Pub Date : 2026-04-01Epub Date: 2026-02-10DOI: 10.1016/j.freeradbiomed.2026.02.018
Jiayi Pi , Hau-Chern Jan , Nong Qin , Cheng-Pin Huang , Mei-Chi Huang , Ye Qiu , Shuen-Ru Yang , Shuangdi Duan , Liyang Shi , Hung-Yu Sun
Chronic kidney disease (CKD) is characterized by multi-organ dysfunction and the systemic accumulation of toxic metabolites. Apolipoprotein J (ApoJ), a stress-responsive chaperone primarily synthesized in the liver, has emerged as a biomarker of disease severity; however, its mechanistic role in CKD pathogenesis remains unclear. Here, we identify ApoJ as a mediator of pathological hepato-renal crosstalk. ApoJ was markedly increased in experimental and human CKD and was closely associated with transcriptional signatures regulated by the aryl hydrocarbon receptor (AhR). Mechanistically, ApoJ stabilized AhR by preventing its ubiquitination, thereby enhancing renal tubular AhR activation, oxidative injury, and epithelial–mesenchymal transition. In the liver, ApoJ induced sulfotransferase 1A1 expression, promoting overproduction of the uremic tryptophan metabolite indoxyl sulfate, which further aggravated kidney injury. Hepatocyte-specific ApoJ deletion or pharmacologic blockade with the ApoJ antagonist peptide MK53 attenuated renal damage, suppressed tubular AhR signaling, and reduced hepatic uremic toxin generation. In human CKD specimens, tubular ApoJ accumulation correlated with injury, and mediation analyses indicated that circulating ApoJ amplifies the nephrotoxic impact of tryptophan metabolites. These findings identify ApoJ as a pathogenic driver of CKD that coordinates toxicological signaling between liver and kidney, and they highlight ApoJ inhibition as a potential therapeutic strategy.
{"title":"Apolipoprotein J-mediated hepato-renal crosstalk drives renal injury in chronic kidney disease","authors":"Jiayi Pi , Hau-Chern Jan , Nong Qin , Cheng-Pin Huang , Mei-Chi Huang , Ye Qiu , Shuen-Ru Yang , Shuangdi Duan , Liyang Shi , Hung-Yu Sun","doi":"10.1016/j.freeradbiomed.2026.02.018","DOIUrl":"10.1016/j.freeradbiomed.2026.02.018","url":null,"abstract":"<div><div>Chronic kidney disease (CKD) is characterized by multi-organ dysfunction and the systemic accumulation of toxic metabolites. Apolipoprotein J (ApoJ), a stress-responsive chaperone primarily synthesized in the liver, has emerged as a biomarker of disease severity; however, its mechanistic role in CKD pathogenesis remains unclear. Here, we identify ApoJ as a mediator of pathological hepato-renal crosstalk. ApoJ was markedly increased in experimental and human CKD and was closely associated with transcriptional signatures regulated by the aryl hydrocarbon receptor (AhR). Mechanistically, ApoJ stabilized AhR by preventing its ubiquitination, thereby enhancing renal tubular AhR activation, oxidative injury, and epithelial–mesenchymal transition. In the liver, ApoJ induced sulfotransferase 1A1 expression, promoting overproduction of the uremic tryptophan metabolite indoxyl sulfate, which further aggravated kidney injury. Hepatocyte-specific ApoJ deletion or pharmacologic blockade with the ApoJ antagonist peptide MK53 attenuated renal damage, suppressed tubular AhR signaling, and reduced hepatic uremic toxin generation. In human CKD specimens, tubular ApoJ accumulation correlated with injury, and mediation analyses indicated that circulating ApoJ amplifies the nephrotoxic impact of tryptophan metabolites. These findings identify ApoJ as a pathogenic driver of CKD that coordinates toxicological signaling between liver and kidney, and they highlight ApoJ inhibition as a potential therapeutic strategy.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"247 ","pages":"Pages 200-212"},"PeriodicalIF":8.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146178855","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: 2026-02-05DOI: 10.1016/j.freeradbiomed.2026.01.064
Zihang Feng , Yuan Xing , Jing Lou , Han Li , Ziang Zhang , Min Li , Qing Zhu , Yang Cui , Jia Li , Feng Gao , Wei Yi , Yang Sun , Xing Zhang
Prolonged exposure to high altitude (HA) results in a range of systemic changes, some of which, specifically for the heart, particularly cardiac changes, remain difficult to reverse after returning to low altitude. Cardiac de-acclimatization after HA exposure and its underlying mechanisms remain unclear. In this study, mice were subjected to a decompression chamber to simulate a 6000-m altitude exposure for 10 days, followed by the other 10-day de-acclimatization period at a lower altitude of 400 m. The cardiac dysfunction induced by HA exposure persisted throughout the de-acclimatization, accompanied with sustained mitochondrial dysfunction and the short peptide mitochondrial open reading frame of the 12S ribosomal RNA type-c (MOTS-c) deficiency. Exogenous supplementation of MOTS-c during de-acclimatization effectively alleviated the cardiac dysfunction post HA exposure. Mechanistically, MOTS-c activated the PTEN-induced putative kinase 1 (Pink1)/Parkin pathway, promoting mitophagy and improving mitochondrial quality. Silencing Pink1 abolished the protective effects of MOTS-c during de-acclimatization. Additionally, reduced circulating MOTS-c levels were observed in patients with high altitude heart disease and acute coronary syndrome. These results suggest that HA exposure leaves a memory of cardiac dysfunction upon return to lower altitude. This is attributed to a sustained deficiency in MOTS-c. MOTS-c maintains mitochondrial quality through promoting mitophagy, highlighting its therapeutic potential for treating HA-induced cardiac dysfunction during de-acclimatization.
