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Targeted activation on bnip3 enhances mitophagy to prevent the progression of osteoarthritis

JOURNAL OF ORTHOPAEDIC TRANSLATION 2025年 51卷 242-255页

作者： Gou, Yong Wang, Chenggui Fu, Kejian Su, Shenkai Zhou, Hangjin Bao, Chunkai Nan, Hui Zhang, Xiang Xu, Yiyuan Chen, Qi Gu, Xinchen Chen, Baiting Zheng, Lin Xie, Chenglong Zhang, Man Xue, Enxing Li, Jiawei Wenzhou Med Univ Affiliated Hosp 2 Dept Orthoped Wenzhou 325027 Peoples R China Wenzhou Med Univ Yuying Childrens Hosp Wenzhou 325027 Peoples R China Key Lab Orthoped Zhejiang Prov Wenzhou 325027 Peoples R China Wenzhou Med Univ Sch Med 2 Wenzhou 325027 Peoples R China Wenzhou Med Univ Wenzhou 325027 Peoples R China

Background: The production of reactive oxygen species (ROS) and mitochondrial dysfunction in chondrocytes are closely related to cartilage degeneration in the procedure of osteoarthritis (OA). Mitophagy is responsible for the scavenging of ROS and dysfunctional mitochondria and is considered a key therapeutic target for the treatment of OA. Tiopronin, a classic thiol antioxidant, has been widely studied for the treatment of various oxidative stress-related diseases. Methods: The expression of mitophagy (PINK1, PARKIN, and TOMM20) in intact and damaged cartilage of OA patients was analyzed by Western blot and histological analysis. RNA sequencing (RNA-seq) analysis was performed to explore the molecular mechanism of tiopronin in regulating mitophagy in chondrocytes, and then to find the specific target of tiopronin. The therapeutic effects of tiopronin were evaluated in the OA model induced by destabilisation of the medial meniscus (DMM), chondrocytes degenerative model with the primary chondrocytes from mouse and human cartilage explants experiment. The downstream molecular mechanisms of tiopronin were further investigated by si-RNA knockdown of mitophagy-related proteins. Results: The level of mitophagy in cartilage was negatively correlated with the severity of OA. We revealed that tiopronin promoted the anabolism of the extracellular matrix (ECM) of hyaline chondrocytes and alleviates ROS in vitro and in vivo by strengthening mitophagy. Moreover, tiopronin strongly activated the expression of bnip3, a protein anchored in the mitochondrial membrane, and subsequently enhanced the Pink1/Parkin signaling pathway. Conclusion: These findings indicate that the bnip3-Pink1-Parkin signaling pathway, targeted and activated by tiopronin, plays a key role in inhibiting the progression of OA. The translational potential of this article: As a classical drug in clinic, tiopronin was developed a new therapeutic approach in the treatment in OA via this study. Based the significan

关键词： bnip3 Cartilage degeneration Mitophagy Osteoarthritis Tiopronin

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Hsp90 and HIF-1α regulate mitophagy by promoting bnip3 expression in renal ischemia-reperfusion injury

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TRANSPLANT IMMUNOLOGY 2025年 89卷 102177-102177页

作者： Dong, Qi Li, Xia Cheng, Ke Cent South Univ Xiangya Hosp 3 Transplantat Ctr Changsha 410000 Hunan Peoples R China

