首页 > 最新文献

Experimental and Molecular Medicine最新文献

英文 中文
Brain metastasis from non-small cell lung cancer: crosstalk between cancer cells and tumor microenvironment components. 非小细胞肺癌脑转移:癌细胞与肿瘤微环境组分之间的串扰。
IF 12.9 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-12-01 Epub Date: 2025-12-22 DOI: 10.1038/s12276-025-01604-z
Myung-Seo Kim, Juyoun Lee, Jeong Eun Lee, Jong Hun An, Jun Young Heo, Min-Kyung Yeo

The majority of patients with lung cancer are diagnosed at an advanced stage, with a substantial proportion exhibiting signs of brain metastases (BMs). BM is associated with debilitating symptoms, including headaches, seizures and neurological or cognitive impairments, which severely impact the quality of life of patients. Despite considerable advancements in lung cancer treatment modalities, the management of BM remains challenging due to the complex cellular and structural nature of the blood-brain barrier and resistance driven by acquired genetic mutations. Non-small cell lung cancer (NSCLC) is characterized by diverse genetic alterations. The application of immunotherapy has successfully enhanced antitumor immune responses within the tumor microenvironment (TME) of affected patients. The intricate interplay between NSCLC cells and the TME plays a critical role in the pathogenesis of BM. This review focuses on the brain-specific TME and its exploitation by tumor cells to establish metastases through strategic, site-specific mechanisms. The reciprocal molecular interactions, immune modulation and adaptation of NSCLC cells to the brain metastatic niche are central to this process. A deeper understanding of the complex crosstalk between tumor cells and TME is essential for devising more effective and targeted therapeutic interventions for BM.

大多数肺癌患者在晚期被诊断出来,其中相当大比例表现出脑转移(BMs)的迹象。脑脊髓炎与使人衰弱的症状有关,包括头痛、癫痫发作和神经或认知障碍,这些症状严重影响患者的生活质量。尽管肺癌治疗方式取得了长足的进步,但由于血脑屏障的复杂细胞和结构性质以及获得性基因突变驱动的耐药性,脑转移的管理仍然具有挑战性。非小细胞肺癌(NSCLC)以多种基因改变为特征。免疫疗法的应用已经成功地增强了受影响患者肿瘤微环境(TME)内的抗肿瘤免疫反应。NSCLC细胞与TME之间复杂的相互作用在脑转移的发病机制中起着关键作用。本文综述了脑特异性TME及其通过战略性、部位特异性机制被肿瘤细胞利用来建立转移。分子相互作用、免疫调节和非小细胞肺癌细胞对脑转移生态位的适应是这一过程的核心。更深入地了解肿瘤细胞和TME之间复杂的串扰,对于设计更有效、更有针对性的脑转移治疗干预措施至关重要。
{"title":"Brain metastasis from non-small cell lung cancer: crosstalk between cancer cells and tumor microenvironment components.","authors":"Myung-Seo Kim, Juyoun Lee, Jeong Eun Lee, Jong Hun An, Jun Young Heo, Min-Kyung Yeo","doi":"10.1038/s12276-025-01604-z","DOIUrl":"10.1038/s12276-025-01604-z","url":null,"abstract":"<p><p>The majority of patients with lung cancer are diagnosed at an advanced stage, with a substantial proportion exhibiting signs of brain metastases (BMs). BM is associated with debilitating symptoms, including headaches, seizures and neurological or cognitive impairments, which severely impact the quality of life of patients. Despite considerable advancements in lung cancer treatment modalities, the management of BM remains challenging due to the complex cellular and structural nature of the blood-brain barrier and resistance driven by acquired genetic mutations. Non-small cell lung cancer (NSCLC) is characterized by diverse genetic alterations. The application of immunotherapy has successfully enhanced antitumor immune responses within the tumor microenvironment (TME) of affected patients. The intricate interplay between NSCLC cells and the TME plays a critical role in the pathogenesis of BM. This review focuses on the brain-specific TME and its exploitation by tumor cells to establish metastases through strategic, site-specific mechanisms. The reciprocal molecular interactions, immune modulation and adaptation of NSCLC cells to the brain metastatic niche are central to this process. A deeper understanding of the complex crosstalk between tumor cells and TME is essential for devising more effective and targeted therapeutic interventions for BM.</p>","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":" ","pages":"2749-2762"},"PeriodicalIF":12.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12800198/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145811950","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Cancer-associated fibroblast-derived extracellular vesicles regulate lipophagy through PLIN2 to modulate dormancy in salivary gland adenoid cystic carcinoma cells. 癌症相关成纤维细胞衍生的细胞外囊泡通过PLIN2调节唾液腺腺样囊性癌细胞的休眠来调节脂质吞噬。
IF 12.9 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-12-01 Epub Date: 2025-12-18 DOI: 10.1038/s12276-025-01600-3
Zhichao Dou, Xu Zhang, Kun Meng, Mao Li, Xin Pang, Wanli Wang, Rongjia Shi, Xinhua Liang, Yaling Tang

Tumor recurrence and metastasis are largely attributed to dormant tumor cells receiving reactivation signals, particularly those originating from the tumor microenvironment. However, the detailed mechanisms of dormant tumor cell reactivation in salivary gland adenoid cystic carcinoma (SACC) remain largely unknown. Here our data revealed that autophagy is activated in dormant SACC cells but becomes downregulated once these cells are reactivated, and that cancer-associated fibroblast (CAF)-mediated autophagy promotes dormant SACC cells to resume proliferation and escape dormancy. Mechanistically, PLIN2 encapsulated in CAFs-derived extracellular vesicles promoted the initial stage of autophagy through the endoplasmic reticulum stress signaling pathway, and directly bound to p62 to promote lipid droplet degradation through the lipophagy pathway, which provided energy for the reactivation of dormant SACC cells. Moreover, we confirmed that PLIN2 expression was remarkably correlated with poor survival in patients with SACC. Finally, we verified that the combination of tozasertib and PLIN2 was stable through molecular docking and molecular dynamics simulation, indicating that tozasertib has the potential to serve as a targeted PLIN2 drug for CAFs in SACC. Our findings suggest that targeting PLIN2 and autophagy inhibition as part of primary SACC treatment may effectively eliminate dormant tumor cells and prevent SACC recurrence.

