Acta Pharmacologica Sinica最新文献

{"title":"Multifaceted roles of UFMylation in health and disease.","authors":"Ru-Na Wang, Lin Li, Jun Zhou, Jie Ran","doi":"10.1038/s41401-024-01456-9","DOIUrl":"10.1038/s41401-024-01456-9","url":null,"abstract":"<p><p>Ubiquitin fold modifier 1 (UFM1) is a newly identified post-translational modifier that is involved in the UFMylation process. Similar to ubiquitination, UFMylation enables the conjugation of UFM1 to specific target proteins, thus altering their stability, activity, or localization. UFM1 chains have the potential to undergo cleavage from their associated proteins via UFM1-specific proteases, thus highlighting a reversible feature of UFMylation. This modification is conserved across nearly all eukaryotic organisms, and is associated with diverse biological activities such as hematopoiesis and the endoplasmic reticulum stress response. The disruption of UFMylation results in embryonic lethality in mice and is associated with various human diseases, thus underscoring its essential role in embryonic development, tissue morphogenesis, and organismal homeostasis. In this review, we aim to provide an in-depth overview of the UFMylation system, its importance in disease processes, and its potential as a novel target for therapeutic intervention.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"805-815"},"PeriodicalIF":6.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11950361/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142942409","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combined in silico/in vitro approaches for identifying modulators of the activity of the p.Tyr110Cys Carnitine O-Acetyltransferase (CRAT) variant associated to an early onset case of Leigh syndrome.","authors":"Lucas Cafferati Beltrame, Maria Noemi Sgobba, Luna Laera, Valeria Scaglione, Sabino Todisco, Serena Barile, Anna Lucia Francavilla, Danila Imperia De Luca, Michele Montaruli, Vito Porcelli, Lorenzo Guerra, Anna De Grassi, Mariateresa Volpicella, Ciro Leonardo Pierri","doi":"10.1038/s41401-024-01435-0","DOIUrl":"10.1038/s41401-024-01435-0","url":null,"abstract":"<p><p>Carnitine O-acetyltransferase (CRAT) is a crucial enzyme involved in mitochondrial energy metabolism. Alterations in CRAT activity have emerged as significant contributors to the pathogenesis of Leigh syndrome and related mitochondrial disorders. In this study we employed an integrated approach combining in silico docking analysis and virtual screening of chemical libraries with subsequent in vitro validation to identify small molecule modulators of the activity of the wild type (WT) CRAT and the p.Tyr110Cys (Y110C) variant associated to an early onset case of Leigh syndrome. Through 3D molecular modeling, docking simulations, and virtual screening of chemical libraries, potential CRAT modulators were prioritized based on their predicted binding affinities and interactions with the 3D models of the WT-CRAT and of the p.Tyr110Cys-CRAT mutant. The performed in silico analyses were validated through in vitro assays on the purified recombinant CRAT proteins and cell-lysates from control fibroblasts and the fibroblasts of a patient with genetic diagnosis of CRAT-deficiency, carrying the compound heterozygous missense variants in the CRAT gene, namely p.Tyr110Cys and p.Val569Met. Based on the above screening by applying the indicated filtering strategy and mentioned criteria, 3 commercially available approved drugs (also known for their possible interactions with mitochondria) namely glimepiride, artemisinin and dorzolamide, as well as suramin (already known for its ability to interact with mitochondrial proteins) were tested in in vitro assays. We found that suramin (1-1000 μM) dose-dependently inhibited the activity of both WT-CRAT and p.Tyr110Cys_CRAT variant. Artemisinin (0.1-200 μM) dose-dependently stimulated the activity of the recombinant p.Tyr110Cys CRAT mutant, whereas glimepiride and dorzolamide did not change the activity of these proteins towards acetyl-CoA. This study demonstrates the effectiveness of this combined approach in identifying novel compounds for modulating CRAT enzyme activity, providing valuable insights for potential therapeutic interventions targeting CRAT-related disorders.