated a mix of healthy oval mitochondria alongside stressed (rounded mitochondria) and increased vacuolization and collagen fibril formation. These findings suggest that mtDNA mutations that may play a role in altered mitochondrial morphology may contribute to mitochondrial dysfunction in the patient's placental pathology, which needs to be further investigated.
{"title":"Mitochondrial heterogeneity in a patient with preeclampsia","authors":"Vasanthi Rajasekaran , Shubham Dubey , Teshi Kaushik , Annalese G. Neuenschwander , Namakkal-Soorappan Rajasekaran , Dan E. Berkowitz , Praveen K. Dubey","doi":"10.1016/j.freeradbiomed.2026.02.025","DOIUrl":"10.1016/j.freeradbiomed.2026.02.025","url":null,"abstract":"<div><div>Preeclampsia (PE) is a pregnancy disorder characterized by high blood pressure and proteinuria after the 20th week. In this condition, reduced blood flow to the placenta leads to placental ischemia and oxidative stress, resulting in mitochondrial DNA damage and dysfunction. In this case of preeclampsia, a unique feature is observed: the presence of mitochondrial heterogeneity and heteroplasmy in the preeclamptic placenta, but not in circulating plasma. We found a single nucleotide addition (m.310C) in the MT-D-loop region and a heteroplasmic mutation (m.7681C < T) in the Cytochrome C Oxidase Subunit II (MT-COX2) gene. This heteroplasmic mutation causes a phenylalanine (F) to serine (S) substitution in the MT-COX2 protein. A cost-effective Tetra ARMS PCR assay was developed to screen this heteroplasmic variation, producing distinctive 269-bp, 197-bp (T), and 132-bp (C) bands. Additionally, mitochondrial mutational burden measurement in placental tissue indicated a higher number of mutant mitochondria than in WT, suggesting a significant mutational burden. Ultrastructural examination of the patient's placenta via electron microscopy demonstrated a mix of healthy oval mitochondria alongside stressed (rounded mitochondria) and increased vacuolization and collagen fibril formation. These findings suggest that mtDNA mutations that may play a role in altered mitochondrial morphology may contribute to mitochondrial dysfunction in the patient's placental pathology, which needs to be further investigated.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"247 ","pages":"Pages 315-318"},"PeriodicalIF":8.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146192577","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}
Air pollution-induced emphysema is accompanied by changes in pulmonary vasculature, leading to pulmonary hypertension (PH) and ultimately heart failure. Pyrroloquinoline Quinone (PQQ), a potent antioxidant with cardio-protective properties, upregulates mitochondrial biogenesis and functions. Previously, we have shown that PQQ protects against PH; however, the effect of PQQ on emphysema and the mitochondrial dysfunction due to air pollution still remains unexplored. In our study, we unraveled the effect of PQQ on Ultrafine carbon particle (UFCP) induced emphysema and PH. In the in vitro studies, human lung adenocarcinoma epithelial cells (A549 cells) were exposed to UFCP (50 μg/ml) and PQQ (100 μM) for 24 h, and following this, the redox state and mitochondrial health of the cells were examined. For the in vivo study, SD rats were administered UFCP (100 μg/dose, three times a week, intranasally) and PQQ (2 mg/kg, oral/day) for four weeks. Plethysmography, 2-D Echo, and invasive blood pressure measurement were used to study pulmonary, hemodynamic, and cardiac functions, and metabolic changes were studied by untargeted metabolomics of the lungs. PQQ treatment improved mitochondrial structure, dynamics, and biogenesis and reduced oxidative stress in UFCP-exposed A549 cells. PQQ significantly improved pulmonary functions, inflammation, structure, and muscularization of vessels in UFCP-exposed rats (#p < 0.01). Metabolomics study showed improved metabolism in the lungs of PQQ-treated rats. Further, PQQ significantly reduced right ventricular pressure (RVP) and hypertrophy (RVH) in UFCP-exposed rats (#p < 0.05). Our findings suggest that improving mitochondrial functions by PQQ preserves alveolar integrity and prevents pulmonary hypertension, and it can be a promising prophylactic, especially for pollution-ridden settings.