肿瘤的复发和转移在很大程度上归因于休眠肿瘤细胞接受再激活信号,特别是那些来自肿瘤微环境的信号。然而,涎腺腺样囊性癌(SACC)中休眠肿瘤细胞活化的详细机制在很大程度上仍然未知。在这里,我们的数据显示,自噬在休眠的SACC细胞中被激活,但一旦这些细胞被重新激活,自噬就会被下调,并且癌症相关成纤维细胞(CAF)介导的自噬促进休眠的SACC细胞恢复增殖并摆脱休眠。机制上,包裹在cafs来源的细胞外囊泡中的PLIN2通过内质网应激信号通路促进初始阶段的自噬,并直接与p62结合,通过脂噬通路促进脂滴降解,为休眠SACC细胞的再激活提供能量。此外,我们证实了PLIN2的表达与SACC患者的低生存率显著相关。最后,我们通过分子对接和分子动力学模拟验证了tozasertib与PLIN2的联合是稳定的,这表明tozasertib具有作为SACC CAFs的PLIN2靶向药物的潜力。我们的研究结果表明,靶向PLIN2和自噬抑制作为SACC原发性治疗的一部分,可以有效地消除休眠肿瘤细胞,防止SACC复发。
{"title":"Cancer-associated fibroblast-derived extracellular vesicles regulate lipophagy through PLIN2 to modulate dormancy in salivary gland adenoid cystic carcinoma cells.","authors":"Zhichao Dou, Xu Zhang, Kun Meng, Mao Li, Xin Pang, Wanli Wang, Rongjia Shi, Xinhua Liang, Yaling Tang","doi":"10.1038/s12276-025-01600-3","DOIUrl":"10.1038/s12276-025-01600-3","url":null,"abstract":"<p><p>Tumor recurrence and metastasis are largely attributed to dormant tumor cells receiving reactivation signals, particularly those originating from the tumor microenvironment. However, the detailed mechanisms of dormant tumor cell reactivation in salivary gland adenoid cystic carcinoma (SACC) remain largely unknown. Here our data revealed that autophagy is activated in dormant SACC cells but becomes downregulated once these cells are reactivated, and that cancer-associated fibroblast (CAF)-mediated autophagy promotes dormant SACC cells to resume proliferation and escape dormancy. Mechanistically, PLIN2 encapsulated in CAFs-derived extracellular vesicles promoted the initial stage of autophagy through the endoplasmic reticulum stress signaling pathway, and directly bound to p62 to promote lipid droplet degradation through the lipophagy pathway, which provided energy for the reactivation of dormant SACC cells. Moreover, we confirmed that PLIN2 expression was remarkably correlated with poor survival in patients with SACC. Finally, we verified that the combination of tozasertib and PLIN2 was stable through molecular docking and molecular dynamics simulation, indicating that tozasertib has the potential to serve as a targeted PLIN2 drug for CAFs in SACC. Our findings suggest that targeting PLIN2 and autophagy inhibition as part of primary SACC treatment may effectively eliminate dormant tumor cells and prevent SACC recurrence.</p>","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":" ","pages":"2852-2868"},"PeriodicalIF":12.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12800263/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145776213","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
SLC6A14-mediated glutamine promotes SYTL4-CXCL8 axis activation to drive gemcitabine resistance and immune evasion in pancreatic cancer. slc6a14介导的谷氨酰胺促进SYTL4-CXCL8轴激活,驱动胰腺癌吉西他滨耐药和免疫逃避。
IF 12.9 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-12-01 Epub Date: 2025-12-25 DOI: 10.1038/s12276-025-01596-w
Hyeon Woong Kang, Ju Hyun Kim, Jae Woong Jeong, Sungsoon Fang, Won-Gun Yun, Hye-Sol Jung, Wooil Kwon, Jin-Young Jang, Hyo Jung Kim, Joon Seong Park

Chemoresistance remains a major challenge in pancreatic ductal adenocarcinoma (PDAC). Glutamine sustains drug resistance and shapes the immunosuppressive tumor microenvironment; however, the underlying mechanisms remain unclear. Identifying key regulators that drive both gemcitabine resistance and immune evasion is crucial for improving theapeutic outcomes in PDAC. Here we identified solute-carrier family 6 member 14 (SLC6A14) as the central regulator of glutamine metabolism that drives gemcitabine resistance. SLC6A14-mediated glutamine metabolism facilitated α-ketoglutarate production, activating mTOR/NF-κB signaling to upregulate PD-L1 expression, playing a central role in immune evasion. Moreover, SLC6A14 induced CXC motif chemokine ligand 8 secretion via synaptotagmin-like 4-mediated exocytosis, paracrinally activating CXCR2 signaling in cancer-associated fibroblasts to enhance mitochondrial fission and amino acid recycling, supporting PDAC progression. Targeting SLC6A14 with α-methyl-tryptophan enhanced gemcitabine sensitivity, suppressed PD-L1 driven immune evasion and reduced tumor growth, metastasis and glutamine production in vivo. These findings underscore SLC6A14 as a pivtoal mediator of glutamine-driven gemcitabine resistance and immune evasion in PDAC. Therapeutic strategies targeting SLC6A14, either alone or in combination with PD-L1 blockade, hold promise for overcoming chemoresistance and enhancing antitumor immunity in gemcitabine-resistant pancreatic cancer.