{"title":"MOTS-c attenuates cardiac dysfunction following high altitude exposure by promoting mitophagy","authors":"Zihang Feng , Yuan Xing , Jing Lou , Han Li , Ziang Zhang , Min Li , Qing Zhu , Yang Cui , Jia Li , Feng Gao , Wei Yi , Yang Sun , Xing Zhang","doi":"10.1016/j.freeradbiomed.2026.01.064","DOIUrl":"10.1016/j.freeradbiomed.2026.01.064","url":null,"abstract":"<div><div>Prolonged exposure to high altitude (HA) results in a range of systemic changes, some of which, specifically for the heart, particularly cardiac changes, remain difficult to reverse after returning to low altitude. Cardiac de-acclimatization after HA exposure and its underlying mechanisms remain unclear. In this study, mice were subjected to a decompression chamber to simulate a 6000-m altitude exposure for 10 days, followed by the other 10-day de-acclimatization period at a lower altitude of 400 m. The cardiac dysfunction induced by HA exposure persisted throughout the de-acclimatization, accompanied with sustained mitochondrial dysfunction and the short peptide mitochondrial open reading frame of the 12S ribosomal RNA type-c (MOTS-c) deficiency. Exogenous supplementation of MOTS-c during de-acclimatization effectively alleviated the cardiac dysfunction post HA exposure. Mechanistically, MOTS-c activated the PTEN-induced putative kinase 1 (Pink1)/Parkin pathway, promoting mitophagy and improving mitochondrial quality. Silencing Pink1 abolished the protective effects of MOTS-c during de-acclimatization. Additionally, reduced circulating MOTS-c levels were observed in patients with high altitude heart disease and acute coronary syndrome. These results suggest that HA exposure leaves a memory of cardiac dysfunction upon return to lower altitude. This is attributed to a sustained deficiency in MOTS-c. MOTS-c maintains mitochondrial quality through promoting mitophagy, highlighting its therapeutic potential for treating HA-induced cardiac dysfunction during de-acclimatization.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"247 ","pages":"Pages 157-172"},"PeriodicalIF":8.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146137376","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: 2026-02-05DOI: 10.1016/j.freeradbiomed.2026.02.009
Zhisheng Hu , Weihua Hao , Na Cui , Xin Gao , Wenqing Dai , Minge Wang , Liangxing Fang , Jian Sun , Hongyan Zhang , Xiaoping Liao
Resveratrol (Res), a natural polyphenol, is widely used as a functional food additive and food preservative due to its antioxidant and anti-inflammatory properties. However, its protective role against drug-induced organ damage, particularly colistin-induced nephrotoxicity (CIN), remains underexplored. This study investigated Res's protective effects and mechanisms against CIN in rat and NRK-52E cells. In vivo, Res (5-20 mg/kg) significantly improved renal function, alleviated histopathological damage, and restored antioxidant status. Mechanistically, Res modulated the Keap1/Nrf2 axis, suppressing excessive Nrf2 activation and its downstream enzymes. Concurrently, Res inhibited ferroptosis by reducing iron accumulation and modulating key ferroptosis markers (GPX4, ACSL4). In vitro, Res (20 μM) reversed CS- and RSL3-induced cytotoxicity, lipid peroxidation, and ferrous iron overload; Nrf2 siRNA abrogated these effects, confirming Nrf2's essential role. These findings highlight Res as a promising strategy to enhance colistin's clinical safety through precise Nrf2 modulation and ferroptosis inhibition, underscoring the therapeutic potential of natural food compounds.