{"title":"Improving mitochondrial health by pyrroloquinoline quinone (PQQ) prevents ultrafine carbon particle (UFCP) induced emphysema and associated pulmonary hypertension","authors":"Mohit Barsain , Rifat Parveen , Kusum Devi , Manendra Singh Tomar , Sarita Yadav , Rakesh Kumar Sharma , Ashutosh Shrivastava , Kalyan Mitra , Baisakhi Moharana , Kashif Hanif","doi":"10.1016/j.freeradbiomed.2026.02.015","DOIUrl":"10.1016/j.freeradbiomed.2026.02.015","url":null,"abstract":"<div><div>Air pollution-induced emphysema is accompanied by changes in pulmonary vasculature, leading to pulmonary hypertension (PH) and ultimately heart failure. Pyrroloquinoline Quinone (PQQ), a potent antioxidant with cardio-protective properties, upregulates mitochondrial biogenesis and functions. Previously, we have shown that PQQ protects against PH; however, the effect of PQQ on emphysema and the mitochondrial dysfunction due to air pollution still remains unexplored. In our study, we unraveled the effect of PQQ on Ultrafine carbon particle (UFCP) induced emphysema and PH. In the <em>in vitro</em> studies, human lung adenocarcinoma epithelial cells (A549 cells) were exposed to UFCP (50 μg/ml) and PQQ (100 μM) for 24 h, and following this, the redox state and mitochondrial health of the cells were examined. For the <em>in vivo</em> study, SD rats were administered UFCP (100 μg/dose, three times a week, intranasally) and PQQ (2 mg/kg, oral/day) for four weeks. Plethysmography, 2-D Echo, and invasive blood pressure measurement were used to study pulmonary, hemodynamic, and cardiac functions, and metabolic changes were studied by untargeted metabolomics of the lungs. PQQ treatment improved mitochondrial structure, dynamics, and biogenesis and reduced oxidative stress in UFCP-exposed A549 cells. PQQ significantly improved pulmonary functions, inflammation, structure, and muscularization of vessels in UFCP-exposed rats (#<em>p</em> < 0.01). Metabolomics study showed improved metabolism in the lungs of PQQ-treated rats. Further, PQQ significantly reduced right ventricular pressure (RVP) and hypertrophy (RVH) in UFCP-exposed rats (#<em>p</em> < 0.05). Our findings suggest that improving mitochondrial functions by PQQ preserves alveolar integrity and prevents pulmonary hypertension, and it can be a promising prophylactic, especially for pollution-ridden settings.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"247 ","pages":"Pages 267-285"},"PeriodicalIF":8.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146149498","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 : 2026-04-01Epub Date: 2026-01-29DOI: 10.1016/j.freeradbiomed.2026.01.052
Changxi Qi , Huiling Xu , Muzi Li , Guodong Cheng , Jiayi Li , Yue Yu , Zhiyuan Lu , Xiaozhou Wang , Jianzhu Liu , Xiaona Zhao
Hexavalent chromium [Cr(VI)] is a widespread environmental contaminant known to cause severe organ damage, with acute exposure leading to significant nephrotoxicity. To elucidate the underlying mechanisms, this study investigated the role of the mitophagy-ferroptosis axis in Cr(VI)-induced renal injury using mouse models and renal tubular epithelial cells (mRTECs). We found that Cr(VI) exposure disrupted mitochondrial iron homeostasis in mRTECs, leading to Mito-Fe2+ accumulation and mitochondrial damage. Consequently, this triggered an overproduction of mitochondrial and total reactive oxygen species (Mito-ROS/total ROS) and initiated lipid peroxidation. Furthermore, our mechanistic studies revealed that Cr(VI) induced FUNDC1-dependent mitophagy, which specifically targeted the degradation of SLC7A11. This event downregulated GPX4 and impaired the glutathione antioxidant system, thereby exacerbating lipid peroxidation and ultimately driving ferroptosis. In vivo studies corroborated these findings, demonstrating evident renal injury in Cr(VI)-exposed mouse. Collectively, Our data reveal a novel mechanism whereby FUNDC1-mediated mitophagy participates in hexavalent Cr(VI)-induced renal ferroptosis through degradation of SLC7A11. These results not only clarify a key pathological pathway but also highlight the therapeutic potential of targeting the SLC7A11-FUNDC1 axis to mitigate Cr(VI) nephrotoxicity.