化疗耐药仍然是胰腺导管腺癌(PDAC)的主要挑战。谷氨酰胺维持耐药并形成免疫抑制肿瘤微环境;然而,潜在的机制仍不清楚。确定驱动吉西他滨耐药和免疫逃避的关键调节因子对于改善PDAC的治疗结果至关重要。在这里,我们发现溶质载体家族6成员14 (SLC6A14)是驱动吉西他滨耐药的谷氨酰胺代谢的中心调节因子。slc6a14介导的谷氨酰胺代谢促进α-酮戊二酸生成,激活mTOR/NF-κB信号,上调PD-L1表达,在免疫逃避中发挥核心作用。此外,SLC6A14通过synaptotagin -样4介导的胞外分泌诱导CXC基序趋化因子配体8分泌,在癌相关成纤维细胞旁激活CXCR2信号,促进线粒体分裂和氨基酸循环,支持PDAC进展。在体内用α-甲基色氨酸靶向SLC6A14增强吉西他滨敏感性,抑制PD-L1驱动的免疫逃避,减少肿瘤生长、转移和谷氨酰胺的产生。这些发现强调SLC6A14是谷氨酰胺驱动的PDAC中吉西他滨耐药和免疫逃避的关键介质。靶向SLC6A14的治疗策略,无论是单独治疗还是联合PD-L1阻断,都有望克服化疗耐药并增强吉西他滨耐药胰腺癌的抗肿瘤免疫。
{"title":"SLC6A14-mediated glutamine promotes SYTL4-CXCL8 axis activation to drive gemcitabine resistance and immune evasion in pancreatic cancer.","authors":"Hyeon Woong Kang, Ju Hyun Kim, Jae Woong Jeong, Sungsoon Fang, Won-Gun Yun, Hye-Sol Jung, Wooil Kwon, Jin-Young Jang, Hyo Jung Kim, Joon Seong Park","doi":"10.1038/s12276-025-01596-w","DOIUrl":"10.1038/s12276-025-01596-w","url":null,"abstract":"<p><p>Chemoresistance remains a major challenge in pancreatic ductal adenocarcinoma (PDAC). Glutamine sustains drug resistance and shapes the immunosuppressive tumor microenvironment; however, the underlying mechanisms remain unclear. Identifying key regulators that drive both gemcitabine resistance and immune evasion is crucial for improving theapeutic outcomes in PDAC. Here we identified solute-carrier family 6 member 14 (SLC6A14) as the central regulator of glutamine metabolism that drives gemcitabine resistance. SLC6A14-mediated glutamine metabolism facilitated α-ketoglutarate production, activating mTOR/NF-κB signaling to upregulate PD-L1 expression, playing a central role in immune evasion. Moreover, SLC6A14 induced CXC motif chemokine ligand 8 secretion via synaptotagmin-like 4-mediated exocytosis, paracrinally activating CXCR2 signaling in cancer-associated fibroblasts to enhance mitochondrial fission and amino acid recycling, supporting PDAC progression. Targeting SLC6A14 with α-methyl-tryptophan enhanced gemcitabine sensitivity, suppressed PD-L1 driven immune evasion and reduced tumor growth, metastasis and glutamine production in vivo. These findings underscore SLC6A14 as a pivtoal mediator of glutamine-driven gemcitabine resistance and immune evasion in PDAC. Therapeutic strategies targeting SLC6A14, either alone or in combination with PD-L1 blockade, hold promise for overcoming chemoresistance and enhancing antitumor immunity in gemcitabine-resistant pancreatic cancer.</p>","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":" ","pages":"2943-2956"},"PeriodicalIF":12.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12800172/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145829076","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Emerging perspectives on the selective autophagy of melanosomes: melanophagy. 关于黑素体选择性自噬的新观点:黑噬。
IF 12.9 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-12-01 Epub Date: 2025-11-14 DOI: 10.1038/s12276-025-01581-3
Na Yeon Park, Seong Hyun Kim, Doo Sin Jo, Dong-Hyung Cho

Melanosomes are highly specialized organelles responsible for melanin synthesis, storage and transport in melanocytes, playing a central role in pigmentation and skin homeostasis. Although melanosome biogenesis and trafficking have been well characterized, emerging evidence emphasizes the importance of melanosome degradation in regulating pigment levels. Among the degradation pathways, melanophagy-a selective form of autophagy targeting melanosomes-has recently emerged as an important mechanism for the turnover of damaged, immature, or excess melanosomes. Here we highlight current insights into melanophagy mechanisms, including molecular regulators and signaling pathways. We also discuss the potential of modulating melanophagy as a novel cosmetic or therapeutic approach for managing hyperpigmentation, offering an alternative to traditional strategies focused solely on inhibiting melanin synthesis. By emphasizing the role of organelle clearance, melanophagy provides a new paradigm in the regulation of skin pigmentation.