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1123-1136"},"PeriodicalIF":6.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11950229/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142833390","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The effects of diazepam on sleep depend on the photoperiod.","authors":"Maria Panagiotou, Johanna H Meijer, Tom Deboer","doi":"10.1038/s41401-024-01440-3","DOIUrl":"10.1038/s41401-024-01440-3","url":null,"abstract":"<p><p>Daylength (i.e., photoperiod) provides essential information for seasonal adaptations of organisms. Earlier studies have demonstrated that photoperiod influences sleep in several species. Notably, photoperiod can change the excitatory/inhibitory balance in the brain, with long photoperiod exhibiting increased γ-aminobutyric-acid (GABA)-mediated excitation. In this study, we first investigated whether different photoperiods influence sleep and the sleep electroencephalogram (EEG) in mice, and, subsequently, whether these photoperiods alter GABAergic functioning by treating mice with diazepam (3 mg/kg, i.p.). EEG and electromyogram (EMG) recordings were conducted in mice well-adapted to long or short photoperiod (16:8 vs. 8:16 light-dark cycle) in baseline conditions, after 4-h sleep deprivation, and following diazepam administration. Different photoperiods led to a redistribution of sleep and wakefulness in 24-h albeit without altering the overall amount of vigilance states; during darkness, mice exposed to the long photoperiod were more awake and showed very little rapid-eye-movement (REM) sleep compared to the short photoperiod. Furthermore, an overall lower EEG power density, across all vigilance states, was found in the long compared to short photoperiod. After diazepam treatment, slow-wave-activity (SWA) in NREM sleep was suppressed independent of the photoperiod. However, following diazepam administration, mice showed more REM sleep in the short photoperiod, and increased EEG power density in the slower frequencies (2.5-7 Hz), during wakefulness in the long photoperiod. These results demonstrate that photoperiod can affect the diazepam-induced changes on sleep architecture and EEG, suggesting that treatments with GABA_A agonists exert dissimilar effects depending on the photoperiod. Future studies are warranted to explore potential photoperiod effects in humans which could have consequences for the treatment of anxiety and sleep disturbances.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"892-903"},"PeriodicalIF":6.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11950407/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926164","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nicotine promotes the progression and metastasis of non-small cell lung cancer by modulating the OTUB1-c-Myc-EZH2 axis.","authors":"Hua Huang, Chen Ding, Wen-Hao Zhao, Hong-Bing Zhang, Ze-Xia Zhao, Xuan-Guang Li, Ying-Jie Wang, Pei-Jie Chen, Bo-Shi Li, Xue-Bing Li, Yong-Wen Li, Hong-Yu Liu, Jun Chen","doi":"10.1038/s41401-025-01527-5","DOIUrl":"https://doi.org/10.1038/s41401-025-01527-5","url":null,"abstract":"<p><p>Smoking has been identified as a major risk factor for the development and progression of non-small cell lung cancer (NSCLC). As a key component of tobacco smoke, nicotine is believed to play a significant role in promoting NSCLC growth and progression. EZH2 is an epigenetic regulator highly expressed in the tumor tissues of smokers. However, whether and how nicotine regulates the expression of EZH2 and the underlying mechanisms remain unclear. Bioinformatics analysis and immunohistochemistry were used to compare the expression of EZH2 in NSCLC samples between smokers and nonsmokers. Western blotting, real-time quantitative PCR, and immunofluorescence were employed to confirm the effects of nicotine on EZH2 expression. Cell Counting Kit-8 assays, colony formation assays, 5-ethynyl-2-deoxyuridine staining, and Transwell assays were conducted to analyze the proliferation and metastasis