{"title":"SLC7A11-FUNDC1 axis drives Cr(VI)-Induced renal injury through mitophagy-ferroptosis crosstalk","authors":"Changxi Qi , Huiling Xu , Muzi Li , Guodong Cheng , Jiayi Li , Yue Yu , Zhiyuan Lu , Xiaozhou Wang , Jianzhu Liu , Xiaona Zhao","doi":"10.1016/j.freeradbiomed.2026.01.052","DOIUrl":"10.1016/j.freeradbiomed.2026.01.052","url":null,"abstract":"<div><div>Hexavalent chromium [Cr(VI)] is a widespread environmental contaminant known to cause severe organ damage, with acute exposure leading to significant nephrotoxicity. To elucidate the underlying mechanisms, this study investigated the role of the mitophagy-ferroptosis axis in Cr(VI)-induced renal injury using mouse models and renal tubular epithelial cells (mRTECs). We found that Cr(VI) exposure disrupted mitochondrial iron homeostasis in mRTECs, leading to Mito-Fe<sup>2+</sup> accumulation and mitochondrial damage. Consequently, this triggered an overproduction of mitochondrial and total reactive oxygen species (Mito-ROS/total ROS) and initiated lipid peroxidation. Furthermore, our mechanistic studies revealed that Cr(VI) induced FUNDC1-dependent mitophagy, which specifically targeted the degradation of SLC7A11. This event downregulated GPX4 and impaired the glutathione antioxidant system, thereby exacerbating lipid peroxidation and ultimately driving ferroptosis. <em>In vivo</em> studies corroborated these findings, demonstrating evident renal injury in Cr(VI)-exposed mouse. Collectively, Our data reveal a novel mechanism whereby FUNDC1-mediated mitophagy participates in hexavalent Cr(VI)-induced renal ferroptosis through degradation of SLC7A11. These results not only clarify a key pathological pathway but also highlight the therapeutic potential of targeting the SLC7A11-FUNDC1 axis to mitigate Cr(VI) nephrotoxicity.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"247 ","pages":"Pages 15-26"},"PeriodicalIF":8.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146096895","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 : 2026-04-01Epub Date: 2026-02-24DOI: 10.1016/j.freeradbiomed.2026.02.063
{"title":"Expression of concern: \"PTEN deletion leads to deregulation of antioxidants and increased oxidative damage in mouse embryonic fibroblasts\" by Yan-Ying Huo [Free Radic. Biol. Med. 44 (2008) 1578-1591, https://doi.org/10.1016/j.freeradbiomed.2008.01.013].","authors":"","doi":"10.1016/j.freeradbiomed.2026.02.063","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2026.02.063","url":null,"abstract":"","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"247 ","pages":"553"},"PeriodicalIF":8.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147431876","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 : 2026-04-01Epub Date: 2026-02-10DOI: 10.1016/j.freeradbiomed.2026.02.019
Yao Song , Xiaolong Lu , Ximeng Ren , Meng Li , Fanrui Meng , Yuxin Miao , Dapeng Ding , Yang Liu
Ischemia-reperfusion injury refers to the damage that occurs in an organ or tissue following the restoration of blood supply after a period of ischemia. Intestinal ischemia-reperfusion injury (I/R) represents a worldwide public health issue characterized by excessive inflammation and currently lacks effective clinical therapies. Activation of the NLRP3 inflammasome is not only a hallmark feature of intestinal I/R but also serves as a significant exacerbating factor in intestinal deterioration. TRIM25 is involved in regulating endoplasmic reticulum stress, the unfolded protein response, and inflammatory responses. However, its specific role in intestinal I/R remains unclear and may be associated with the activation of the NLRP3 inflammasome. In the intestinal tissues of mice subjected to intestinal I/R, TRIM25 expression was significantly upregulated and showed a positive correlation with NLRP3 inflammasome activation. Knockdown of TRIM25 suppressed hypoxia-reoxygenation (H/R)-induced activation of the NLRP3 inflammasome and the cGAS-STING pathway. It also reduced mitochondrial reactive oxygen species production, alterations in mitochondrial membrane potential, and cytosolic release of mitochondrial DNA. Moreover, NLRP3 inflammasome activation during intestinal I/R was attenuated by both cGAS knockdown and treatment with a specific cGAS inhibitor. Mechanistically, TRIM25 interacts with and potentially ubiquitinates the mitochondrial outer membrane phosphatase PGAM5, which leads to increased mitochondrial membrane permeability and thereby promotes the leakage of mtDNA into the cytosol. The leaked mtDNA is subsequently recognized by cGAS, initiating the activation of its downstream coupled STING pathway—a key component of the innate immune system responsible for detecting the presence of cytosolic DNA. Consequently, our results demonstrate that TRIM25-mediated mtDNA release, induced through its direct interaction with PGAM5, which in turn leads to the activation of the cGAS-STING pathway. This activation represents a critical determinant of NLRP3 inflammasome activation and intestinal injury. Accordingly, therapeutic targeting of this signaling pathway may hold potential for the treatment of intestinal I/R.