{"title":"Protective effect of resveratrol against colistin-induced nephrotoxicity through regulating Nrf2 pathway and inhibiting ferroptosis","authors":"Zhisheng Hu , Weihua Hao , Na Cui , Xin Gao , Wenqing Dai , Minge Wang , Liangxing Fang , Jian Sun , Hongyan Zhang , Xiaoping Liao","doi":"10.1016/j.freeradbiomed.2026.02.009","DOIUrl":"10.1016/j.freeradbiomed.2026.02.009","url":null,"abstract":"<div><div>Resveratrol (Res), a natural polyphenol, is widely used as a functional food additive and food preservative due to its antioxidant and anti-inflammatory properties. However, its protective role against drug-induced organ damage, particularly colistin-induced nephrotoxicity (CIN), remains underexplored. This study investigated Res's protective effects and mechanisms against CIN in rat and NRK-52E cells. <em>In vivo</em>, Res (5-20 mg/kg) significantly improved renal function, alleviated histopathological damage, and restored antioxidant status. Mechanistically, Res modulated the Keap1/Nrf2 axis, suppressing excessive Nrf2 activation and its downstream enzymes. Concurrently, Res inhibited ferroptosis by reducing iron accumulation and modulating key ferroptosis markers (GPX4, ACSL4). <em>In vitro</em>, Res (20 μM) reversed CS- and RSL3-induced cytotoxicity, lipid peroxidation, and ferrous iron overload; Nrf2 siRNA abrogated these effects, confirming Nrf2's essential role. These findings highlight Res as a promising strategy to enhance colistin's clinical safety through precise Nrf2 modulation and ferroptosis inhibition, underscoring the therapeutic potential of natural food compounds.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"247 ","pages":"Pages 39-53"},"PeriodicalIF":8.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146137413","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: 2026-02-09DOI: 10.1016/j.freeradbiomed.2026.02.010
Feng Jin , Zengtao Song , Yu Deng , Hongkai Yang , Yajiang Yuan , Zhanpeng Guo , Haosen Zhao , Xifan Mei
Spinal cord injury (SCI) induces secondary damage characterized by mitochondrial dysfunction, excessive reactive oxygen species (ROS) production, and chronic neuroinflammation. Cytosolic release of mitochondrial DNA (mtDNA) acts as a potent damage-associated molecular pattern (DAMP) that activates the cGAS-STING pathway and amplifies inflammation. However, the precise mechanisms by which mtDNA-driven innate immune signaling contributes to SCI pathology and how this pathway can be therapeutically modulated remain incompletely understood. In this study, we identify zinc as a dual-function regulator that preserves mitochondrial integrity and attenuates mtDNA-triggered innate immune activation after SCI. In both in vivo and in vitro models, zinc enhanced PINK1-Parkin dependent mitophagy, promoted the removal of damaged mitochondria, and stabilized mitochondrial membranes through the regulation of BAX, BAK, and VDAC1. These actions collectively reduced mtDNA leakage, thereby suppressing cGAS-STING signaling. Zinc further promoted anti-inflammatory microglial polarization and improved locomotor recovery in SCI mice. These findings uncover a previously unrecognized role of mtDNA-cGAS-STING signaling in SCI and identify zinc as a potential therapeutic candidate that restores mitochondrial-immune homeostasis to achieve neuroprotection.
{"title":"Zinc protects against neuroinflammation after spinal cord injury by regulating mitophagy-dependent mtDNA-cGAS-STING signaling","authors":"Feng Jin , Zengtao Song , Yu Deng , Hongkai Yang , Yajiang Yuan , Zhanpeng Guo , Haosen Zhao , Xifan Mei","doi":"10.1016/j.freeradbiomed.2026.02.010","DOIUrl":"10.1016/j.freeradbiomed.2026.02.010","url":null,"abstract":"<div><div>Spinal cord injury (SCI) induces secondary damage characterized by mitochondrial dysfunction, excessive reactive oxygen species (ROS) production, and chronic neuroinflammation. Cytosolic release of mitochondrial DNA (mtDNA) acts as a potent damage-associated molecular pattern (DAMP) that activates the cGAS-STING pathway and amplifies inflammation. However, the precise mechanisms by which mtDNA-driven innate immune signaling contributes to SCI pathology and how this pathway can be therapeutically modulated remain incompletely understood. In this study, we identify zinc as a dual-function regulator that preserves mitochondrial integrity and attenuates mtDNA-triggered innate immune activation after SCI. In both <em>in vivo</em> and <em>in vitro</em> models, zinc enhanced PINK1-Parkin dependent mitophagy, promoted the removal of damaged mitochondria, and stabilized mitochondrial membranes through the regulation of BAX, BAK, and VDAC1. These actions collectively reduced mtDNA leakage, thereby suppressing cGAS-STING signaling. Zinc further promoted anti-inflammatory microglial polarization and improved locomotor recovery in SCI mice. These findings uncover a previously unrecognized role of mtDNA-cGAS-STING signaling in SCI and identify zinc as a potential therapeutic candidate that restores mitochondrial-immune homeostasis to achieve neuroprotection.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"247 ","pages":"Pages 286-302"},"PeriodicalIF":8.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146164869","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: 2026-02-01DOI: 10.1016/j.freeradbiomed.2026.01.061
Rasheed A. Abdulraheem , Ammar U. Danazumi , Philipp Nitschke , Luke Gray Whiley , Abdulrahman Ibrahim Tudu , Ranil Coorey , Zhoyu Li , Prashant Bharadwaj , Vijay Jayasena , Stuart K. Johnson , Ralph N. Martins , W.M.A.D Binosha Fernando
Accumulation of amyloid-beta (Aβ42) senile plaques in the brain is a hallmark of Alzheimer's disease (AD). Although some drug have been approvaled recently, none has demonstrated robust disease-modifying outcome. The 3-deoxyanthocyanidins (3-DXA) and their derivatives represent a more stable class of polyphenols, present at uniquely high concentrations in sorghum grains. Although 3-DXA exhibit strong potential to modulate protein aggregation processes, their effects on AD pathology remain unexplored. In this study, we investigated the inhibitory effects of three 3-DXA derivatives, apigeninidin chloride (AC), luteolinidin chloride (LC), and 7-methoxy apigeninidin (7-MAC), on Aβ42 aggregation and associated neurotoxicity. Thioflavin T fluorescence assay was employed to assess alterations in Aβ42 aggregation, while nuclear magnetic resonance spectroscopy and circular dichroism were used to evaluate compounds-protein interactions and secondary-structure changes. The neuroprotective effects of the three compounds were further examined in MC-65 cells under Aβ-induced toxicity. Additionally, generalized replica exchange with solute tempering based molecular dynamics simulations was conducted to explore the effects of AC and LC on Aβ42 dimer stability and β-sheet disruption. Our findings demonstrate that AC, LC, and 7-MAC significantly reduced Aβ42 aggregation by up to 88%, with AC and LC showing strong disruption of β-sheet structures. All three compounds significantly rescued MC-65 cells from Aβ42-induced toxicity (62–77%), accompanied by enhanced mitochondrial activity. Molecular dynamics simulations analyses further revealed that AC and LC disrupted hydrophobic interactions within Aβ42 dimers, contributing to destabilisation of neurotoxic aggregates. Overall, AC and LC exhibited strong multitarget activity against AD pathology by inhibiting Aβ42 aggregation, restoring intracellular energy balance, and disrupting key neurotoxic structural motifs.