of A549 and H1650 cells treated with siRNA or EZH2 inhibitors. Real-time quantitative PCR and chromatin immunoprecipitation assays were performed to assess the regulatory effect of nicotine on EZH2 transcript levels via c-Myc. Coimmunoprecipitation and ubiquitination assays were used to assess the deubiquitination of c-Myc by OTUB1. Finally, a nude mouse model was used to evaluate the impact of combined c-Myc and EZH2 inhibitors on tumor proliferation and metastasis in vivo. EZH2 is expressed at relatively high levels in NSCLC patients, as determined by both bioinformatic and IHC analyses. Nicotine upregulates EZH2 expression and promotes the proliferation and metastatic ability of lung cancer cells. Inhibition of EZH2 with either DZNep or EPZ6438, EZH2 inhibitors, or siRNA significantly decreased the proliferative and metastatic capacity of NSCLC cells induced by nicotine treatment. Moreover, the study revealed that nicotine induces OTUB1 expression, stabilizes the c-Myc protein via deubiquitination, and enables c-Myc-mediated transcriptional activation of EZH2. Furthermore, the c-Myc inhibitor 10058-F4 exhibited synergistic effects with the EZH2 inhibitor DZNep in suppressing NSCLC cell proliferation and metastasis both in vitro and in vivo.Nicotine regulates the c-Myc/EZH2 signaling pathway via OTUB1-mediated deubiquitination, thereby promoting the proliferation and metastasis of NSCLC cells. This research reveals novel molecular mechanisms of nicotine in the development of NSCLC, providing a theoretical foundation for future therapeutic strategies.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143762637","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PU.1/Spi1 exacerbates ischemia-reperfusion induced acute kidney injury via upregulating Gata2 and promoting fibroblast activation.","authors":"Chen Zong, Guo-Li Xu, Ming Ning, Jing-Yao Li, Xin Wang, Heng-Jiang Guo, Li-Hong Zhang, Li Zhou, Chen Xu, Zhen-Hao Yang, Li-Min Lu, Jian-Ying Niu","doi":"10.1038/s41401-025-01530-w","DOIUrl":"https://doi.org/10.1038/s41401-025-01530-w","url":null,"abstract":"<p><p>Previous studies on acute kidney injury (AKI) have predominantly focused on renal tubular cells, while the specific role of fibroblasts has been largely neglected. Recent evidence shows that PU.1/Spi1, a transcription factor, is an important modulator of fibroblast activation, whereas pharmacological and genetic silencing of PU.1/Spi1 disrupts the fibrotic network and reprograms activated fibroblasts into quiescent fibroblasts. In this study we investigated whether and how PU.1/Spi1 regulated renal fibroblast activation during AKI. An AKI model was established in male mice by clamping bilateral renal arteries for 30 min. Mice were sacrificed and blood and kidney samples were collected 48 h after the surgery. We showed that the expression level of PU.1/Spi1 was significantly upregulated in ischemia/reperfusion (I/R)-induced AKI and PU.1/Spi1 was specifically localized in fibroblasts. Meanwhile, we observed that a massive activation of fibroblasts occurred at the early stage of AKI. PU.1/Spi1 knockout significantly attenuated the activation of fibroblasts along with the decreased release of inflammatory factors and tubular injury. Bioinformatic analysis revealed that GATA binding protein 2 (Gata2), an evolutionarily conserved gene, might be a downstream target gene of PU.1/Spi1. In primary cultured mouse kidney fibroblasts subjected to hypoxia/reoxygenation (H/R), the expression levels of PU.1/Spi1, Gata2 and α-SMA were significantly upregulated. Activated fibroblasts exhibited elevated proliferative capacity, evidenced by upregulated proliferating cell nuclear antigen (PCNA) and cell cycle proteins such as cyclin B1 and cyclin D3. The secretion of inflammatory factors was increased in the activated fibroblasts. Conditioned medium from H/R-treated fibroblasts induced tubular cell injury and increased apoptosis. Using chromatin immunoprecipitation and promoter-luciferase assays, we demonstrated that PU.1/Spi1 was able to bind to the promoter region of Gata2 and enhanced its transcription. Our results show that interstitial fibroblasts are activated at the early stage of I/R-induced AKI and involved in renal injury. Upregulated PU.1/Spi1 stimulates fibroblast activation by upregulating its downstream gene Gata2. Inhibiting the activation of fibroblasts may have a beneficial effect on AKI.