{"title":"TRIM25 triggers pyroptosis through mitochondrial DNA release in intestinal ischemia-reperfusion injury","authors":"Yao Song , Xiaolong Lu , Ximeng Ren , Meng Li , Fanrui Meng , Yuxin Miao , Dapeng Ding , Yang Liu","doi":"10.1016/j.freeradbiomed.2026.02.019","DOIUrl":"10.1016/j.freeradbiomed.2026.02.019","url":null,"abstract":"<div><div>Ischemia-reperfusion injury refers to the damage that occurs in an organ or tissue following the restoration of blood supply after a period of ischemia. Intestinal ischemia-reperfusion injury (I/R) represents a worldwide public health issue characterized by excessive inflammation and currently lacks effective clinical therapies. Activation of the NLRP3 inflammasome is not only a hallmark feature of intestinal I/R but also serves as a significant exacerbating factor in intestinal deterioration. TRIM25 is involved in regulating endoplasmic reticulum stress, the unfolded protein response, and inflammatory responses. However, its specific role in intestinal I/R remains unclear and may be associated with the activation of the NLRP3 inflammasome. In the intestinal tissues of mice subjected to intestinal I/R, TRIM25 expression was significantly upregulated and showed a positive correlation with NLRP3 inflammasome activation. Knockdown of TRIM25 suppressed hypoxia-reoxygenation (H/R)-induced activation of the NLRP3 inflammasome and the cGAS-STING pathway. It also reduced mitochondrial reactive oxygen species production, alterations in mitochondrial membrane potential, and cytosolic release of mitochondrial DNA. Moreover, NLRP3 inflammasome activation during intestinal I/R was attenuated by both cGAS knockdown and treatment with a specific cGAS inhibitor. Mechanistically, TRIM25 interacts with and potentially ubiquitinates the mitochondrial outer membrane phosphatase PGAM5, which leads to increased mitochondrial membrane permeability and thereby promotes the leakage of mtDNA into the cytosol. The leaked mtDNA is subsequently recognized by cGAS, initiating the activation of its downstream coupled STING pathway—a key component of the innate immune system responsible for detecting the presence of cytosolic DNA. Consequently, our results demonstrate that TRIM25-mediated mtDNA release, induced through its direct interaction with PGAM5, which in turn leads to the activation of the cGAS-STING pathway. This activation represents a critical determinant of NLRP3 inflammasome activation and intestinal injury. Accordingly, therapeutic targeting of this signaling pathway may hold potential for the treatment of intestinal I/R.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"247 ","pages":"Pages 333-347"},"PeriodicalIF":8.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146178852","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 : 2026-04-01Epub Date: 2026-01-27DOI: 10.1016/j.freeradbiomed.2026.01.051
Xinyi Zeng, Deijian Peng, Yunlong Shen, Li Tang, Tianlu Ran, Ziheng Pan, Hui Liu
Alzheimer's disease (AD) is a common neurodegenerative disorder characterized by the abnormal aggregation of amyloid-β (Aβ). Bletilla striata polysaccharide (BSP), the primary active component of the traditional Chinese medicine Bletilla striata, exhibits various pharmacological effects including hemostatic, antioxidant, anti-inflammatory, and immunomodulatory activities. This study aimed to systematically investigate the protective effects and molecular mechanisms of BSP in Caenorhabditis elegans AD model. We found that BSP effectively alleviated the paralysis phenotype in AD worms, with optimal efficacy observed at a concentration of 100 μg/mL. Furthermore, BSP significantly extended the lifespan of both wild type and AD worms, reduced lipofuscin deposition and egg-laying capacity, improved neuromuscular function, learning ability, and stress resistance, and lowered the level of oxidative stress in vivo. Additionally, BSP treatment markedly suppressed Aβ aggregation in AD worms. Transcriptomic analysis revealed that BSP significantly regulates the autophagy pathway. In combination with genetic experiments, we further elucidated that BSP coordinates the insulin and AMPK signaling pathways to modulate autophagy, thereby reducing abnormal autophagosome accumulation and restoring autophagic homeostasis. Notably, the neuroprotective effects of BSP were completely abolished in mutants of key insulin signaling pathway genes (daf-2, age-1, akt-1, akt-2, daf-16) and the AMPK homologous gene aak-2, indicating that its efficacy is associated with the insulin/AMPK-autophagy regulatory axis. This study reveals the mechanism by which BSP ameliorates AD pathology through multi-target and multi-pathway regulation of autophagy, providing a new theoretical basis for its development as a candidate therapeutic agent for AD and further highlighting the potential medical value of Bletilla striata in combating AD.