黑素小体是黑色素细胞中负责黑色素合成、储存和运输的高度特化的细胞器,在色素沉着和皮肤稳态中起着核心作用。虽然黑素小体的生物发生和运输已经很好地表征,新出现的证据强调黑素小体降解在调节色素水平中的重要性。在降解途径中,黑素自噬——一种选择性的针对黑素小体的自噬形式——最近被认为是受损、未成熟或过量黑素小体更新的重要机制。在这里,我们强调了目前对黑噬机制的见解,包括分子调节和信号通路。我们还讨论了调节黑素吞噬的潜力,作为一种新的美容或治疗方法来管理色素沉着,提供了一种替代传统的策略,专注于抑制黑色素合成。通过强调细胞器清除的作用,噬黑为皮肤色素沉着的调节提供了一个新的范例。
{"title":"Emerging perspectives on the selective autophagy of melanosomes: melanophagy.","authors":"Na Yeon Park, Seong Hyun Kim, Doo Sin Jo, Dong-Hyung Cho","doi":"10.1038/s12276-025-01581-3","DOIUrl":"10.1038/s12276-025-01581-3","url":null,"abstract":"<p><p>Melanosomes are highly specialized organelles responsible for melanin synthesis, storage and transport in melanocytes, playing a central role in pigmentation and skin homeostasis. Although melanosome biogenesis and trafficking have been well characterized, emerging evidence emphasizes the importance of melanosome degradation in regulating pigment levels. Among the degradation pathways, melanophagy-a selective form of autophagy targeting melanosomes-has recently emerged as an important mechanism for the turnover of damaged, immature, or excess melanosomes. Here we highlight current insights into melanophagy mechanisms, including molecular regulators and signaling pathways. We also discuss the potential of modulating melanophagy as a novel cosmetic or therapeutic approach for managing hyperpigmentation, offering an alternative to traditional strategies focused solely on inhibiting melanin synthesis. By emphasizing the role of organelle clearance, melanophagy provides a new paradigm in the regulation of skin pigmentation.</p>","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":" ","pages":"2709-2716"},"PeriodicalIF":12.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12800028/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145551703","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Hirudin suppresses hematogenous metastasis by targeting desmosome junction transition in circulating tumor cell clusters via HIF-1α-DSG2 signaling. 水蛭素通过HIF-1α-DSG2信号通路靶向循环肿瘤细胞簇的桥粒连接转移,从而抑制血液转移。
IF 12.9 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-12-01 Epub Date: 2025-12-12 DOI: 10.1038/s12276-025-01598-8
Jueyao Zou, Junfeng Shi, Qiong Chen, Ziyan Zhu, Tongyao Hu, Zhengyu Zhang, Zhiqiang Pan, Fei Xu, Yong Zhu, Yuanyuan Wu, Yang Zhao, Aiyun Wang, Yin Lu, Yanhong Pan, Wenxing Chen

Circulating tumor cell (CTC) clusters, key in metastasis, rely on intercellular junctions for stability. However, the specific mechanisms governing intercellular connections within CTC clusters and the strategy targeting intercellular junctions to break CTC clusters remain elusive. Anticoagulants, commonly used to manage tumor-associated thrombosis, may potentially serve as CTC cluster dissociators, but their effects and mechanisms in inhibiting tumor metastasis are unclear. Hirudin, an anticoagulant peptide was used as a tool drug and found to inhibit breast tumor lung retention and colonization through its disruption of CTC clusters rather than directly inhibiting cell migration. Further research confirmed that within CTC clusters, desmosome junctions play a dominant role in maintaining CTC cluster formation with high expression of related proteins, while adhesion junctions express rarely. Desmoglein 2 (DSG2) mediates conversion between desmosome and adhesion junctions in CTC clusters. When DSG2 is highly expressed, the intercellular junctions within the CTC clusters are mainly composed of desmosomes. Reversely, low expression of DSG2 results in adhesion junctions. In addition, hypoxia-inducible factor-1 alpha (HIF-1α) positively controls DSG2-mediated desmosome junctions. Inhibiting HIF-1α promotes the conversion from desmosome to adhesion junctions, destabilizing CTC clusters. Hirudin inhibits hematogenous metastasis of breast cancer through suppression of HIF-1α-controlled DSG2-mediated desmosome junctions, ultimately leading to the disintegration of CTC clusters. Our findings highlight the therapeutic potential of targeting HIF-1α-controlled DSG2-mediated desmosome junction conversion and position hirudin as a promising CTC clusters dissociator optimized for the clinical prevention of breast cancer metastasis.

