Biochemical pharmacology最新文献

{"title":"Didox, a ribonucleotide reductase inhibitor with iron chelator properties, counteracts the in vitro and in vivo growth of rhabdomyosarcoma cells","authors":"Luca Cantamessa ,&nbsp;Michela Asperti ,&nbsp;Magdalena Gryzik ,&nbsp;Silvia Codenotti ,&nbsp;Leonardo Sandrini ,&nbsp;Manuela Cominelli ,&nbsp;Francesca Pagani ,&nbsp;Federica Maccarinelli ,&nbsp;Mattia Bugatti ,&nbsp;Pietro Luigi Poliani ,&nbsp;Francesco Marampon ,&nbsp;Alessandro Fanzani ,&nbsp;Maura Poli","doi":"10.1016/j.bcp.2025.117312","DOIUrl":"10.1016/j.bcp.2025.117312","url":null,"abstract":"<div><div>Ribonucleotide reductase (RR) is the rate-limiting enzyme for NTPs conversion into dNTPs, playing a central role in genome replication and maintenance. It is composed by two catalytic (RRM1) and two regulatory (alternatively RRM2 and p53R2) subunits, of which RRM2′s functionality depends on a diferric center in the active site and is one of the most expressed genes in many tumors, among which Rhabdomyosarcoma (RMS), a rare and aggressive pediatric tumor. Didox (3,4-dihydroxy-benzohydroxamic acid) is a highly effective RRM2 inhibitor with iron chelating properties which shows fewer <em>in vivo</em> side effects than classical RR inhibitors. In the present work, we analyzed the impact of didox on RMS cells. Our data clearly showed that didox effectively reduces cell viability, clonogenic capability and motility of both RD and RH30 cells (representative of embryonal named ERMS and alveolar subtype named ARMS), with higher potency in ARMS cells. Interestingly, didox is effective in inhibiting the cell viability of RMS radioresistant. Mechanistically, didox modulates the main iron-related proteins (TfR1 and H-ferritin), confirming its iron chelating properties; it induces mitochondrial ROS formation and caused an increase in double positive annexin-V/PI cells, confirming apoptosis as mechanism of cell death. Moreover, didox also potently reduces <em>in vivo</em> tumor proliferation of RH30 cells, without significant side effects on animals. Finally, the combination of sublethal doses of Actinomycin-D and didox is effective in decreasing cell viability and clonogenicity of RMS cells. Therefore, our data suggests the effectiveness of the RR inhibitor didox on both <em>in vitro</em> and <em>in vivo</em> RMS proliferation.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117312"},"PeriodicalIF":5.6,"publicationDate":"2025-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145028855","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DNA methylation as an oncogenic driver in breast cancer: Therapeutic targeting via epigenetic reprogramming of DNA methyltransferases","authors":"Sweta Kundu,&nbsp;Sampriti Sarkar ,&nbsp;Suparna Ghosh,&nbsp;Avik Acharya Chowdhury","doi":"10.1016/j.bcp.2025.117313","DOIUrl":"10.1016/j.bcp.2025.117313","url":null,"abstract":"<div><div>The malignant manifestation of breast cancer is driven by complex molecular alterations that extend beyond genetic mutations to include epigenetic dysregulation. Among these, DNA methylation is a critical and reversible epigenetic modification that significantly influences breast cancer initiation, progression, and therapeutic resistance. This process, mediated by DNA methyltransferases (DNMTs), involves the addition of methyl groups to cytosine residues within CpG dinucleotides, resulting in transcriptional repression of genes. Aberrant methylation patterns are characterized by promoter hypermethylation of tumor suppressor genes (<em>BRCA1, CDH1, PTEN, RARβ</em>), which leads to their suppression, and global hypomethylation that activates oncogenes and promotes genomic instability. Central to these events is the dysregulation of DNA methyltransferases which drive maladaptive epigenetic programming. Nucleoside DNMT inhibitors (DNMTis) incorporate into DNA to trap and deplete DNMTs, while non-nucleoside DNMTis avoid DNA integration and directly target DNMT through catalytic site binding, cofactor competition, DNMT-DNA interaction disruption, or DNMT degradation to achieve improved selectivity and reduced toxicity. Preclinical and clinical studies demonstrate that DNMTis not only restore the expression of silenced tumor suppressor genes but also enhance the efficacy of chemotherapy, sensitize homologous recombination-deficient tumors to PARP inhibitors, and synergize with histone deacetylase inhibitors and immunotherapies. Notably, DNMTi monotherapies have shown significant antitumor effects in breast cancer models. Furthermore, methylation profiling holds translational potential as predictive biomarker, particularly in triple-negative breast cancer, where DNMT inhibition may expand therapeutic opportunities. This review highlights the mechanistic underpinnings of DNMT dysregulation, the therapeutic landscape of DNMT inhibitors, and the integration of methylation profiling into precision oncology.