Background: Ischemia-reperfusion injury (IRI) is a major cause of acute kidney injury (AKI). Studies have shown that mitochondrial damage is involved in the pathogenesis of AKI, and that inhibition of Hsp90 expression can improve IR-induced AKI. However, the mechanisms by which Hsp90 improves IR-induced AKI and whether it is involved in mitochondrial autophagy remain unclear. Methods: An IR-induced AKI mouse model was established, and the degree of renal injury was analyzed using hematoxylin and eosin (H&E) and periodic acid-Schiff (PAS) staining. The expression of Hsp90, HIF-1 alpha, bnip3, and mitochondrial autophagy proteins was detected by western blotting in vivo and in vitro. HK2 cell viability, apoptosis, mitochondrial autophagy, reactive oxygen species (ROS), and inflammatory cytokines levels were detected using Cell Counting Kit 8 (CCK8) assays, Terminal center dot deoxynucleotidyl transferase-mediated dUTP nick end center dot labeling (TUNEL) labeling, immunofluorescence, and enzyme-linked immunosorbent (ELISA). Results: A murine IR-induced AKI model was successfully generated, and increased expression levels of Hsp90, HIF-1 alpha, and inflammatory cytokines were observed, accompanied by a worsening of renal injury. After induction of IRI in HK2 cells, downregulation of Hsp90 or HIF-1 alpha expression resulted in decreased downstream bnip3 expression, an increase in HK2 cell viability, and a decrease in the level of mitochondrial autophagy. Conclusion: Hsp90 upregulated the expression of HIF-1 alpha and bnip3, thereby enhancing mitochondrial autophagy in IR-induced AKI.

关键词： IR-induced AKI Mitophagy Hsp90 HIF-1 alpha bnip3

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Shen-fu Injection Modulates HIF-1α/bnip3-Mediated Mitophagy to Alleviate Myocardial Ischemia-Reperfusion Injury

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CARDIOVASCULAR TOXICOLOGY 2025年 1-17页

作者： Chen, Zhian Liu, Tianying Xiong, Lihui Liu, Zhi Changchun Univ Chinese Med Sch Integrated Chinese Med Changchun 130117 Peoples R China Changchun Univ Chinese Med Sch Basic Med Sci Changchun 130117 Peoples R China Changchun Univ Chinese Med Sch Clin Med 1035 Boshuo Rd Changchun 130117 Jilin Peoples R China

Coronary reperfusion therapy is the most common surgical treatment for myocardial infarction, but it can further induce myocardial ischemia-reperfusion injury (MIRI). Therefore, MIRI following coronary intervention is a challenging clinical issue. This study aims to investigate the involvement of HIF- 1 alpha/bnip3-mediated mitophagy in the protective effects of Shen-fu Injection (SFI) on MIRI in rats. Key targets and signaling pathways of myocardial MIRI were analyzed using high-throughput transcriptome data from the GSE240842 dataset in the GEO *** establish the MIRI rat model, the left anterior descending coronary artery was ligated for 30 min, followed by reperfusion for 120 min. Hypoxia/reoxygenation (H/R) in neonatal rat primary cardiomyocytes was induced by oxygen-glucose deprivation for 4 h, followed by reoxygenation for 2 h. Two hours after reperfusion, assessments included myocardial infarction area, CK-MB, CTnI, HE staining, TUNEL, mitochondrial ultrastructure and autophagosomes, HIF- 1 alpha, bnip3, LC3B-II, LC3B-I protein expression, immunofluorescence, and qRT-PCR. Cardiac function was also evaluated using M-mode ultrasound 2 h after reperfusion. In cardiomyocytes, CCK- 8, EdU cell proliferation levels, scratch assay, mitochondrial membrane potential, ROS levels, cardiomyocyte apoptosis, protein expression levels, and immunofluorescence were assessed 2 h after reoxygenation. Our results indicate that HIF- 1 alpha and bnip3 are key targets in MIRI. SFI upregulates HIF- 1 alpha expression, promoting moderate mitophagy. This process clears excessively damaged mitochondria, reduces cardiomyocyte apoptosis, and decreases myocardial injury. Additionally, SFI reduces autophagosome accumulation, lowers ROS production, and stabilizes membrane potential. Consequently, the area of myocardial infarction is reduced, and cardiac function is improved. SFI activates the HIF- 1 alpha/bnip3 pathway to mediate moderate mitophagy, effectively reducing cardiomyocyt

关键词： Shen-fu injection Myocardial ischemia-reperfusion injury Mitophagy HIF-1 alpha bnip3