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143762639","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypocrellin A from an ethnic medicinal fungus protects against NLRP3-driven gout in mice by suppressing inflammasome activation.","authors":"Le-Jin Yan, Shuang Qi, Chao Wu, Rui Jin, Chen Hu, Ao-Li Wang, Bei-Lei Wang, Hong-Wei Yu, Li Wang, Jing Liu, Zi-Ping Qi, Wen-Chao Wang, Qing-Song Liu","doi":"10.1038/s41401-024-01434-1","DOIUrl":"10.1038/s41401-024-01434-1","url":null,"abstract":"<p><p>Abnormal activation of NLRP3 inflammasome causes the progression of gout, and no small-molecule inhibitor of NLRP3 has been approved yet for clinical use. In this study we established a nigericin-induced inflammasome activation cell model for screening of a natural product library by measuring IL-1β secretion in cell supernatants. Among 432 compounds tested, we found that hypocrellin A (HA), one of the major active components of a traditional ethnic medicinal fungus Hypocrella bambusea in the Northwest Yunnan of China, exhibited the highest inhibition on IL-1β production (IC₅₀ = 0.103 μM). In PMA-primed THP-1 cells or bone marrow derived macrophages (BMDMs) treated with multiple stimuli (nigericin, ATP or MSU), HA dose-dependently suppressed the activation of NLRP3 inflammasome, reducing the subsequent release of inflammatory cytokines and LDH. Furthermore, the suppression of inflammasome activation by HA was specific to NLRP3, but not to AIM2 or NLRC4. In LPS-primed BMDMs treated with nigericin, HA inhibited ASC oligomerization and speckle formation, and blocked the NLRP3-NEK7 interaction during inflammasome assembly without influencing the priming stage. Moreover, we demonstrated that HA directly bound to the NACHT domain of NLRP3, and that Arg578 and Glu629 were the critical residues for HA binding to NLRP3. In MSU-induced peritonitis and acute gouty arthritis mouse models, administration of HA (10 mg/kg, i.p., once or twice daily) effectively suppressed the inflammatory responses mediated by NLRP3 inflammasome. We conclude that HA is a broad-spectrum and specific NLRP3 inhibitor, and a valuable lead compound to develop novel therapeutic inhibitors against NLRP3-driven diseases. This study also elucidates the anti-inflammation mechanisms and molecular targets of HA, a major active component in medicinal fungus Hypocrella bambusea that has been long used by Chinese ethnic groups.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1016-1029"},"PeriodicalIF":6.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11950337/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142833392","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activation of glutamine synthetase (GS) as a new strategy for the treatment of major depressive disorder and other GS-related diseases.","authors":"Jae Soon Kang, Hwajin Kim, Ji Hyeong Baek, Miyoung Song, Hyeongchan Park, Wonjune Jeong, Hye Jin Chung, Dae Young Yoo, Dong Kun Lee, Sang Won Park, Hyun Joon Kim","doi":"10.1038/s41401-024-01441-2","DOIUrl":"10.1038/s41401-024-01441-2","url":null,"abstract":"<p><p>Glutamine synthetase (GS) plays a crucial role in the homeostasis of the glutamate-glutamine cycle in the brain. Hypoactive GS causes depressive behaviors. Under chronic stress, GS has no change in expression, but its activity is decreased due to nitration of tyrosine (Tyr). Thus, we speculate that agents that prevent nitration or facilitate denitration of GS would be candidates for new antidepressants. Using human recombinant GS and mouse lysate from the medial prefrontal cortex, we demonstrated that Tyr (0.0313-0.5 µM) dose-dependently protected GS activity against peroxynitrite-induced Tyr-nitration of GS. Diet supplementation with Tyr exerted significant antidepressant effects in a chronic immobilization stress depression mouse model. We further found that dipeptides, such