CELL DEATH AND DIFFERENTIATION
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2026
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IF 13.6
Sun Ya-Zhou,Li Xin-Yan,Wang Jia,Zeng Meng-Liu,Qu Wei-Yi,Cheng Xu,Luo Lei,Wang Wei,Yang Juan,Zhang Jun,Tian Han,Zhang Peng,She Zhi-Gang,Li Hongliang,Zhang Xiao-Jing
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are severe conditions lacking specific pharmacological treatments. Endoplasmic reticulum (ER) stress plays a pivotal role in their pathophysiology, yet the precise regulatory mechanisms remain elusive. In this study, we identify the E3 ubiquitin ligase ring finger protein 5 (RNF5) as a critical driver of ALI/ARDS. RNF5 is markedly upregulated in response to ALI and significantly exacerbates lung injury by stabilizing HSPA5 (heat shock protein family A member 5), a master regulator of the unfolded protein response (UPR). Notably, in vivo Rnf5 ablation effectively attenuated pulmonary edema, inflammatory cell infiltration, and apoptosis, whereas lung-specific Rnf5 overexpression worsened inflammation and cell death in mice. Mechanistically, RNF5 interacts with HSPA5 and competitively blocks its binding to PERK, facilitating PERK release. Furthermore, RNF5 promotes the retro-translocation of HSPA5 from the ER lumen to the cytosol. In the cytosol, RNF5 mediates the K6- and K63-linked polyubiquitination of HSPA5, enhancing its thermal stability and preventing its re-entry into the ER. This spatial sequestration sustains the persistent dissociation of the PERK-HSPA5 complex, leading to the hyperactivation of the pro-apoptotic and pro-inflammatory PERK-eIF2α-CHOP signaling cascade. The ability of RNF5 to promote ALI is strictly dependent on its E3 ligase activity. In conclusion, our findings uncover a compartment-specific regulatory mechanism of HSPA5, suggesting that the RNF5-HSPA5-PERK axis represents a promising therapeutic target for ALI/ARDS.
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Scientific Reports
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2024
·Vol. 14
·期 1
·1-12
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IF 3.8
Hu Deliang,Yang Yuqing,Fang Lei,Fan Shijie,Lin Ling,Luo Puying,Xiong Yuanhuan,Su Yufang
Isoliquiritigenin (ISL), a naturally occurring flavonoid derived from licorice root, exhibits antioxidant, anticancer, anti-inflammatory, and anti-allergic properties, and is frequently detected in both environmental and human samples. Previous studies from our lab have demonstrated that ISL exposure can lead to developmental deformities and aberrant immune responses. However, the molecular mechanisms underlying ISL toxicity in zebrafish embryos remain incompletely elucidated. Therefore, this study aimed to elucidate the effects of ISL exposure on endoplasmic reticulum (ER) stress in zebrafish embryos by assessing the expression levels of ER stress markers HSPA5 and CHOP , along with associated apoptosis factors, under various ISL concentrations, with tunicamycin (TM) serving as a positive control. Furthermore, targeted analyses of ER stress-related pathways were conducted using RNA transcriptome sequencing, and the up-regulated gene was verified by western blot. The results revealed that ISL exposure significantly elevated the expression levels of HSPA5 and CHOP , concomitantly activating ER stress pathways, including pPERK-eIF2α-ATF4 and ATF6 pathways in zebrafish embryos. These findings suggest that the activation of endoplasmic reticulum stress signaling pathways may contribute to the developmental deformities observed in zebrafish embryos following ISL exposure, thereby highlighting the potential ecological risks associated with ISL usage.