阿尔茨海默病（AD）是一种常见的神经退行性疾病，其特征是淀粉样蛋白-β (a β)异常聚集。白芨多糖（Bletilla striata多糖，BSP）是中药白芨的主要活性成分，具有止血、抗氧化、抗炎、免疫调节等多种药理作用。本研究旨在系统探讨BSP对秀丽隐杆线虫AD模型的保护作用及其分子机制。我们发现BSP能有效缓解AD蠕虫的麻痹表型，在100 μg/mL浓度下效果最佳。此外，BSP显著延长了野生型和AD蠕虫的寿命，减少了脂褐素沉积和产卵能力，改善了神经肌肉功能、学习能力和抗逆性，降低了体内氧化应激水平。此外，BSP处理显著抑制AD蠕虫的Aβ聚集。转录组学分析显示，BSP显著调节自噬通路。结合基因实验，我们进一步阐明了BSP协调胰岛素和AMPK信号通路调节自噬，从而减少异常的自噬体积累，恢复自噬稳态。值得注意的是，BSP的神经保护作用在胰岛素信号通路关键基因（daf-2、age-1、akt-1、akt-2、daf-16）和AMPK同源基因aak-2突变体中完全消失，表明其作用与胰岛素/AMPK自噬调节轴有关。本研究揭示了白芨多糖通过多靶点、多途径调控自噬改善AD病理的机制，为白芨多糖作为AD候选治疗剂的开发提供了新的理论依据，进一步凸显了白芨多糖在AD治疗中的潜在医学价值。
{"title":"Bletilla striata polysaccharide alleviates Alzheimer's disease in Caenorhabditis elegans by modulating autophagy via the insulin/AMPK pathway","authors":"Xinyi Zeng, Deijian Peng, Yunlong Shen, Li Tang, Tianlu Ran, Ziheng Pan, Hui Liu","doi":"10.1016/j.freeradbiomed.2026.01.051","DOIUrl":"10.1016/j.freeradbiomed.2026.01.051","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is a common neurodegenerative disorder characterized by the abnormal aggregation of amyloid-β (Aβ). <em>Bletilla striata</em> polysaccharide (BSP), the primary active component of the traditional Chinese medicine <em>Bletilla striata</em>, exhibits various pharmacological effects including hemostatic, antioxidant, anti-inflammatory, and immunomodulatory activities. This study aimed to systematically investigate the protective effects and molecular mechanisms of BSP in <em>Caenorhabditis elegans</em> AD model. We found that BSP effectively alleviated the paralysis phenotype in AD worms, with optimal efficacy observed at a concentration of 100 μg/mL. Furthermore, BSP significantly extended the lifespan of both wild type and AD worms, reduced lipofuscin deposition and egg-laying capacity, improved neuromuscular function, learning ability, and stress resistance, and lowered the level of oxidative stress in vivo. Additionally, BSP treatment markedly suppressed Aβ aggregation in AD worms. Transcriptomic analysis revealed that BSP significantly regulates the autophagy pathway. In combination with genetic experiments, we further elucidated that BSP coordinates the insulin and AMPK signaling pathways to modulate autophagy, thereby reducing abnormal autophagosome accumulation and restoring autophagic homeostasis. Notably, the neuroprotective effects of BSP were completely abolished in mutants of key insulin signaling pathway genes (<em>daf-2</em>, <em>age-1</em>, <em>akt-1</em>, <em>akt-2</em>, <em>daf-16</em>) and the AMPK homologous gene <em>aak-2</em>, indicating that its efficacy is associated with the insulin/AMPK-autophagy regulatory axis. This study reveals the mechanism by which BSP ameliorates AD pathology through multi-target and multi-pathway regulation of autophagy, providing a new theoretical basis for its development as a candidate therapeutic agent for AD and further highlighting the potential medical value of <em>Bletilla striata</em> in combating AD.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"247 ","pages":"Pages 27-38"},"PeriodicalIF":8.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146085140","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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