as tyrosyl-glutamine (YQ), that had appropriate chemical properties for medication also increased GS activity both in vitro and in vivo and exerted antidepressant effects. Because reduced GS activity also occurs in epilepsy and hyperammonemia, we evaluated whether Tyr and YQ had therapeutic effects. Interestingly, Tyr or YQ administration significantly attenuated kainic acid-induced seizures in mice and reduced blood ammonia levels in azoxymethane- or bile duct ligation-induced hyperammonemia mouse models, which was accompanied by an increment in GS activity. The activation of GS was accomplished by a decrement in Tyr-nitration, so-called Tyr-denitration. Therefore, this study demonstrates that the activation of GS could be a new strategy to treat depression and other GS-related diseases.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"880-891"},"PeriodicalIF":6.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11950325/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142942454","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endothelial histone deacetylase 9 promotes diabetic retinopathy in mice by regulating endothelial-mesenchymal transition.","authors":"Yun Bei, Ze-Xu Shen, Hao-Ran Lin, Tao-Feng Wei, Yi-Hao Wang, Zhi-Tao Su, Yun-Jian Dai, Yan-Hong Wang, Ling-Ling Huang, Tao Zhu, Wei Hu, Juan Ye, Gong-Xiong Wu, Hai-Bin Dai","doi":"10.1038/s41401-025-01523-9","DOIUrl":"https://doi.org/10.1038/s41401-025-01523-9","url":null,"abstract":"<p><p>Diabetic retinopathy (DR) is a common and specific microvascular complication of diabetes and the leading cause of blindness in working-age adults. Endothelial-mesenchymal transition (EndoMT) underlies various chronic vascular diseases, while histone deacetylase 9 (HDAC9) is involved in the pathological process of cardiovascular diseases, cerebrovascular diseases, autoimmune diseases, and breast cancer. Recent evidence has shown that HDAC9 promotes EndoMT, thereby affecting the progression of atherosclerotic disease. In this study, we investigated the critical role of HDAC9 in DR and the underlying mechanism. DR model was established in mice by injecting streptozotocin (STZ, 50 mg/kg) for 5 consecutive days. Blood glucose was monitored regularly and DR experiments were performed 12 weeks after modeling. We showed that the expression levels of HDAC9 were significantly elevated in the vitreous fluid of diabetic patients and the retinal endothelial cells of DR model mice. Knockdown of endothelial HDAC9 reduced EndoMT and alleviated DR pathology in vivo, whereas overexpression of HDAC9 exacerbated EndoMT in DR model mice. To elucidate the downstream target genes of HDAC9 implicated in DR, we conducted integrated ChIP-seq and RNA-seq analysis of the retina in STZ-induced retinopathy and established that HDAC9 was involved in the transcriptional regulation of annexin A2 (ANXA2). We demonstrated that HDAC9 was bound to the promoter region of ANXA2, leading to the downregulation of ANXA2 expression in high glucose-treated human retinal microvascular endothelial cells and STZ-induced DR model mice. Overexpression of ANXA2 significantly reduced the EndoMT process in STZ-induced DR model mice. Collectively, our results demonstrate that HDAC9 promotes EndoMT by regulating ANXA2 transcription, thereby disrupting vascular homeostasis during DR. This study sheds light on the roles of HDAC9 and ANXA2 in DR pathology and provides a theoretical foundation for the potential therapeutic strategies to target DR.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750628","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"KLX ameliorates liver cancer progression by mediating ZBP1 transcription and ubiquitination and increasing ZBP1-induced PANoptosis.","authors":"Zhuo Wang, Yang Yang, Fang-Ting Yao, Feng Zhang, Ke-Ying Lin, Hong-Tao Diao, Qiao-Yue Zhao, Xue Kong, Wei Si, Ya-Ting Xie, Jing-Lun Song, Ling-Hua Zeng, Chun-Lei Wang, Yu-Ting Xiong, Kun-Kun Zou, Xiao-Man Wang, Xin-Yue Zhang, Han Wu, Wei-Tao Jiang, Yu Bian, Bao-Feng Yang","doi":"10.1038/s41401-025-01528-4","DOIUrl":"10.1038/s41401-025-01528-4","url":null,"abstract":"<p><p>Liver cancer