Acta Pharmacologica Sinica最新文献

{"title":"p-Coumaric acid alleviates neuronal damage in ischemic stroke mice by promoting BACH1 nuclear export and degradation.","authors":"Meng-Lu Song, Yun-Yun Sun, Hai-Jun Yin, Yi Li, Hua Yang","doi":"10.1038/s41401-025-01510-0","DOIUrl":"10.1038/s41401-025-01510-0","url":null,"abstract":"<p><p>Oxidative damage induced by glutamate triggers neuronal death in cerebral ischemic/reperfusion injury. BTB and CNC homology 1 (BACH1) is a major link between the cellular heme level, the redox state and the transcriptional response. p-Coumaric acid (p-CA) is a natural antioxidant that has been shown to ameliorate ischemic/reperfusion injury. In this study, we investigated whether and how p-CA regulated BACH1 in ischemic/reperfusion injury from the perspective of BACH1 subcellular localization and function. Middle cerebral artery occlusion (MCAO) model was established in male mice. MCAO mice were treated with p-CA (50, 100 mg/kg, ip) twice 5 min after MCAO and 5 h after reperfusion operation, respectively. We showed that p-CA treatment exerted dramatic neuroprotective effects, which were associated with the inhibition of BACH1. In HT22 cells, treatment with p-CA (20 μM) ameliorated OGD/R or glutamate-induced oxidative damage and mitochondrial dysfunction through decreasing the protein level of BACH1, the beneficial effect of p-CA was blocked by BACH1 overexpression. We demonstrated that BACH1 level was markedly elevated in the nucleus of HT22 cells under glutamate stimulation, and transcriptionally regulated NADPH oxidase 4 (NOX4) expression, thus mediating ROS outbreak. p-CA treatment activated the activated Cdc42-associated kinase 1 (ACK1)/protein kinase B (AKT) cascade to facilitate the phosphorylation of BACH1, augmented its interaction with chromosome region maintenance 1 (CRM1), thereby leading to the export of BACH1 from the nucleus and degradation mediated by heme-oxidized IRP2 ubiquitin ligase-1 (HOIL-1). In accord with this, administration of ACK1 inhibitor AIM-100 (20 mg/kg, ip) 5 min after MCAO significantly attenuated the neuroprotective effects of p-CA in MCAO mice. We concluded that ACK1/AKT/BACH1 axis may serve as a promising therapeutic approach for the management of ischemic stroke, thereby broadening the clinical utility of p-CA.Keywords: ischemic/reperfusion injury; p-Coumaric acid; BACH1; NOX4; ACK1/AKT; AIM-100.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2136-2150"},"PeriodicalIF":6.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12274441/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143633280","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":"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":"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":"2225-2236"},"PeriodicalIF":6.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12274575/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Huperzine A attenuates epileptic seizures via enhancing dCA1-projecting septal cholinergic transmission.","authors":"Yu Wang, Ke-Yu Hu, Qing-Yang Zhang, Ying-Jie Song, Ling-Jie Li, Fei Wang, Gang Tian, Fan Fei, Ceng-Lin Xu, Jia-Jia Fang, Xu-Hong Jiang, Jian-Nong Wu, Wen-Lu Li, Yi Wang, Zhong Chen","doi":"10.1038/s41401-025-01522-w","DOIUrl":"10.1038/s41401-025-01522-w","url":null,"abstract":"<p><p>Cholinergic transmission, independent of classical glutamatergic and GABAergic signaling, critically plays a crucial role in epilepsy. Huperzine A (Hup A), an acetylcholinesterase (AChE) inhibitor, exerts potent anticonvulsant activity, but its mechanism of action within cholinergic circuits remains unclear. Here, we show that Hup A mitigates epileptic seizures by enhancing hippocampal dorsal CA1 (dCA1)-projecting cholinergic transmission. We found that systemic injection of Hup A not only reduces seizures in acute models, including the maximal-electroshock seizure (MES), pentylenetetrazol (PTZ), and kainic acid (KA) models but also alleviates the seizure severity in chronic epilepsy models induced by kindling and KA, indicating a broad-spectrum anti-seizure efficacy. Interestingly, using immunohistochemistry, viral tracing, and in vivo fiber photometry, we found that Hup A selectively inhibits AChE in the dCA1 rather than in other hippocampal subregions or cortex, enhancing dCA1-projecting septal cholinergic transmission. Significantly, selective ablation of septal ChAT⁺ neurons reversed the anti-seizure effects of Hup A. We further identified that α7 nicotinic acetylcholine receptors in the dCA1 region mediate the anti-seizures cholinergic circuit modulated by Hup A. Together, our results demonstrate that Hup A exerts broad-spectrum anti-seizure efficacy via modulating dCA1-projecting septal cholinergic transmission, providing potential therapeutic avenues for epilepsy through targeted cholinergic modulation.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2151-2162"},"PeriodicalIF":6.