{"title":"3-Deoxyanthocyanidins inhibit β-amyloid aggregation, toxicity, and mitochondrial dysfunction: Evidence from MC-65 cells and molecular dynamics simulations","authors":"Rasheed A. Abdulraheem , Ammar U. Danazumi , Philipp Nitschke , Luke Gray Whiley , Abdulrahman Ibrahim Tudu , Ranil Coorey , Zhoyu Li , Prashant Bharadwaj , Vijay Jayasena , Stuart K. Johnson , Ralph N. Martins , W.M.A.D Binosha Fernando","doi":"10.1016/j.freeradbiomed.2026.01.061","DOIUrl":"10.1016/j.freeradbiomed.2026.01.061","url":null,"abstract":"<div><div>Accumulation of amyloid-beta (Aβ<sub>42</sub>) senile plaques in the brain is a hallmark of Alzheimer's disease (AD). Although some drug have been approvaled recently, none has demonstrated robust disease-modifying outcome. The 3-deoxyanthocyanidins (3-DXA) and their derivatives represent a more stable class of polyphenols, present at uniquely high concentrations in sorghum grains. Although 3-DXA exhibit strong potential to modulate protein aggregation processes, their effects on AD pathology remain unexplored. In this study, we investigated the inhibitory effects of three 3-DXA derivatives, apigeninidin chloride (AC), luteolinidin chloride (LC), and 7-methoxy apigeninidin (7-MAC), on Aβ<sub>42</sub> aggregation and associated neurotoxicity. Thioflavin T fluorescence assay was employed to assess alterations in Aβ<sub>42</sub> aggregation, while nuclear magnetic resonance spectroscopy and circular dichroism were used to evaluate compounds-protein interactions and secondary-structure changes. The neuroprotective effects of the three compounds were further examined in MC-65 cells under Aβ-induced toxicity. Additionally, generalized replica exchange with solute tempering based molecular dynamics simulations was conducted to explore the effects of AC and LC on Aβ<sub>42</sub> dimer stability and β-sheet disruption. Our findings demonstrate that AC, LC, and 7-MAC significantly reduced Aβ<sub>42</sub> aggregation by up to 88%, with AC and LC showing strong disruption of β-sheet structures. All three compounds significantly rescued MC-65 cells from Aβ<sub>42</sub>-induced toxicity (62–77%), accompanied by enhanced mitochondrial activity. Molecular dynamics simulations analyses further revealed that AC and LC disrupted hydrophobic interactions within Aβ<sub>42</sub> dimers, contributing to destabilisation of neurotoxic aggregates. Overall, AC and LC exhibited strong multitarget activity against AD pathology by inhibiting Aβ<sub>42</sub> aggregation, restoring intracellular energy balance, and disrupting key neurotoxic structural motifs.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"247 ","pages":"Pages 213-223"},"PeriodicalIF":8.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146112340","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.2026.01.059
Huan Yang , Yi Zhang , Mengxiong Li , Kaixuan Zeng , Yaoyao Xu , Ruohong Pan , Jiayu Huang , Lu Sun , Yuqing Yao , Jin Luo , Tian Li
Intrauterine adhesion (IUA) is characterized by the formation of endometrial fibrosis within the uterine cavity, which can lead to thin endometrium, hypomenorrhea, infertility, and recurrent abortion, exerting a detrimental impact on women's physical and psychological health. Currently, its pathogenesis is not fully elucidated, absence of effective therapies and coupled with a high recurrence rate. In this study, single-cell RNA sequencing was applied for the first time to a mouse IUA model, revealing significant changes in the expression of senescence markers in endometrial epithelial cells (EECs). Specifically, upregulation of Cdkn1a, and Il6, and downregulation of Lamin B1. Further bioinformatic analysis showed significant enrichment of gene sets related to calcium overload, ER stress, and Endoplasmic Reticulum/Plasma Membrane (ER/PM) contacts in the EECs of IUA mice. Mechanistically, ER/PM contacts in IUA activates the STIM1/Orai1 channel complex, leading to ER stress and intracellular calcium overload, which induces cellular senescence in EECs and ultimately drives IUA progression. Intrauterine administration of the STIM1/Orai1 channel inhibitor BTP2 significantly suppressed ER/PM contacts-induced senescence in EECs and effectively alleviated endometrial fibrosis in the mouse IUA model. In conclusion, targeting the STIM1/Orai1 calcium channel dependent on ER/PM contact sites significantly ameliorates endometrial fibrosis, offering a promising therapeutic strategy for IUA.