is a highly aggressive malignancy with poor survival rates. Current treatments, including liver transplantation, immunotherapy, and gene therapy, are often limited by late-stage diagnosis and significant side effects, highlighting the urgent need for novel therapeutic agents. In this study, we evaluated the therapeutic potential of Kanglexin (KLX), a novel anthraquinone derivative, in the treatment of liver cancer. In vitro, KLX inhibited the proliferation and migration of HepG2 and Hep3B cells in a dose-dependent manner. Mechanistically, KLX upregulated Z-DNA binding protein 1 (ZBP1) expression, inducing PANoptosis by directly binding to ZBP1, altering its conformation, and reducing its affinity for the E3 ubiquitin ligase ring finger protein 180 (RNF180). This interaction decreased ZBP1 ubiquitination, thereby increasing its stability. Additionally, KLX upregulated the expression of the transcription factor homeobox D10 (HOXD10), which further increased ZBP1 expression. Elevated ZBP1 levels significantly suppressed liver cancer cell proliferation and migration, whereas the inhibitory effects of KLX were reversed upon ZBP1 knockdown. In a xenograft model, KLX significantly inhibited tumor growth with a lower toxicity than oxaliplatin (OXA). In conclusion, KLX promoted PANoptosis in liver cancer cells by upregulating ZBP1 and preventing its degradation, thereby inhibiting liver cancer progression and migration. These findings suggest that KLX is a promising therapeutic agent for liver cancer.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143727159","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HIF-1α mediates mitochondrial damage by down-regulating ALKBH7 expression to promote the aberrant activation of FLS in rheumatoid arthritis.","authors":"Han Wang, Yu-Chen Zhao, Li Xu, Tian-Jing Zhang, Liang-Hu Liu, Meng-Qi Zhou, Han Zhang, Yin-Ning Yang, Pin Pan, Lin Jin, Zi-Wei Zhang, Xian-Zheng Zhang, Ling-Ling Zhang","doi":"10.1038/s41401-025-01520-y","DOIUrl":"https://doi.org/10.1038/s41401-025-01520-y","url":null,"abstract":"<p><p>Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial inflammation and progressive joint destruction. Existing evidence indicates that hypoxia potentially contributes to the pathology of RA, though the specific mechanism remains unidentified. In this study, we explored the molecular mechanism through which the hypoxia-inducible factor (HIF-1α) contributed to the pathological process of RA. Our preliminary results suggested that hypoxia stimulates the activation of fibroblast-like synoviocytes (FLS) by inducing mitochondrial damage to activate cGAS-STING signaling, which can be effectively inhibited by silencing HIF-1α. In line with this, HIF-1α deficiency significantly alleviated the symptoms of collagen-induced arthritis (CIA) mice. RNA-Seq and CUT-Tag analysis revealed that HIF-1α down-regulated the expression of AlkB homologue 7 (ALKBH7) by acting on the ALKBH7 promoter site on chromosome 19 6372400-6372578. Using dual luciferase reporter analysis, we identified that ACCGTGGC as the motif to which HIF-1α bound directly. Subsequently, we demonstrated that knockdown of ALKBH7 induces mitochondrial damage and activates cGAS-STING signaling by downregulating the expression of UQCRC2. Conversely, overexpression of ALKBH7 could resist hypoxia-induced mitochondrial damage and FLS activation. In conclusion, HIF-1α triggers mitochondrial damage by downregulating the expression of ALKBH7 thereby promoting FLS activation, which may be the molecular mechanism by which hypoxia is involved in the pathological process of RA. Hypoxia promotes the activation of FLS through the induction of mitochondrial damage, which subsequently activates cGAS-STING signaling. Mechanistically, HIF-1α triggers mitochondrial damage by downregulating the expression of ALKBH7 in a target manner. Furthermore, the deletion of ALKBH7 leads to mitochondrial damage under hypoxic conditions, primarily through the downregulation of UQCRC2, as opposed to other complexes.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143717599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}