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12274539/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143717613","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":"Glabridin as a selective Kv2.1 inhibitor ameliorates DPN pathology by disrupting the Aβ/Kv2.1/JNK/NF-κB/NLRP3/p-Tau pathway.","authors":"Jia-Wen Xu, Lin Ma, Yu Xiang, Meng-Qing Dai, Qiu-Hui Li, Xiao-Yan Jin, Yuan Ruan, Yang Li, Jia-Ying Wang, Xu Shen","doi":"10.1038/s41401-025-01526-6","DOIUrl":"10.1038/s41401-025-01526-6","url":null,"abstract":"<p><p>Diabetic peripheral neuropathy (DPN) is a common diabetic complication. DPN has a complicated pathogenesis, and the currently clinical drugs against this disease show only limited efficacy and undesirable side effects. Thus, it is of great challenges to discover effective targets and drugs against DPN. Glabridin (GLA) is a natural prenylated isoflavone from the roots of Glycyrrhiza glabra. It exhibits a wide range of pharmacological activities including anti-inflammatory, antioxidant, cardiovascular protective, neuroprotective, hepatoprotective, anti-obesity and anti-diabetic effects, etc. In this study we investigated the beneficial effects of GLA on late-stage DPN and the underlying mechanisms. Using electrophysiological recording from CHO-Kv2.1 cells, we identified GLA as a new Kv2.1-selective inhibitor with an IC₅₀ value of 2.07 μM. We showed that oral administration of GLA (30, 60 mg·kg^-1·d^-1) for 4 weeks significantly improved all neurological dysfunctions and peripheral vascular dysfunctions in DPN mice. Furthermore, we demonstrated that GLA administration improved intraepidermal nerve fiber (IENF) density damage and myelin sheath injury, promoted neurite outgrowth of DRG neurons and alleviated the apoptosis of DRG neurons in DPN mice. All these beneficial effects of GLA were deprived in Kv2.1-knockdown DPN mice specifically in the DRG and sciatic nerve tissues by injection of adeno associated virus AAV8-Kv2.1-RNAi (AAV8-Kv2.1). We showed that the levels of Aβ and hyperphosphorylated tau proteins (p-Tau) were pathologically increased in serum of DPN patients. We demonstrated that Kv2.1 channels bridged Aβ to activate NLRP3 inflammasome in Schwann cells and promote p-Tau production in DRG neurons through Schwann cells/DRG neurons crosstalk. GLA interrupted Aβ/Kv2.1/NLRP3/p-Tau axis to ameliorate the DPN-like pathology in mice. Our results support that Kv2.1 inhibition is a therapeutic strategy for DPN and highlight the potential of GLA in treating this disease.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2163-2179"},"PeriodicalIF":6.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12274400/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143668628","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":"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":"2213-2224"},"PeriodicalIF":6.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12274476/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetic regulation of iron metabolism and ferroptosis in Parkinson's disease: Identifying novel epigenetic targets.","authors":"Xiao-Die Gao, Jian-E Ding, Jun-Xia Xie, Hua-Min Xu","doi":"10.1038/s41401-025-01499-6","DOIUrl":"10.1038/s41401-025-01499-6","url":null,"abstract":"<p><p>Parkinson's disease (PD) is a neurodegenerative disease, and emerging evidence has shown that iron deposition, ferroptosis and epigenetic modifications are implicated in the pathogenesis of PD. However, the interplay among these factors in PD has not been fully understood. In this review, we provide an overview of the current research progress on iron metabolism, ferroptosis and epigenetic alterations associated with PD. Furthermore, we present new frontiers concerning various epigenetic modifications related to iron metabolism and ferroptosis that might contribute to the pathology of PD. Notably, epigenetic modifications of iron metabolism and ferroptosis as both diagnostic and therapeutic targets in PD have been discussed. This opens new avenues for the regulation of iron homeostasis and ferroptosis in PD from epigenetic perspectives, and provides evidence for their potential implications in the diagnosis and treatment of PD.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2075-2092"},"PeriodicalIF":6.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12274621/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603109","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":"Targeting the HuR/E2F7 axis synergizes with bortezomib against multiple myeloma.","authors":"Ming-Yuan Jia, Chao Wu, Ze Fu, Wen-Bin Xu, Jia Liu, Cheng-Yu Wu, Xin-Yi Zeng, Ying-Li Wu, Hua Yan","doi":"10.1038/s41401-025-01529-3","DOIUrl":"10.1038/s41401-025-01529-3","url":null,"abstract":"<p><p>Multiple myeloma (MM) is a malignant hematological disease caused by the proliferation of abnormal plasma cells in the bone marrow and is still incurable. Relapse and drug resistance are common in MM. New therapeutic targets are urgently needed for MM treatment. Human antigen R (HuR) has been reported to play an important role in the malignant biological behavior of a variety of tumors, but its role in MM remains unclear. In this study, we found that HuR was highly expressed in MM patients and associated with a poor prognosis by analyzing public datasets. We found that targeting HuR with short hairpin RNA (shRNA) or its inhibitor CMLD-2 had significant anti-MM effects both in vitro and in vivo. The overexpression of HuR promotes MM cell proliferation in vitro and