{"title":"Inhibiting Endoplasmic Reticulum/Plasma Membrane contact ameliorates endometrial fibrosis by preventing senescence in endometrial epithelial cells","authors":"Huan Yang , Yi Zhang , Mengxiong Li , Kaixuan Zeng , Yaoyao Xu , Ruohong Pan , Jiayu Huang , Lu Sun , Yuqing Yao , Jin Luo , Tian Li","doi":"10.1016/j.freeradbiomed.2026.01.059","DOIUrl":"10.1016/j.freeradbiomed.2026.01.059","url":null,"abstract":"<div><div>Intrauterine adhesion (IUA) is characterized by the formation of endometrial fibrosis within the uterine cavity, which can lead to thin endometrium, hypomenorrhea, infertility, and recurrent abortion, exerting a detrimental impact on women's physical and psychological health. Currently, its pathogenesis is not fully elucidated, absence of effective therapies and coupled with a high recurrence rate. In this study, single-cell RNA sequencing was applied for the first time to a mouse IUA model, revealing significant changes in the expression of senescence markers in endometrial epithelial cells (EECs). Specifically, upregulation of <em>Cdkn1a</em>, and <em>Il6</em>, and downregulation of <em>Lamin B1</em>. Further bioinformatic analysis showed significant enrichment of gene sets related to calcium overload, ER stress, and Endoplasmic Reticulum/Plasma Membrane (ER/PM) contacts in the EECs of IUA mice. Mechanistically, ER/PM contacts in IUA activates the STIM1/Orai1 channel complex, leading to ER stress and intracellular calcium overload, which induces cellular senescence in EECs and ultimately drives IUA progression. Intrauterine administration of the STIM1/Orai1 channel inhibitor BTP2 significantly suppressed ER/PM contacts-induced senescence in EECs and effectively alleviated endometrial fibrosis in the mouse IUA model. In conclusion, targeting the STIM1/Orai1 calcium channel dependent on ER/PM contact sites significantly ameliorates endometrial fibrosis, offering a promising therapeutic strategy for IUA.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"247 ","pages":"Pages 251-266"},"PeriodicalIF":8.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146131808","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.2026.02.004
Jing Yang , Li Zhang , Huirong An , Xin Guan , Yuan Zhang , Junlong Zhang , Shasha Liu , Shihan Du , Jia Shi , Yan Guo , Jianbo Yu
Sepsis-induced acute lung injury (ALI) remains a devastatingly lethal clinical syndrome driven by aberrant inflammatory dysregulation, wherein monocytes play critical roles in disease pathogenesis. This study elucidates the mechanistic basis by which the HO-1 inducer Hemin alleviates ALI by activating the HO-1/Nrf2 pathway to target pro-inflammatory monocytes. RNA-seq analysis revealed that the most prominently dysregulated genes in LPS-stimulated human THP-1 monocytes (relative to untreated controls) were predominantly enriched in pathways governing inflammatory responses and oxidative stress. In vitro experiments revealed that Hemin suppressed the p38-MAPK/mTOR pathways in human monocytes, inhibiting inflammatory activation, differentiation, and LPS-induced cell death while preserving phagocytosis. The murine ALI model was established in WT, CCR2−/−, and Nrf2−/− mice via tail vein injection of LPS, with assessments conducted 12 h later. In LPS-challenged mice, Hemin pretreatment selectively inhibited the recruitment of CCR2hi monocytes (but not CCR2lo monocytes or neutrophils) into the lungs, thereby attenuating histopathological injury, reducing TNF-α and IL-6 levels, and diminishing monocyte-derived macrophages and their M1/M2 polarization. CCR2 deficiency not only abrogated the therapeutic efficacy of Hemin in ALI, evidenced by the failure to prevent the LPS-induced increase in the proportion of monocyte-derived macrophages and the elevation of macrophage polarization, but also paradoxically elevated pulmonary TNF-α concentrations. Furthermore, experiments using Nrf2−/− mice revealed that the protective benefits of Hemin are strictly Nrf2-dependent. Nrf2 deficiency prevented Hemin from restoring the redox balance (GSH/GSSG ratio) and abolished its systemic and pulmonary anti-inflammatory effects, along with its suppression of CCR2hi subsets and inhibition of macrophages polarization. Collectively, our findings establish that activation of the HO-1/Nrf2 pathway mitigates ALI by selectively targeting CCR2hi pro-inflammatory monocytes, positioning Hemin as a promising therapeutic candidate for ALI and identifying the proportion of CCR2hi monocyte and Nrf2-mediated redox markers as potential biomarkers to guide precision medicine strategies for ALI management.