循环肿瘤细胞(CTC)集群是转移的关键,依赖于细胞间连接的稳定性。然而,控制CTC簇内细胞间连接的具体机制以及靶向细胞间连接以破坏CTC簇的策略仍然难以捉摸。抗凝剂通常用于治疗肿瘤相关血栓,可能作为CTC簇解离剂,但其抑制肿瘤转移的作用和机制尚不清楚。水蛭素是一种抗凝血肽,被用作工具药物,发现它通过破坏CTC簇而不是直接抑制细胞迁移来抑制乳腺肿瘤的肺保留和定植。进一步研究证实,在CTC簇内,桥粒连接在维持CTC簇形成中起主导作用,相关蛋白高表达,而粘附连接表达较少。在CTC簇中,桥粒蛋白2 (DSG2)介导桥粒和粘附连接之间的转化。当DSG2高表达时,CTC簇内的细胞间连接主要由桥粒组成。相反,DSG2的低表达导致粘附连接。此外,缺氧诱导因子-1α (HIF-1α)正调控dsg2介导的桥粒连接。抑制HIF-1α促进桥粒向粘附连接的转化,破坏CTC簇的稳定。水蛭素通过抑制hif -1α-控制的dsg2介导的桥粒连接来抑制乳腺癌的血行转移,最终导致CTC簇的解体。我们的研究结果强调了靶向hif -1α-控制的dsg2介导的桥粒连接转化的治疗潜力,并将水龙素定位为一种有前途的CTC簇解离剂,用于临床预防乳腺癌转移。
{"title":"Hirudin suppresses hematogenous metastasis by targeting desmosome junction transition in circulating tumor cell clusters via HIF-1α-DSG2 signaling.","authors":"Jueyao Zou, Junfeng Shi, Qiong Chen, Ziyan Zhu, Tongyao Hu, Zhengyu Zhang, Zhiqiang Pan, Fei Xu, Yong Zhu, Yuanyuan Wu, Yang Zhao, Aiyun Wang, Yin Lu, Yanhong Pan, Wenxing Chen","doi":"10.1038/s12276-025-01598-8","DOIUrl":"10.1038/s12276-025-01598-8","url":null,"abstract":"<p><p>Circulating tumor cell (CTC) clusters, key in metastasis, rely on intercellular junctions for stability. However, the specific mechanisms governing intercellular connections within CTC clusters and the strategy targeting intercellular junctions to break CTC clusters remain elusive. Anticoagulants, commonly used to manage tumor-associated thrombosis, may potentially serve as CTC cluster dissociators, but their effects and mechanisms in inhibiting tumor metastasis are unclear. Hirudin, an anticoagulant peptide was used as a tool drug and found to inhibit breast tumor lung retention and colonization through its disruption of CTC clusters rather than directly inhibiting cell migration. Further research confirmed that within CTC clusters, desmosome junctions play a dominant role in maintaining CTC cluster formation with high expression of related proteins, while adhesion junctions express rarely. Desmoglein 2 (DSG2) mediates conversion between desmosome and adhesion junctions in CTC clusters. When DSG2 is highly expressed, the intercellular junctions within the CTC clusters are mainly composed of desmosomes. Reversely, low expression of DSG2 results in adhesion junctions. In addition, hypoxia-inducible factor-1 alpha (HIF-1α) positively controls DSG2-mediated desmosome junctions. Inhibiting HIF-1α promotes the conversion from desmosome to adhesion junctions, destabilizing CTC clusters. Hirudin inhibits hematogenous metastasis of breast cancer through suppression of HIF-1α-controlled DSG2-mediated desmosome junctions, ultimately leading to the disintegration of CTC clusters. Our findings highlight the therapeutic potential of targeting HIF-1α-controlled DSG2-mediated desmosome junction conversion and position hirudin as a promising CTC clusters dissociator optimized for the clinical prevention of breast cancer metastasis.</p>","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":" ","pages":"2798-2815"},"PeriodicalIF":12.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12800233/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145745557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Targeting DDOST improves the efficacy of lenvatinib and immunotherapy in hepatocellular carcinoma. 靶向DDOST提高了lenvatinib和免疫治疗在肝细胞癌中的疗效。
IF 12.9 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-12-01 Epub Date: 2025-12-19 DOI: 10.1038/s12276-025-01597-9
Jun Pu, Jingjing Ma, Yan Liu, Rongrong Cui, Yao Yao, Guanjun Zhang, Peng Hou, Xi Liu, Qi Yang, Meiju Ji

Hepatocellular carcinoma (HCC) remains one of the most lethal malignancies, with limited efficacy of systemic therapies due to poor survival benefit and drug resistance. Dolichyl-diphosphooligosaccharide-protein glycosyltransferase noncatalytic subunit (DDOST), a critical component of oligosaccharyltransferase (OST), is upregulated in multiple cancers, yet its role in HCC is unclear. Here we demonstrate that DDOST expression is elevated in HCC tissues and correlated with poor prognosis. Functional studies showed that DDOST knockdown suppressed cell proliferation, induced cell cycle arrest and enhanced their lenvatinib sensitivity both in vitro and in vivo. Mechanistically, DDOST depletion impaired EGFR N-glycosylation, suppressing downstream AKT, ERK5 and ERK1/2 signaling, thereby sensitizing HCC cells to lenvatinib. Loss of DDOST also reduced PD-L1 glycosylation. Furthermore, the OST inhibitor NGI-1 and NGI-1-loaded nanoparticles exerted potent antitumor effects and further augmented the efficacy of lenvatinib and immunotherapy. These findings highlight DDOST as a promising therapeutic target to improve treatment outcomes in HCC.