in vivo. Moreover, we demonstrated that bortezomib drug sensitivity increased and decreased with the knockdown and overexpression of HuR, respectively. This result provides a rationale for our subsequent combination of CMLD-2 with bortezomib in the treatment of MM. To further explore the mechanism of HuR in MM, we performed RNA sequencing and identified its downstream molecule, E2F7. HuR upregulated E2F7 expression by increasing the stability of its mRNA in MM cells. Higher levels of E2F7 were associated with a poorer prognosis. E2F7 knockdown had anti-MM effects in vitro and in vivo. E2F7 overexpression partially rescued the cell proliferation inhibition and apoptosis caused by targeting HuR in MM cells. We subsequently demonstrated that CMLD-2 synergized with the anti-MM effect of bortezomib both in vitro and in vivo. In conclusion, targeting the HuR/E2F7 axis synergizes with bortezomib against MM. Therefore, the HuR/E2F7 axis may serve as a promising therapeutic target for MM.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2296-2309"},"PeriodicalIF":6.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12274554/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143708031","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":"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":"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":"2251-2266"},"PeriodicalIF":6.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12274587/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"G-protein coupled receptor kinase 2 mediates rheumatoid arthritis-induced depression-like behaviors via the hippocampal CRHR1 signaling pathway.","authors":"Qian Meng, Meng-Hui Guo, Rui Zhang, Jing Wei, Qian Chen, Xue-Chun Zhao, Cai-Qi Xu, Yao-Yao Wu, Jia-Jie Kuai, Jie-Min Zhao, Yu-Jing Wu, Chong-Huan Ye, Hong-Rui Wei, Xia Zhu, Yan Jin, Zhi Zhang, Wei Wei","doi":"10.1038/s41401-025-01621-8","DOIUrl":"https://doi.org/10.1038/s41401-025-01621-8","url":null,"abstract":"<p><p>Rheumatoid arthritis with depressive symptoms is frequently encountered in clinic. In this study, we investigated the molecular mechanisms responsible for comorbid depression with rheumatoid arthritis in collagen-induced arthritis (CIA) model mice. We showed that depression-like behaviors were developed at 5 weeks after establishing CIA model. Furthermore, we found that in the hippocampus of CIA mice, G-protein coupled receptor kinase 2 (GRK2) was significantly upregulated, while the expression of its target, corticotropin releasing hormone receptor 1 (CRHR1) was notably decreased, as was the downstream cAMP/PKA/CREB/BDNF signaling. We demonstrated that GRK2 could directly interact with CRHR1, suppressing CRHR1-dependent signaling. Knockdown of hippocampal GRK2 or pharmacological inhibition with CP-25 (35 mg·kg^-1·d^-1, i.g. for 21 days) could alleviate the depression-like behaviors in CIA mice, whereas GRK2 overexpression induced depression-like behaviors in naive mice. Our study identifies hippocampal GRK2 as a regulator of depression-like behaviors associated with rheumatoid arthritis in CIA model mice, suggesting both a therapeutic target and potential treatment strategy.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144681781","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":"Identification of AKOS, a Chikungunya virus inhibitor, as a USP14 inhibitor for colorectal cancer treatment.","authors":"Bin Lu, Yi-Yun Sun, Jia-Hao Zhou, Dan-Ni Chen, Yue Guo, Yu-Lu Chen, Cheng-Hao Pan, Zheng-Yang Chen, Qiao-Jun He, Meng Yuan, Ji Cao, Li Jiang, Bo Yang","doi":"10.1038/s41401-025-01616-5","DOIUrl":"https://doi.org/10.1038/s41401-025-01616-5","url":null,"abstract":"<p><p>Ubiquitin-specific protease 14 (USP14) is a crucial modulator of proteasomal function and cellular proteostasis, which plays an important role in the development and progression of various cancers including colorectal cancer (CRC). In this study we screened 670 covalent compounds using the in vitro Ub-AMC hydrolysis assay, and identified AKOS, initially a Chikungunya virus inhibitor, as a novel small-molecule inhibitor of USP14. We showed that AKOS inhibiting USP14 deubiquitinase activity with an IC₅₀ value of 0.98 μM. AKOS directly bound to USP14, covalently modifying the active-site cysteine residue (Cys¹¹⁴), thereby effectively inhibiting its deubiquitinase activity. We demonstrated that inhibition of USP14 by AKOS might destabilize MEF2D, a critical substrate, resulting in downregulation of the expression and translation of ECM-related transcription factors such as ITGB4. AKOS exhibited potent anti-cancer effects: the USP14 inhibitor significantly inhibited the proliferation and metastasis of CRC cells in vitro with IC₅₀ values of 9.88 and 16.57 μM, respectively, in SW620 cells and HCT116 cells. Intratumoral injection of AKOS (15, 30 mg/kg, every 5 days) effectively suppressed the tumor growth in HCT116 xenograft mouse models in vivo. Collectively, we demonstrate that AKOS is a promising chemical probe for targeting USP14 in CRC, offering a novel strategy for disrupting the malignant progression of CRC.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144658061","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}