研究领域:
毒理学
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发育生物学
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分子生物学
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环境科学
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FREE RADICAL BIOLOGY AND MEDICINE
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2026
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IF 8
Shenghui Zhang,Qin Liu,Bo Chen,Hui Chang,Ying Pan,Yanli Liu,Xin Zhao,Juntang Lin
MenSC-EVs alleviate STZ-induced ovarian dysfunction in diabetic mice. • MenSC-EVs suppress high-glucose-induced ferroptosis in granulosa cells. • EV-associated HSPA5 mediates protection via AKT/mTOR–BECN1/SLC7A11 signaling. Type 1 diabetes mellitus (T1DM) is associated with ovarian dysfunction, including menstrual irregularities, impaired ovarian reserve, and premature reproductive aging, yet effective therapeutic strategies to safeguard ovarian function against metabolic stress remain limited. Mesenchymal stem cells (MSCs) have emerged as pivotal regulators of tissue homeostasis, with their paracrine effects largely mediated by extracellular vesicles (EVs). Here, we demonstrate that menstrual blood-derived endometrial stem cell-EVs (MenSC-EVs) alleviate streptozotocin (STZ)-induced ovarian dysfunction and inhibit granulosa cells (GCs) ferroptosis by delivering HSPA5. Mechanistically, EV-associated HSPA5 restored AKT/mTOR signaling and was accompanied by reduced BECN1 phosphorylation, thereby preserving the SLC7A11/GPX4-associated antioxidant pathway. We further show that BECN1 directly interacts with SLC7A11, linking BECN1 signaling to regulation of the system Xc−/GPX4 antioxidant axis. MenSC-EVs preserved this antioxidant pathway and reduced lipid peroxidation in injured GCs. Collectively, these findings identify an HSPA5-dependent anti-ferroptotic mechanism through which MenSC-EVs ameliorate T1DM-associated ovarian dysfunction, supporting their potential as an ovarian-protective strategy under diabetic conditions. Download: Download high-res image (241KB) Download: Download full-size image
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Advanced Healthcare Materials
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2026
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IF 11
Yanlin Li,Xiaotian Jiang,Jiale Li,Hanwen Gu,Qi Li,Jiaxin Li,Yunqing Ji,Xiang Min,Bin Chen,Qingjia Xu,Junhao Lin
Osteoarthritis (OA), a prevalent degenerative joint disorder characterized by articular cartilage deterioration, represents a major global health challenge. Recent studies highlight the pivotal role of reactive oxygen species (ROS)-mediated ferroptosis in OA pathogenesis. Here, we report a microenvironment-adaptive hydrogel system based on 2D vanadium nitride (V 2 N) MXene nanoenzyme (hereafter denoted as V 2 N MXenzyme@Gel). This system features a dual-crosslinked network that optimally balances between mechanical robustness and flexibility. Crucially, the V 2 N MXenzyme establishes a self-sustaining “capture-conversion-recycling” catalytic cycle, mimicking both superoxide dismutase (SOD) and catalase (CAT) activities. The cycle not only neutralizes detrimental ROS into water (H 2 O) and oxygen (O 2 ) but also generates nitric oxide (NO), collectively alleviating oxidative damage. Mechanistically, V 2 N MXenzyme@Gel effectively scavenges ROS, attenuates oxidative stress, and suppresses ferroptosis by regulating the Hspa5/GPX4 axis, while concurrently restoring the metabolic homeostasis of chondrocyte extracellular matrix (ECM). Meanwhile, intra-articular administration of V 2 N MXenzyme@Gel significantly attenuates cartilage degradation and inflammation levels in OA rats. Collectively, our work presents a V 2 N MXenzyme@Gel with dual capabilities for ROS elimination and ferroptosis blockade, demonstrating its efficacy in arresting OA progression and proposing a novel precision strategy for managing chronic joint diseases.