肝细胞癌(HCC)仍然是最致命的恶性肿瘤之一,由于生存期和耐药性差,全身治疗的疗效有限。多利基-二磷酸寡糖-蛋白糖基转移酶非催化亚基(DDOST)是寡糖转移酶(OST)的一个关键组成部分,在多种癌症中表达上调,但其在HCC中的作用尚不清楚。本研究表明,DDOST在HCC组织中表达升高,并与预后不良相关。功能研究表明,DDOST敲低抑制细胞增殖,诱导细胞周期阻滞,增强lenvatinib在体外和体内的敏感性。从机制上讲,DDOST缺失会破坏EGFR n -糖基化,抑制下游AKT、ERK5和ERK1/2信号,从而使HCC细胞对lenvatinib敏感。DDOST的缺失也降低了PD-L1的糖基化。此外,OST抑制剂NGI-1和负载NGI-1的纳米颗粒具有强大的抗肿瘤作用,进一步增强了lenvatinib和免疫治疗的疗效。这些发现强调DDOST是一个有希望改善HCC治疗结果的治疗靶点。
{"title":"Targeting DDOST improves the efficacy of lenvatinib and immunotherapy in hepatocellular carcinoma.","authors":"Jun Pu, Jingjing Ma, Yan Liu, Rongrong Cui, Yao Yao, Guanjun Zhang, Peng Hou, Xi Liu, Qi Yang, Meiju Ji","doi":"10.1038/s12276-025-01597-9","DOIUrl":"10.1038/s12276-025-01597-9","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) remains one of the most lethal malignancies, with limited efficacy of systemic therapies due to poor survival benefit and drug resistance. Dolichyl-diphosphooligosaccharide-protein glycosyltransferase noncatalytic subunit (DDOST), a critical component of oligosaccharyltransferase (OST), is upregulated in multiple cancers, yet its role in HCC is unclear. Here we demonstrate that DDOST expression is elevated in HCC tissues and correlated with poor prognosis. Functional studies showed that DDOST knockdown suppressed cell proliferation, induced cell cycle arrest and enhanced their lenvatinib sensitivity both in vitro and in vivo. Mechanistically, DDOST depletion impaired EGFR N-glycosylation, suppressing downstream AKT, ERK5 and ERK1/2 signaling, thereby sensitizing HCC cells to lenvatinib. Loss of DDOST also reduced PD-L1 glycosylation. Furthermore, the OST inhibitor NGI-1 and NGI-1-loaded nanoparticles exerted potent antitumor effects and further augmented the efficacy of lenvatinib and immunotherapy. These findings highlight DDOST as a promising therapeutic target to improve treatment outcomes in HCC.</p>","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":" ","pages":"2869-2885"},"PeriodicalIF":12.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12800229/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145783900","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Author Correction: Long-term correction of hemophilia A via integration of a functionally enhanced FVIII gene into the AAVS1 locus by nickase in patient-derived iPSCs. 作者更正:通过在患者来源的iPSCs中通过缺口酶将功能增强的FVIII基因整合到AAVS1位点,长期纠正血友病A。
IF 12.9 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-12-01 DOI: 10.1038/s12276-025-01595-x
Do-Hun Kim, Sang-Hwi Choi, Jin Jea Sung, Sieun Kim, Hanui Yi, Sanghyun Park, Chan Wook Park, Young Woo Oh, Jungil Lee, Dae-Sung Kim, Jong-Hoon Kim, Chul-Yong Park, Dong-Wook Kim
{"title":"Author Correction: Long-term correction of hemophilia A via integration of a functionally enhanced FVIII gene into the AAVS1 locus by nickase in patient-derived iPSCs.","authors":"Do-Hun Kim, Sang-Hwi Choi, Jin Jea Sung, Sieun Kim, Hanui Yi, Sanghyun Park, Chan Wook Park, Young Woo Oh, Jungil Lee, Dae-Sung Kim, Jong-Hoon Kim, Chul-Yong Park, Dong-Wook Kim","doi":"10.1038/s12276-025-01595-x","DOIUrl":"10.1038/s12276-025-01595-x","url":null,"abstract":"","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":" ","pages":"2985-2987"},"PeriodicalIF":12.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12800195/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145662540","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A novel DCSTAMP antagonist impedes preosteoclast fusion via modulation of RAP1B-RAC1-mediated cytoskeletal remodeling. 一种新的DCSTAMP拮抗剂通过调节rap1b - rac1介导的细胞骨架重塑来阻碍破骨前细胞融合。
IF 12.9 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-12-01 Epub Date: 2025-12-22 DOI: 10.1038/s12276-025-01591-1
Zheng Zhang, Zhengbo Tao, Weijin Zhang, Zhanrong Zhang, Xuanrui Zhang, Xunpei Xu, Biao Yang, Yichen Meng, Xia Tao, Xuhui Zhou

DCSTAMP serves as a critical fusogenic protein orchestrating cell-cell fusion during osteoclastogenesis. The disruption of DCSTAMP functionality preserves preosteoclasts, thereby augmenting bone mass through both anabolic and anti-catabolic mechanisms. Despite its therapeutic potential, specific DCSTAMP inhibitors remain undiscovered. Here we used structure-based virtual screening utilizing AlphaFold predictions to identify a novel small molecule, E8431, which selectively targets the endoplasmic domain of DCSTAMP. In vitro investigations confirm E8431's capacity to impede preosteoclast fusion, concurrently inhibiting bone resorption while stimulating PDGFBB secretion, thus promoting osteogenic and angiogenic processes. We further elucidated a previously uncharacterized DCSTAMP signaling cascade involving DCSTAMP-RAP1B interaction, which activates RAP1-RAC1 signaling-dependent cytoskeletal reorganization. Notably, E8431 demonstrates potent inhibitory effects on this DCSTAMP-RAP1B molecular interface. Moreover, E8431 administration effectively attenuates ovariectomy-induced bone loss in murine models without apparent toxicity, underscoring its potential as a therapeutic agent for osteoporosis.