{"title":"HO-1/Nrf2 activation orchestrates protection in sepsis-induced lung injury by suppressing CCR2hi monocyte recruitment and MAPK-driven inflammation","authors":"Jing Yang , Li Zhang , Huirong An , Xin Guan , Yuan Zhang , Junlong Zhang , Shasha Liu , Shihan Du , Jia Shi , Yan Guo , Jianbo Yu","doi":"10.1016/j.freeradbiomed.2026.02.004","DOIUrl":"10.1016/j.freeradbiomed.2026.02.004","url":null,"abstract":"<div><div>Sepsis-induced acute lung injury (ALI) remains a devastatingly lethal clinical syndrome driven by aberrant inflammatory dysregulation, wherein monocytes play critical roles in disease pathogenesis. This study elucidates the mechanistic basis by which the HO-1 inducer Hemin alleviates ALI by activating the HO-1/Nrf2 pathway to target pro-inflammatory monocytes. RNA-seq analysis revealed that the most prominently dysregulated genes in LPS-stimulated human THP-1 monocytes (relative to untreated controls) were predominantly enriched in pathways governing inflammatory responses and oxidative stress. In vitro experiments revealed that Hemin suppressed the p38-MAPK/mTOR pathways in human monocytes, inhibiting inflammatory activation, differentiation, and LPS-induced cell death while preserving phagocytosis. The murine ALI model was established in WT, CCR2<sup>−/−</sup>, and Nrf2<sup>−/−</sup> mice via tail vein injection of LPS, with assessments conducted 12 h later. In LPS-challenged mice, Hemin pretreatment selectively inhibited the recruitment of CCR2<sup>hi</sup> monocytes (but not CCR2<sup>lo</sup> monocytes or neutrophils) into the lungs, thereby attenuating histopathological injury, reducing TNF-α and IL-6 levels, and diminishing monocyte-derived macrophages and their M1/M2 polarization. CCR2 deficiency not only abrogated the therapeutic efficacy of Hemin in ALI, evidenced by the failure to prevent the LPS-induced increase in the proportion of monocyte-derived macrophages and the elevation of macrophage polarization, but also paradoxically elevated pulmonary TNF-α concentrations. Furthermore, experiments using Nrf2<sup>−/−</sup> mice revealed that the protective benefits of Hemin are strictly Nrf2-dependent. Nrf2 deficiency prevented Hemin from restoring the redox balance (GSH/GSSG ratio) and abolished its systemic and pulmonary anti-inflammatory effects, along with its suppression of CCR2<sup>hi</sup> subsets and inhibition of macrophages polarization. Collectively, our findings establish that activation of the HO-1/Nrf2 pathway mitigates ALI by selectively targeting CCR2<sup>hi</sup> pro-inflammatory monocytes, positioning Hemin as a promising therapeutic candidate for ALI and identifying the proportion of CCR2<sup>hi</sup> monocyte and Nrf2-mediated redox markers as potential biomarkers to guide precision medicine strategies for ALI management.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"247 ","pages":"Pages 122-138"},"PeriodicalIF":8.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146131785","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}
Mycobacterium tuberculosis (Mtb) Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is indispensable for glycolysis, it also performs several critical non-metabolic functions. In the present study, we demonstrate that CRISPRi silencing of GAPDH inhibited enzyme activity and iron acquisition via human transferrin (Tf)/lactoferrin (Lf). GAPDH silencing also enhanced reactive oxygen species (ROS) and ROS induced damage suggesting its role as a redox sensor. We then examined the impact of GAPDH inhibition in Mtb using small molecule inhibitors. Vitamin C (VC) was selected considering its potent bactericidal effects against Mtb and its inhibition of human GAPDH resulting in its efficacy against cancer cells. The GAPDH inhibitors Ethyl bromopyruvate (EBP) and Koningic acid (KA) are anti-cancer agents that target the glycolytic activity of GAPDH. In contrast, TCH346 was identified as a neuroprotective agent, wherein it targets the non-metabolic function of GAPDH induced apoptotic signalling. The effects of inhibitors, alone or in combination with VC mirrored the cellular effects of GAPDH silencing, resulting in significant anti-bacterial activity. VC induced iron mobilization which coupled with GAPDH inhibitors induced a veritable “double whammy” resulting in massive increase in ROS and downstream effects. The efficacy of these treatments was assessed in a murine model, confirming that VC augmented the potent anti-tubercular activity induced by EBP and TCH346. Overall, this study identifies the crucial function of Mtb GAPDH as a redox sensor and highlights the potential of targeting its pleiotropic cellular functions towards drug discovery. In addition, the efficacy of TCH346 provides an opportunity of drug-repurposing as a strategy for therapy.