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Inhibiting HSP90 changes the expression pattern of PINK1 and bnip3 and induces oxidative stress in colon cancer cells

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MOLECULAR BIOLOGY REPORTS 2025年第1期52卷 1-11页

作者： Abu-El-Rub, Ejlal Alzu'bi, Ayman Almahasneh, Fatimah A. Khaswaneh, Ramada R. Almazari, Rawan Kasasbeh, Amani Aldamen, Ala A. AI-jariri, Heba F. Alomari, Amal Yousef, Tuqa Al-Zoubi, Raed M. Yarmouk Univ Fac Med Dept Basic Med Sci Irbid 21163 Jordan Hamad Med Corp Dept Surg Surg Res Sect Doha Qatar Qatar Univ Coll Hlth Sci Dept Biomed Sci QU Hlth Doha 2713 Qatar Jordan Univ Sci & Technol Dept Chem POB 3030 Irbid 22110 Jordan

BackgroundCancer cells can modulate the expression of many proteins that are essential for supporting their uncontrolled proliferation. Heat shock protein 90 (HSP90) is ubiquitously expressed in most cell types and participates in controlling many survival pathways. Cancer cells utilize HSP90 in order to prolong their survival, thus they tend to overexpress it. Based on its importance for cancer cells, we aim to investigate the molecular mechanisms that link HSP90 inhibition in colon cancer cells with oxidative stress and mitochondrial stress-related *** and methodsWe used RKO colon cancer cells, blocking HSP90 with the inhibitor AT13387 and HSP90 siRNA. Cell proliferation and apoptosis were measured via CCK8 ELISA and Fluorescent Apoptosis Assays. Western blotting and immunocytochemistry assessed oxidative and mitochondrial stress markers bnip3, PINK1, GP91/NOX2, and IRE1 alpha in treated *** findings reveal that inhibiting HSP90 with AT13387 reduces RKO cell viability by suppressing proliferation and enhancing Annexin-V expression, indicative of increased apoptosis. This rise in apoptosis is associated with PINK1 downregulation and bnip3 upregulation, markers of mitochondrial dysfunction and oxidative stress, respectively. Additionally, AT13387 treatment elevated the protein level of GP91, a marker of oxidative stress, and IRE1 alpha, a marker of ER stress. Similarly, genetic knockdown of HSP90 in RKO cells produced comparable effects, including reduced cell survival and a decreased PINK1/bnip3 *** HSP90 in colon cancer cells disrupts their survival by decreasing PINK1 and increasing bnip3, which activates oxidative and endoplasmic reticulum stress, ultimately triggering apoptosis.

关键词： RKO cells HSP90 PINK1 bnip3 Oxidative stress Apoptosis

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Hypoxia-induced bnip3 facilitates the progression and metastasis of uveal melanoma by driving metabolic reprogramming

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AUTOPHAGY 2025年第1期21卷 191-209页

作者： Sun, Jie Ding, Jie Yue, Han Xu, Binbin Sodhi, Akrit Xue, Kang Ren, Hui Qian, Jiang Fudan Univ Eye Ear Nose & Throat Hosp Dept Ophthalmol 83 Fenyang Rd Shanghai 200031 Peoples R China Jinan Univ Shenzhen Eye Hosp Shenzhen Peoples R China Shanghai Key Lab Visual Impairment & Restorat Shanghai Peoples R China Johns Hopkins Univ Wilmer Eye Inst Sch Med Baltimore MD USA