在破骨细胞发生过程中,DCSTAMP作为一种关键的融合蛋白协调细胞-细胞融合。DCSTAMP功能的破坏保留了破骨前细胞,从而通过合成代谢和抗分解代谢机制增加骨量。尽管具有治疗潜力,但特异性DCSTAMP抑制剂仍未被发现。在这里,我们使用基于结构的虚拟筛选,利用AlphaFold预测,鉴定了一种新的小分子E8431,它选择性地靶向DCSTAMP的内质域。体外研究证实E8431能够阻碍破骨细胞前融合,同时抑制骨吸收,刺激PDGFBB分泌,从而促进成骨和血管生成过程。我们进一步阐明了一个先前未被表征的DCSTAMP信号级联,涉及DCSTAMP- rap1b相互作用,激活RAP1-RAC1信号依赖性的细胞骨架重组。值得注意的是,E8431对DCSTAMP-RAP1B分子界面表现出强烈的抑制作用。此外,E8431在小鼠模型中有效减轻卵巢切除引起的骨质流失,且无明显毒性,强调其作为骨质疏松症治疗剂的潜力。
{"title":"A novel DCSTAMP antagonist impedes preosteoclast fusion via modulation of RAP1B-RAC1-mediated cytoskeletal remodeling.","authors":"Zheng Zhang, Zhengbo Tao, Weijin Zhang, Zhanrong Zhang, Xuanrui Zhang, Xunpei Xu, Biao Yang, Yichen Meng, Xia Tao, Xuhui Zhou","doi":"10.1038/s12276-025-01591-1","DOIUrl":"10.1038/s12276-025-01591-1","url":null,"abstract":"<p><p>DCSTAMP serves as a critical fusogenic protein orchestrating cell-cell fusion during osteoclastogenesis. The disruption of DCSTAMP functionality preserves preosteoclasts, thereby augmenting bone mass through both anabolic and anti-catabolic mechanisms. Despite its therapeutic potential, specific DCSTAMP inhibitors remain undiscovered. Here we used structure-based virtual screening utilizing AlphaFold predictions to identify a novel small molecule, E8431, which selectively targets the endoplasmic domain of DCSTAMP. In vitro investigations confirm E8431's capacity to impede preosteoclast fusion, concurrently inhibiting bone resorption while stimulating PDGFBB secretion, thus promoting osteogenic and angiogenic processes. We further elucidated a previously uncharacterized DCSTAMP signaling cascade involving DCSTAMP-RAP1B interaction, which activates RAP1-RAC1 signaling-dependent cytoskeletal reorganization. Notably, E8431 demonstrates potent inhibitory effects on this DCSTAMP-RAP1B molecular interface. Moreover, E8431 administration effectively attenuates ovariectomy-induced bone loss in murine models without apparent toxicity, underscoring its potential as a therapeutic agent for osteoporosis.</p>","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":" ","pages":"2898-2915"},"PeriodicalIF":12.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12800066/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145805904","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Bone marrow-derived CD169+ macrophages promote autoimmune hepatitis by recruiting CCR2+ monocytes via secreting CCL12. 骨髓源性CD169+巨噬细胞通过分泌CCL12募集CCR2+单核细胞促进自身免疫性肝炎。
IF 12.9 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-12-01 Epub Date: 2025-12-22 DOI: 10.1038/s12276-025-01607-w
Bingru Lin, Huayang Zhang, Pengwei Zhu, Jianing Chen, Dingwu Li, Jiaming Zhou, Tiantian Zhang, Qingxia Chen, Chenxi Tang, Xin Song, Hang Zeng, Jinghua Wang, Jie Zhang, Zhengrui You, Xiong Ma, Chaohui Yu

CD169+ macrophages, a unique subset of macrophages that cannot be simply defined as M1 or M2 macrophages, have been reported to be associated with various autoimmune diseases. However, the role of CD169+ macrophages in autoimmune hepatitis (AIH) is largely unknown. Here we found that the infiltration of CD169+ macrophages increased in the liver of patients with AIH and strongly positively correlated with inflammation degree. In a mouse model, depletion of CD169+ macrophages ameliorated ConA-induced acute liver injury. Immune homeostasis was also improved when CD169+ macrophages were depleted, as the infiltration of monocytes, macrophages and T cells decreased. Bone marrow-derived Ly6ChiCD169+ macrophages were further identified as the crucial subset in AIH. Next, we found that CD169+ macrophages were IFNγ-responsive and IFNγ could induce the expression of CD169. In response to the IFNγ signal, CD169+ macrophages actively secrete chemokine (C-C motif) ligand (CCL12), thus recruiting CCR2+ monocytes and macrophages to exacerbate AIH. Finally, neutralizing CCL12 improved AIH. Our results suggest that bone marrow-derived CD169+ macrophages, the key subset of macrophages in AIH, actively secrete CCL12 in response to IFNγ to recruit CCR2+ monocytes and macrophages, thus exacerbating AIH. The CD169+ macrophages are a potential therapeutic target in AIH.