{"title":"Targeting Mycobacterium tuberculosis GAPDH elicits potent bactericidal responses by dysregulating enzyme activity, redox dynamics and iron acquisition","authors":"Zahid Gani , Mohammad Naiyaz Ahmad , Anurag Sindhu , Ajay Kumar , Anjali Kumari , Mohmmad Imran , Pradip Malik , Asmita Dhiman , Vinay Kumar Yadav , Gaddam Laxmi Priya , Gattadi Sravani , Nisheeth Agarwal , Rajender Kumar , Prabha Garg , Arunava Dasgupta , Sidharth Chopra , Manoj Raje , Chaaya Iyengar Raje","doi":"10.1016/j.freeradbiomed.2026.01.044","DOIUrl":"10.1016/j.freeradbiomed.2026.01.044","url":null,"abstract":"<div><div><em>Mycobacterium tuberculosis</em> (Mtb) Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is indispensable for glycolysis, it also performs several critical non-metabolic functions. In the present study, we demonstrate that CRISPRi silencing of GAPDH inhibited enzyme activity and iron acquisition via human transferrin (Tf)/lactoferrin (Lf). GAPDH silencing also enhanced reactive oxygen species (ROS) and ROS induced damage suggesting its role as a redox sensor. We then examined the impact of GAPDH inhibition in Mtb using small molecule inhibitors. Vitamin C (VC) was selected considering its potent bactericidal effects against Mtb and its inhibition of human GAPDH resulting in its efficacy against cancer cells. The GAPDH inhibitors Ethyl bromopyruvate (EBP) and Koningic acid (KA) are anti-cancer agents that target the glycolytic activity of GAPDH. In contrast, TCH346 was identified as a neuroprotective agent, wherein it targets the non-metabolic function of GAPDH induced apoptotic signalling. The effects of inhibitors, alone or in combination with VC mirrored the cellular effects of GAPDH silencing, resulting in significant anti-bacterial activity. VC induced iron mobilization which coupled with GAPDH inhibitors induced a veritable “double whammy” resulting in massive increase in ROS and downstream effects. The efficacy of these treatments was assessed in a murine model, confirming that VC augmented the potent anti-tubercular activity induced by EBP and TCH346. Overall, this study identifies the crucial function of Mtb GAPDH as a redox sensor and highlights the potential of targeting its pleiotropic cellular functions towards drug discovery. In addition, the efficacy of TCH346 provides an opportunity of drug-repurposing as a strategy for therapy.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"247 ","pages":"Pages 54-70"},"PeriodicalIF":8.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146100139","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: 2026-02-07DOI: 10.1016/j.freeradbiomed.2026.02.012
Jiaqi Chen , Wenyu Wang , Xia Li , Rui Wang , Yating Xiao , Changyuan Wang , Chong Wang , Renchao Dong , Lina Hao , Qiang Meng
Alcoholic liver disease (ALD) is a common chronic liver disease worldwide, directly caused by excessive and prolonged alcohol consumption. To date, there are no acknowledged therapeutic approaches for treating ALD. The reason is that ALD pathogenesis is multifactorial and only partially understood. Mitochondrial dysfunction-related mitophagy and inflammation are essential factors that play critical roles in the pathogenesis and progression of ALD. The farnesoid X receptor (FXR), a member of the nuclear receptor superfamily, plays a well-established role in liver protection, but whether and how it counteracts ALD by regulating mitophagy remains unknown. This study aimed to demonstrate the protective effect of FXR overexpression against ethanol-induced liver injury by suppressing NLR family pyrin domain containing 3 (NLRP3) inflammasome activation, thereby promoting mitophagy recovery. The mouse ALD models were established using the DeCarli liquid diet with 5% ethanol (v/v). We established FXR-overexpressing mice by intravenous injection of FXR-mediating lentivirus (LV-FXR). The results revealed that FXR expression was significantly downregulated in liver tissues of ALD patients compared to normal subjects using the Gene Expression Omnibus (GEO) database. FXR overexpression reduced the liver-to-body weight ratio and improved biochemical markers in mice. Overexpression of FXR in mice significantly alleviated ethanol-induced hepatitis, improved mitophagy, and inhibited NLRP3 inflammasome activation and the secretion of IL-18 and IL-1β. In vitro, we transfected AML-12 cells with either pcDNA-FXR or FXR siRNA plasmids before ethanol exposure. Overexpression of FXR markedly attenuated ethanol-induced mitochondrial damage and NLRP3 inflammasome activation. Conversely, FXR knockdown exacerbated both outcomes. In conclusion, FXR overexpression protects against ethanol-induced liver injury through a novel mechanism by suppressing mitochondrial damage, oxidative stress, and NLRP3 inflammasome activation.