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Italian Journal of Animal Science
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2021
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IF 2.217
Yi Ma,Mawda Elmhadi,Chao Wang,Hao Zhang,Hongrong Wang
Several studies have demonstrated that high-concentrate (HC) diet with thiamine supplementation can alleviate rumen epithelium inflammation and protecting the barrier function in goats. This study aimed to investigate the effects of dietary supply of thiamine on mitophagy and endoplasmic reticulum stress (ERS) during high-concentrate diet feeding. Twenty-four Boer goats (35.62 ± 2.4 kg) were used in this study, goats were subsequently assigned to 3 treatment groups (8 goats in each group) as follows: a low-concentrate diet (CON; concentrate: forage 30:70), a high-concentrate diet (HC; concentrate: forage 70:30) and high-concentrate diet with 200 mg thiamine/kg DMI (HCT; concentrate: forage 70:30) for 12 weeks. Compared with the HC group, the goats of HCT group had a markedly higher final weight, net weight gain, and average daily gain (ADG). The blood physiological and biochemical results showed that the HCT group expressed a lower the content of lymphocytes and leukocytes but a higher total protein and monocytes compared with that of HC group. The rumen epithelial mitochondrial membrane potential change (ΔΨm), relative mitochondrial DNA (mtDNA) content, adenosine triphosphate (ATP) level, together with the activities of the respiratory complexes I, III, and IV were markedly higher in the HCT group relative to HC ones. Relative to the HC group, the unc-51 like autophagy activating kinase 1 (ULK1), microtubule-associated protein 1 light chain 3 (LC3), autophagy-related 5 (ATG5), autophagy related 7 (ATG7), Beclin1, PTEN induced putative kinase 1 (PINK1), PERK (PKR-Endoplasmic Reticulum Kinase), activating transcription factor 4 (ATF4), activating transcription factor 6 (ATF6), X-box binding protein 1 (XBP1), heat shock 70 kDa protein 5 (HSPA5), DNA damage-inducible transcript 3 (DDIT3) and DNA damage-inducible transcript 4 (DDIT4) mRNA levels were decreased, but the breast cancer 1 (BRCA1), ataxia telangiectasia mutated (ATM), heat shock factor binding protein 1 (HSBP1) were increased in rumen epithelium of the HCT group. The results of transmission electron micrographs showed that the cell structure of the HCT group was higher integrity than that in the HC group, and the damage degree of mitochondria as well as endoplasmic reticulum being lower than the HC group. These results demonstrated that dietary thiamine could enhance rumen epithelial integrity by suppressing the responses of ERS and mitophagy during long-term HC diet feeding.HIGHLIGHTSThis study is the first to demonstrate that the reduction of inflammatory response is related to the down-regulation of autophagy and endoplasmic reticulum stress in goats.Thiamine has good anti-inflammatory and anti-oxidation properties, which can be applied in intensive industry to reduce the negative effects caused by long-term high-concentrate diet.
研究领域:
动物营养
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分子生物学
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兽医学
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营养基因组学
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JOURNAL OF ETHNOPHARMACOLOGY
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2026
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IF 6.8
Wei ZHANG,Wen-tao ZHANG,Jia-xing FAN,Ya-yun WANG,Meng-jiao KANG,Xiang LI,Shan WANG,Lin-hua ZHAO
Ethnopharmacological relevance Gengnianshou Formula (GNS), a traditional Chinese medicine formula composed of 9 herbs, has long been used for regulating menopausal syndromes based on the TCM theory. However, its mechanistic basis for ameliorating perimenopausal obesity (a common estrogen deficiency-induced metabolic disorder) remains unelucidated. Aim of the study This study aimed to investigate the anti-obesity effects of GNS under estrogen-deficient conditions and to explore the potential involvement of HSPA5 and phosphatidylcholine (PC) metabolism using network pharmacology and multi-omics approaches. Materials and methods An ovariectomized (OVX) rat model was established using female Sprague-Dawley rats, which were randomly assigned to six groups (n = 6 per group) to evaluate the therapeutic effects of GNS. Network pharmacology analysis was conducted to identify potential targets. Transcriptomics and lipidomics analyses were integrated to explore molecular alterations. In vitro experiments using human adipose-derived stem cells (hADSCs) under estrogen-deprived conditions were performed to functionally validate the role of HSPA5 through siRNA-mediated knockdown, followed by Oil Red O staining and gene expression analysis. Results The OVX model successfully induced obesity, as evidenced by significant increases in body weight, visceral and subcutaneous white adipose tissue (vWAT/sWAT) volume, and adipocyte hypertrophy. GNS dose-dependently attenuated these OVX-induced alterations of body weight gain, vWAT/sWAT accumulation, and adipocyte hypertrophy in rats, and normalized perturbed serum lipid profiles (TG, LDL-C, HDL-C). Network pharmacology identified HSPA5 as a potential key target. Multi-omics analysis revealed significant alterations in lipid metabolism, particularly in PC-related species, which were associated with HSPA5 expression changes. Functional experiments demonstrated that silencing HSPA5 attenuated lipid accumulation and downregulated adipogenic markers, including PPARγ and C/EBPα, under estrogen-deficient conditions. Conclusion These findings support a functional role of HSPA5 in regulating adipogenesis, while alterations in PC metabolism may represent associated downstream metabolic changes. GNS ameliorates estrogen deficiency-induced obesity, potentially involving HSPA5 and PC metabolism. This study provides integrative evidence supporting HSPA5 as a functional regulator in this context, while highlighting a possible link to PC metabolic remodeling.
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