CD169+巨噬细胞是一种独特的巨噬细胞亚群,不能简单地定义为M1或M2巨噬细胞,已被报道与多种自身免疫性疾病相关。然而,CD169+巨噬细胞在自身免疫性肝炎(AIH)中的作用在很大程度上是未知的。我们发现AIH患者肝脏中CD169+巨噬细胞的浸润增加,且与炎症程度呈强正相关。在小鼠模型中,CD169+巨噬细胞的缺失改善了cona诱导的急性肝损伤。CD169+巨噬细胞减少,单核细胞、巨噬细胞和T细胞的浸润减少,免疫稳态也得到改善。骨髓来源的Ly6ChiCD169+巨噬细胞进一步被确定为AIH的关键亚群。接下来,我们发现CD169+巨噬细胞具有ifn - γ响应性,ifn - γ可以诱导CD169的表达。CD169+巨噬细胞响应IFNγ信号,积极分泌趋化因子(C-C motif)配体(CCL12),从而募集CCR2+单核细胞和巨噬细胞加重AIH。最后,中和CCL12改善AIH。我们的研究结果表明,骨髓来源的CD169+巨噬细胞是AIH中巨噬细胞的关键亚群,它响应IFNγ积极分泌CCL12来招募CCR2+单核细胞和巨噬细胞,从而加剧AIH。CD169+巨噬细胞是AIH的潜在治疗靶点。
{"title":"Bone marrow-derived CD169<sup>+</sup> macrophages promote autoimmune hepatitis by recruiting CCR2<sup>+</sup> monocytes via secreting CCL12.","authors":"Bingru Lin, Huayang Zhang, Pengwei Zhu, Jianing Chen, Dingwu Li, Jiaming Zhou, Tiantian Zhang, Qingxia Chen, Chenxi Tang, Xin Song, Hang Zeng, Jinghua Wang, Jie Zhang, Zhengrui You, Xiong Ma, Chaohui Yu","doi":"10.1038/s12276-025-01607-w","DOIUrl":"10.1038/s12276-025-01607-w","url":null,"abstract":"<p><p>CD169<sup>+</sup> macrophages, a unique subset of macrophages that cannot be simply defined as M1 or M2 macrophages, have been reported to be associated with various autoimmune diseases. However, the role of CD169<sup>+</sup> macrophages in autoimmune hepatitis (AIH) is largely unknown. Here we found that the infiltration of CD169<sup>+</sup> macrophages increased in the liver of patients with AIH and strongly positively correlated with inflammation degree. In a mouse model, depletion of CD169<sup>+</sup> macrophages ameliorated ConA-induced acute liver injury. Immune homeostasis was also improved when CD169<sup>+</sup> macrophages were depleted, as the infiltration of monocytes, macrophages and T cells decreased. Bone marrow-derived Ly6C<sup>hi</sup>CD169<sup>+</sup> macrophages were further identified as the crucial subset in AIH. Next, we found that CD169<sup>+</sup> macrophages were IFNγ-responsive and IFNγ could induce the expression of CD169. In response to the IFNγ signal, CD169<sup>+</sup> macrophages actively secrete chemokine (C-C motif) ligand (CCL12), thus recruiting CCR2<sup>+</sup> monocytes and macrophages to exacerbate AIH. Finally, neutralizing CCL12 improved AIH. Our results suggest that bone marrow-derived CD169<sup>+</sup> macrophages, the key subset of macrophages in AIH, actively secrete CCL12 in response to IFNγ to recruit CCR2<sup>+</sup> monocytes and macrophages, thus exacerbating AIH. The CD169<sup>+</sup> macrophages are a potential therapeutic target in AIH.</p>","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":" ","pages":"2930-2942"},"PeriodicalIF":12.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12800274/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145811988","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Optogenetic engineering of BAX to control mitochondrial permeabilization and attenuate apoptosis in cells. BAX光基因工程控制线粒体通透性和减轻细胞凋亡。
IF 12.9 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-12-01 Epub Date: 2025-12-26 DOI: 10.1038/s12276-025-01605-y
Dain Lee, Hyunjun Bae, Dongwoo Oh, Minseop Kim, Ju-Hee Kim, Jinchul Ahn, Seok-Hyeon Kang, Seo-Hee You, Dong-Hwee Kim, Hyun Jeong Oh, Won Do Heo, Seok Chung

Although considerable research has focused on enhancing the apoptotic function of BAX for several decades, inhibition of its functionality remains relatively underexplored, despite intensive BAX activation occurring in various neurodegenerative diseases. Here we present a protein engineering approach to modulate BAX integration into the mitochondrial outer membrane, establishing a tunable strategy for antiapoptosis. Utilizing optogenetic methods that employ cryptochrome 2 and its binding partner cryptochrome-interacting basic helix loop helix 1, we achieved precise spatial control over BAX localization, a critical determinant of its function. Our results demonstrate that the engineered BAX variant is effectively incapacitated in its apoptotic function while also modulating endogenous BAX activity to enhance cellular resistance to apoptosis. These findings not only advance our understanding of BAX regulation but also offer promising prospects for the development of therapeutic strategies against apoptosis-related diseases.

尽管几十年来大量的研究集中在增强BAX的凋亡功能上,但尽管在各种神经退行性疾病中发生了大量的BAX激活,但对其功能的抑制仍然相对缺乏探索。在这里,我们提出了一种蛋白质工程方法来调节BAX整合到线粒体外膜,建立抗细胞凋亡的可调策略。利用光遗传学方法,利用隐花色素2及其结合伙伴隐花色素相互作用的基本螺旋环螺旋1,我们实现了对BAX定位的精确空间控制,这是其功能的关键决定因素。我们的研究结果表明,工程BAX变体有效地丧失了其凋亡功能,同时也调节内源性BAX活性以增强细胞对凋亡的抵抗力。这些发现不仅促进了我们对BAX调控的理解,而且为开发针对凋亡相关疾病的治疗策略提供了良好的前景。
{"title":"Optogenetic engineering of BAX to control mitochondrial permeabilization and attenuate apoptosis in cells.","authors":"Dain Lee, Hyunjun Bae, Dongwoo Oh, Minseop Kim, Ju-Hee Kim, Jinchul Ahn, Seok-Hyeon Kang, Seo-Hee You, Dong-Hwee Kim, Hyun Jeong Oh, Won Do Heo, Seok Chung","doi":"10.1038/s12276-025-01605-y","DOIUrl":"10.1038/s12276-025-01605-y","url":null,"abstract":"<p><p>Although considerable research has focused on enhancing the apoptotic function of BAX for several decades, inhibition of its functionality remains relatively underexplored, despite intensive BAX activation occurring in various neurodegenerative diseases. Here we present a protein engineering approach to modulate BAX integration into the mitochondrial outer membrane, establishing a tunable strategy for antiapoptosis. Utilizing optogenetic methods that employ cryptochrome 2 and its binding partner cryptochrome-interacting basic helix loop helix 1, we achieved precise spatial control over BAX localization, a critical determinant of its function. Our results demonstrate that the engineered BAX variant is effectively incapacitated in its apoptotic function while also modulating endogenous BAX activity to enhance cellular resistance to apoptosis. These findings not only advance our understanding of BAX regulation but also offer promising prospects for the development of therapeutic strategies against apoptosis-related diseases.</p>","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":" ","pages":"2972-2984"},"PeriodicalIF":12.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12800262/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145835169","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
期刊
Experimental and Molecular Medicine
全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1