Uveal melanoma (UM) is an aggressive intraocular malignancy derived from melanocytes in the uvea tract of the eye. Up to 50% of patients with UM develop distant metastases which is usually fatal within one year;preventing metastases is therefore essential. Metabolic reprogramming plays a critical role in UM progression and metastasis. However, the metabolic phenotype of UM cells in the hypoxic tumor is not well understood. Here, we report that hypoxia-induced bnip3 reprograms tumor cell metabolism, promoting their survival and metastasis. In response to hypoxia, bnip3-mediated mitophagy alleviates mitochondrial dysfunction and enhances mitochondrial oxidative phosphorylation (OXPHOS) while simultaneously reducing mitochondrial reactive oxygen species (mtROS) production. This, in turn, impairs HIF1A/HIF-1 alpha protein stability and inhibits glycolysis. Inhibition of mitophagy significantly suppresses bnip3-induced UM progression and metastasis in vitro and in vivo. Collectively, these observations demonstrate a novel mechanism whereby bnip3 promotes UM metabolic reprogramming and malignant progression by mediating hypoxia-induced mitophagy and suggest that bnip3 could be an important therapeutic target to prevent metastasis in patients with ***: AOD: average optical density;bnip3: BCL2/adenovirus E1B interacting protein 3;CQ: chloroquine;CoCl2: cobalt chloride;GEPIA: Gene Expression Profiling Interactive Analysis;HIF1A: hypoxia inducible factor 1, alpha subunit;IHC: immunohistochemistry;mtROS: mitochondrial reactive oxygen species;NAC: N-acetylcysteine;OCR: oxygen consumption rate;OXPHOS: oxidative phosphorylation;ROS: reactive oxygen species;TCGA: The Cancer Genome Atlas;UM: uveal melanoma.

关键词： bnip3 glycolysis HIF1A mitophagy oxidative phosphorylation uveal melanoma

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Twist2 knockdown alleviates renal ischemia-reperfusion injury by maintaining mitochondrial function and enhancing mitophagy through bnip3

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HUMAN CELL 2025年第2期38卷 1-16页

作者： Zhang, Lexi Ye, Jianfeng Qiu, Cheng Univ Sci & Technol China USTC Affiliated Hosp 1 Dept Kidney TransplantatDiv Life Sci & Med Hefei Anhui Peoples R China

Renal ischemia-reperfusion injury (IRI) is a major cause of acute kidney injury (AKI). Twist-related protein 2 (Twist2) is a basic helix/loop/helix transcription factor. However, the underlying effects of Twist2 in IRI remain to be elucidated. Herein, we found that the expression of Twist2 was significantly upregulated in renal tissues of mice induced by ischemia/reperfusion (I/R) and in human renal tubular epithelial cell HK-2 exposed to hypoxia-reoxygenation. We silenced Twist2 with RNAi technology. Twist2 knockdown alleviated renal pathological damage in mice. Twist2 depletion ameliorated IRI-induced mitochondrial dysfunction, such as increasing ATP content and mitochondrial DNA copy number and restoring mitochondrial membrane potential in the kidneys of mice, and similar results were observed in in vitro experiments. Twist2 interference increased the expression of LC3B and decreased the expression of p62 and mitochondrial membrane proteins TIMM23 and TOMM20 both in vivo and in vitro. Electron microscope and the co-localization of LC3B and mitotracker DsRed suggested the induction of autophagy and mitophagy after Twist2 knockdown in kidneys or cells. Mechanism studies revealed that Twist2 exerted a direct inhibitory effect on BCL2 interacting protein 3 (bnip3) transcriptional activity by targeting the bnip3 promoter. In hypoxia/reoxygenation-induced renal tubular epithelial cells, the interference of bnip3 reversed the effect of Twist2 depletion on mitochondrial function and mitophagy. In conclusion, our findings suggest that the depletion of Twist2 exerts renoprotective effect in I/R-induced AKI. Twist2 regulates mitochondrial function and mitophagy in part by targeting and downregulating bnip3. Our study provides new insights into the pathological mechanisms of I/R-induced AKI.