{"title":"FXR overexpression restores NLRP3-mediated mitophagy and improves mitochondrial dysfunction in alcoholic liver disease","authors":"Jiaqi Chen , Wenyu Wang , Xia Li , Rui Wang , Yating Xiao , Changyuan Wang , Chong Wang , Renchao Dong , Lina Hao , Qiang Meng","doi":"10.1016/j.freeradbiomed.2026.02.012","DOIUrl":"10.1016/j.freeradbiomed.2026.02.012","url":null,"abstract":"<div><div>Alcoholic liver disease (ALD) is a common chronic liver disease worldwide, directly caused by excessive and prolonged alcohol consumption. To date, there are no acknowledged therapeutic approaches for treating ALD. The reason is that ALD pathogenesis is multifactorial and only partially understood. Mitochondrial dysfunction-related mitophagy and inflammation are essential factors that play critical roles in the pathogenesis and progression of ALD. The farnesoid X receptor (FXR), a member of the nuclear receptor superfamily, plays a well-established role in liver protection, but whether and how it counteracts ALD by regulating mitophagy remains unknown. This study aimed to demonstrate the protective effect of FXR overexpression against ethanol-induced liver injury by suppressing NLR family pyrin domain containing 3 (NLRP3) inflammasome activation, thereby promoting mitophagy recovery. The mouse ALD models were established using the DeCarli liquid diet with 5% ethanol (v/v). We established FXR-overexpressing mice by intravenous injection of FXR-mediating lentivirus (LV-FXR). The results revealed that FXR expression was significantly downregulated in liver tissues of ALD patients compared to normal subjects using the Gene Expression Omnibus (GEO) database. FXR overexpression reduced the liver-to-body weight ratio and improved biochemical markers in mice. Overexpression of FXR in mice significantly alleviated ethanol-induced hepatitis, improved mitophagy, and inhibited NLRP3 inflammasome activation and the secretion of IL-18 and IL-1β. <em>In vitro</em>, we transfected AML-12 cells with either pcDNA-FXR or FXR siRNA plasmids before ethanol exposure. Overexpression of FXR markedly attenuated ethanol-induced mitochondrial damage and NLRP3 inflammasome activation. Conversely, FXR knockdown exacerbated both outcomes. In conclusion, FXR overexpression protects against ethanol-induced liver injury through a novel mechanism by suppressing mitochondrial damage, oxidative stress, and NLRP3 inflammasome activation.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"247 ","pages":"Pages 173-186"},"PeriodicalIF":8.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146149524","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: 2026-02-09DOI: 10.1016/j.freeradbiomed.2026.02.005
Chuncheng Liu, Xiaoyu Li, Wenhua Pu, Jing Jing, Wenjia Cui, Guojun Liu, Lu Cai
Intermittent hypoxia (IH) is a hallmark pathological feature of obstructive sleep apnea and a critical risk factor for neurodegenerative diseases such as Alzheimer's disease. Transcription factors (TFs) and splicing factors (SFs) serve as pivotal regulators orchestrating cellular adaptations to hypoxia. This study aimed to elucidate the dynamic changes and identify candidate key TFs and SFs in the mouse hippocampus under IH. By establishing an IH mouse model (7% O2, 1/3/5/7 weeks) and integrating multi-time points RNA-seq with bioinformatic analysis and experimental validation, we systematically identified putative core TFs and SFs involved in hippocampal hypoxia response and inferred their potential functions. Our study revealed that the TFs Lef1 and Foxj1, along with the SF Rbm47, emerge as candidate key regulators. Lef1 may modulate apoptosis-related genes such as Il31ra, while Foxj1 could be linked to ciliary function and neural development by regulating genes like Rsph1. The SF Rbm47 potentially contributes to hippocampal hypoxic adaptation by modulating alternative splicing of genes such as Apc and Hnrnpa2b1. The Lef1 gene itself undergoes alterations in exon retention rates during intermittent hypoxia. These findings provide critical data to decipher hippocampal IH adaptation and offer theoretical insights into the mechanisms of AD and related neurodegenerative disorders.
{"title":"Multi-time points RNA-seq screening identifies key transcription factors and splicing factors responsive to intermittent hypoxia in the mouse hippocampus","authors":"Chuncheng Liu, Xiaoyu Li, Wenhua Pu, Jing Jing, Wenjia Cui, Guojun Liu, Lu Cai","doi":"10.1016/j.freeradbiomed.2026.02.005","DOIUrl":"10.1016/j.freeradbiomed.2026.02.005","url":null,"abstract":"<div><div>Intermittent hypoxia (IH) is a hallmark pathological feature of obstructive sleep apnea and a critical risk factor for neurodegenerative diseases such as Alzheimer's disease. Transcription factors (TFs) and splicing factors (SFs) serve as pivotal regulators orchestrating cellular adaptations to hypoxia. This study aimed to elucidate the dynamic changes and identify candidate key TFs and SFs in the mouse hippocampus under IH. By establishing an IH mouse model (7% O<sub>2</sub>, 1/3/5/7 weeks) and integrating multi-time points RNA-seq with bioinformatic analysis and experimental validation, we systematically identified putative core TFs and SFs involved in hippocampal hypoxia response and inferred their potential functions. Our study revealed that the TFs Lef1 and Foxj1, along with the SF Rbm47, emerge as candidate key regulators. Lef1 may modulate apoptosis-related genes such as <em>Il31ra</em>, while Foxj1 could be linked to ciliary function and neural development by regulating genes like <em>Rsph1</em>. The SF Rbm47 potentially contributes to hippocampal hypoxic adaptation by modulating alternative splicing of genes such as <em>Apc</em> and <em>Hnrnpa2b1</em>. The <em>Lef1</em> gene itself undergoes alterations in exon retention rates during intermittent hypoxia. These findings provide critical data to decipher hippocampal IH adaptation and offer theoretical insights into the mechanisms of AD and related neurodegenerative disorders.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"247 ","pages":"Pages 187-199"},"PeriodicalIF":8.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146164859","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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