关键词： Twist2 bnip3 Ischemia-reperfusion injury Acute kidney injury Mitophagy

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The role of HIF-1α/bnip3/mitophagy in acrylonitrile-induced neuronal death in HT22 cells and mice: A potential neuroprotection target

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CHEMICO-BIOLOGICAL INTERACTIONS 2025年 406卷 111327页

作者： Hu, Jing Yang, Bobo Tao, Zehua Chen, Jian Zhang, Xinyu Wang, Suhua Xing, Guangwei Ngeng, Ngwa Adeline Malik, Abdul Appiah-Kubi, Kwaku Farina, Marcelo V. Skalny, Anatoly Tinkov, Alexey A. Aschner, Michael Lu, Rongzhu Jiangsu Univ Sch Med Dept Prevent Med & Publ Hlth Lab Sci Zhenjiang 212013 Jiangsu Peoples R China Jiangsu Univ Dept Gen Surg Affiliated Hosp Zhenjiang 212001 Jiangsu Peoples R China CK Tedam Univ Technol & Appl Sci Dept Appl Biol Navrongo 02155321 Ghana Univ Fed Santa Catarina Dept Biochem BR-88040900 Florianopolis SC Brazil Sechenov Univ IM Sechenov Moscow State Med Univ 1 Lab Mol Dietet Bolshaya Pirogovskaya St 2-4 Moscow 119146 Russia Orenburg State Univ Pobedy Ave13 Orenburg 460018 Russia Yaroslavl State Univ Lab Ecobiomonitoring & Qual Control Yaroslavl 150000 Russia Albert Einstein Coll Med Dept Mol Pharmacol Bronx NY 10461 USA

Acrylonitrile (AN) is a widely utilized organic compound in the production of diverse industrial synthetic materials. While acute exposure to AN can cause neurotoxicity, the precise mechanism remains unclear. Hypoxiainducible factor 1 alpha (HIF-1 alpha) is a pivotal transcription factor that coordinates and orchestrates multiple physiological processes to adapt to hypoxic conditions, ensuring cellular survival and homeostasis. In this study, we used in vitro (cultured mouse hippocampal neuronal cell line, HT22) and in vivo (AN exposed mice) approaches to investigate the potential modulator effects of HIF-1 alpha in AN-induced neurotoxicity. In vitro, AN exposure caused concentration-dependent toxicity in HT22 cells, which was paralleled by increased Bax levels while decreasing Bcl-2. Exposure to AN resulted in reduced protein levels of HIF-1 alpha, Bcl-2 19-kDa interacting protein 3 (bnip3), microtubule-associated protein 1 light chain 3 beta (LC3B) and Beclin1, while increased the protein levels of the translocase of outer mitochondrial membrane 20 (TOM20). Furthermore, mitochondrial morphology and function were compromised, suggesting that AN impaired HIF-1 alpha/bnip3-mediated mitochondrial autophagy and promoted apoptosis. Treatment with a HIF-1 alpha activator, cobalt chloride (CoCl2), reversed these effects, while pretreatment with a HIF-1 alpha inhibitor, 2-methoxyestradiol (2-MeOE2), augmented them. In bnip3 overexpressing HT22 cells, enhanced cell viability and reduced apoptosis rates were observed. Furthermore, the HIF-1 alpha/bnip3 pathway was activated by the prolyl hydroxylase (PHD2) inhibitor, deferoxamine (DFO), which increased HT22 cell viability. Similarly, the activation of HIF-1 alpha by administering 20 mg/kg of CoCl2 was found to alleviate neurotoxicity in mice. This treatment enhanced elevations of autophagy protein expression and co-localization of bnip3 and LC3B. In summary, under normoxia, AN induced neurotoxicity by promoting PHD2-mediated

关键词： Acrylonitrile Neurotoxicity HIF-1 alpha bnip3 Mitophagy Apoptosis

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LncRNA XIST inhibits mitophagy and increases mitochondrial dysfunction by promoting bnip3 promoter methylation to facilitate the progression of KBD

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MOLECULAR IMMUNOLOGY 2025年 182卷 62-75页

作者： Liu, Ruoxi Xiao, Yi Huang, Sihua Wu, Hao Dong, Jun Zeng, Sixiang Li, Yongwei Ye, Jintao Wu, Wei Wang, Mengxin Zhang, Sanpeng Lin, Zhaoxing Song, Huanjin Xi An Jiao Tong Univ Affiliated Hosp 2 Dept Orthopaed 157 Xiwu Rd Xian 710004 Peoples R China Shaanxi Prov Ctr Dis Control & Prevent 3 Jiandong St Xian 710054 Peoples R China Xi An Jiao Tong Univ Affiliated Hosp 2 Operating Room Xian Peoples R China

The primary mechanisms underlying cartilage destruction in Kashin-Beck disease (KBD) involve excessive chondrocyte death and extracellular matrix (ECM) degradation. While long non-coding RNA XIST (lncRNA XIST) has been implicated in promoting chondrocyte injury in osteoarthritis (OA), its role in KBD-related chondrocyte injury remains poorly understood. In this study, joint tissues were collected from four healthy and four KBD-affected children, as well as five healthy and five KBD-affected adults, to assess the expression of lncRNA XIST. The results revealed a significant upregulation of lncRNA XIST in the cartilage tissues of KBD patients. To model KBD-induced chondrocyte damage in vitro, hypertrophic ATDC5 cells were exposed to 10 ng/ml T-2 toxin for 24 hours, which resulted in increased lncRNA XIST expression. Silencing lncRNA XIST was found to mitigate T-2 toxin-induced ECM degradation and chondrocyte apoptosis by alleviating defects in mitochondrial autophagy and dysfunction. Mechanistically, lncRNA XIST promoted the methylation of the bnip3 promoter by recruiting DNA methyltransferases (DNMTs) to the bnip3 promoter region, thereby suppressing bnip3-mediated mitophagy and exacerbating mitochondrial dysfunction. To establish a KBD rat model, rats were fed a low-selenium diet supplemented with T-2 toxin for four weeks. Knockdown of lncRNA XIST in these rats attenuated articular cartilage damage and apoptosis, while enhancing collagen II expression. In conclusion, lncRNA XIST accelerates KBD progression by inhibiting mitophagy and promoting mitochondrial dysfunction through increased bnip3 promoter methylation.

关键词： LncRNA XIST bnip3 Mitophagy DNA methylation Chondrocyte Kashin-Beck disease

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bnip3 as a potential target of esculetin for treating ovarian cancer and prognostic biomarker in ovarian cancer patients

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European Journal of Pharmacology 2025年 999卷 177698页

作者： Fan, Wen Zhang, Yongjun Yang, Xiangqun Liu, Zhenyan Wu, Xingyan Li, Lvzhou Zhao, Taoyu Li, Haoran Liu, Xiaolin Cui, Daolei Wan, Qianqian Li, Wenliang Yang, Hongying Zhang, Hongping Jia, Yue Department of Gynecology The Third Affiliated Hospital of Kunming Medical University Yunnan Cancer Hospital Kunming 650118 China Department of Obstetrics and Gynecology Dehong Affiliated Hospital of Kunming Medical University Dehong People's Hospital of Yunnan Province Dehong 678400 China Medical School Kunming University of Science and Technology Kunming 650500 China Department of Gastroenterology Shanghai Municipal Hospital of Traditional Chinese Medicine Shanghai University of Traditional Chinese Medicine Shanghai 200071 China Institute of Environmental Remediation and Human Health School of Ecology and Environment Southwest Forestry University Kunming 650224 China Medical Affairs Department The First Affiliated Hospital of Yunnan University of Traditional Chinese Medicine Kunming 650021 China

Among gynecological tumors, ovarian cancer has the highest mortality rate and worst prognosis. Therefore, it is crucial to identify and develop novel methods and targets for treating ovarian cancer. Previous studies have shown that esculetin exerts antitumor effects in a variety of cancers, however, its anti-ovarian cancer effects and mechanisms of action remain unclear. In the present study, we investigated the anti-ovarian cancer effects and mechanisms of esculetin in A2780 and OVCAR3 ovarian cancer cells and established an xenograft ovarian cancer mouse model. Esculetin significantly inhibited ovarian cancer cell proliferation, blocked cell cycle progression, and promoted apoptosis and DNA damage in a concentration-dependent manner. Furthermore, esculetin inhibited tumor growth in an xenograft ovarian cancer mouse model. Moreover, RNA-seq showed that 2114 genes were significantly altered in A2780 cells after esculetin treatment. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis indicated that these differentially expressed genes were mainly enriched in the calcium, HIF-1, and Rap1 signaling pathways. Interestingly, bnip3 expression was notably upregulated in ovarian cancer cells after esculetin treatment. Finally, we found that low bnip3 expression was correlated with poor prognosis in patients with ovarian cancer. These results prove that esculetin may be a valuable anti-ovarian cancer drug, and that bnip3 is a potential treatment target for esculetin and a potential prognostic biomarker for ovarian cancer. © 2025 Elsevier B.V.

关键词： bnip3 Cell apoptosis Cell damage Esculetin Ovarian cancer

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Brevilin A, a novel bnip3 inhibitor suppresses osteoclastogenesis and prevents ovariectomy-induced bone loss via impairing mitophagy and mitochondrial metabolism

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Phytomedicine 2025年 143卷 156774页

作者： Zhou, Rui Wang, Yiyuan Liu, Siyi Su, Yuangang Liu, Zhijuan Yang, Baihui Li, Xiangde Zhao, Jinmin Xu, Jiake Liu, Qian Song, Fangming Collaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Co-constructed by the Province and Ministry Guangxi Medical University Nanning 530021 China Guangxi Key Laboratory of Regenerative Medicine Orthopaedics Trauma and Hand Surgery the First Affiliated Hospital of Guangxi Medical University Nanning 530021 China Life Sciences Institute Guangxi Medical University Nanning 530021 China The First Clinical Medical College Guangxi Medical University Nanning 530021 China School of Biomedical Sciences the University of Western Australia Perth Australia Shenzhen Institute of Advanced Technology Chinese Academy of Sciences Shenzhen 518000 China Shenzhen University of Advanced Technology Shenzhen 518000 China

Background: The mitochondrial dysfunction and overactive osteoclasts is involved in the progress of osteoporosis. Brevilin A (BA), a sesquiterpene lactone, is a compound extracted and purified from Centipeda minima. It exhibits a range of pharmacological activities, such as anti-inflammatory and antioxidant effects. However, its specific impact on osteoporosis remains unclear. The present study is designed to explore BA as a novel osteoclast inhibitor for the treatment of osteoporosis as well as its molecular mechanisms of action via bnip3-mediated mitophagy. Methods: The cytotoxicity of BA in vitro was evaluated using the CCK8 assay, while tartrate-resistant acid phosphatase (TRAcP) staining and bone resorption assays were conducted to examine its effects on osteoclastogenesis and osteoclast function. To elucidate the molecular mechanisms by which BA targets bnip3 in osteoclasts, RNA-seq, molecular docking analysis, Surface plasmon resonance (SPR), qPCR, western blot, mitochondrial oxygen consumption rate (OCR), transmission electron microscopy (TEM), Single cell sequencing and immunofluorescence staining were employed. In addition, a specific bnip3 agonist IOX5, was used to revalidate the inhibitory effect of BA on bnip3. To investigate the effects and protective role of BA in modulating bnip3 on bone loss in osteoporotic mice induced by ovariectomy (OVX), we employed in vivo micro-CT scanning and histological immunostaining techniques. Results: Our study demonstrated that BA inhibited RANKL-induced osteoclastogenesis in a concentration-dependent manner without any cell cytotoxicity. Further, BA abrogated MAPK-related proteins and intracellular and mitochondrial ROS level, subsequently inhibiting NFATc1 activity. RNA-seq analysis revealed that the molecular mechanism by which BA inhibited osteoclasts is closely related to mitophagy and mitochondrial function. Here, we found that BA suppressed oxygen consumption rate and mitochondrial oxidative phosphorylation duri

关键词： bnip3 Brevilin A Mitochondrial function Mitophagy Osteoclast Osteoporosis

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