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117313"},"PeriodicalIF":5.6,"publicationDate":"2025-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145028804","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oridonin mitigates bacterial pneumonia by regulating mitochondrial integrity and ferroptosis via targeting KEAP1/NRF2 signaling","authors":"Wei Zhang ,&nbsp;Xiang Chen ,&nbsp;Haoyu Zhang ,&nbsp;Xiaoling Liu ,&nbsp;Changjiang Chen ,&nbsp;Nianyin Lv ,&nbsp;Yanan Gao ,&nbsp;Liuzhou Gao ,&nbsp;Liyun Shi","doi":"10.1016/j.bcp.2025.117310","DOIUrl":"10.1016/j.bcp.2025.117310","url":null,"abstract":"<div><div>Methicillin-resistant Staphylococcus aureus (MRSA) is a highly virulent and drug-resistant pathogen frequently causing bacterial pneumonia. Currently, there are limited effective treatments available due to the rapidly evolving resistance of bacteria. Therefore, there is an urgent need to develop novel therapies that focus on host-pathogen interactions. Oridonin is a naturally occurring diterpenoid with multiple pharmacological effects, but its therapeutic potential in bacterial pneumonia, as well as its action mode, remains largely unknown. Here, we demonstrated that oridonin conferred protection against MRSA pneumonia. Macrophages, the major innate immune cells against respiratory infection, exhibited enhanced bactericidal capability, alleviated inflammatory response, and resistance to ferroptosis upon oridonin treatment. Importantly, we further showed that oridonin covalently associates with the Kelch-like ECH-associated protein 1 (KEAP1), hindering its binding by nuclear factor erythroid 2-related factor 2 (NRF2). Enhanced activation of NRF2 subsequently activated the genes responsible for mitochondrial lipid peroxidation and iron homeostasis, thereby orchestrating the activity and survival of alveolar macrophages. Collectively, we present the first evidence demonstrating the therapeutic potential of oridonin in combating drug-resistant bacterial pneumonia, establishing it as a novel regulator of both mitochondrial and ferroptotic pathways. This may have significant implications for the development of host-directed therapies against formidable pathogens.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117310"},"PeriodicalIF":5.6,"publicationDate":"2025-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145028826","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bacterial toxins as immunomodulatory agents in cancer therapy","authors":"Kantrol Kumar Sahu ,&nbsp;N. Saleem Basha ,&nbsp;Madhulika Pradhan ,&nbsp;Sucheta ,&nbsp;Akhilesh Dubey ,&nbsp;Krishna Yadav","doi":"10.1016/j.bcp.2025.117309","DOIUrl":"10.1016/j.bcp.2025.117309","url":null,"abstract":"<div><div>Bacterial toxins have emerged as promising anticancer therapeutics, transforming from pathogenic agents to precision treatment modalities. They provide exceptional specificity for cancer cells while largely leaving healthy tissue unaffected, which solves one of the major limitations of traditional chemotherapy. This review explores the emerging trends of bacterial-derived immunotoxins and chimeric toxins for target specificity and their promise as future anticancer therapies. It defines the potential of bacterial toxins as anticancer agents through an immuno-modular design using the targeting moieties of antibodies, affibodies, antimicrobial peptides (AMPs), and cytokines. Further, this encompasses current drug delivery applications of bacterial toxins and bacterial extracellular vesicles in cancer-targeted therapy and clinical translation challenges. This review represents a systematic approach by describing bacterial toxin-based immunotherapy as a new paradigm shift for the useful employment of bacterial components in precision oncology.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117309"},"PeriodicalIF":5.6,"publicationDate":"2025-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145022766","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Isoliquiritigenin inhibits the activation of the ANXA2/STAT3 pathway by down-regulating TAGLN2, thereby alleviating alcoholic fatty liver","authors":"Furong Fan ,&nbsp;Furong Zhu ,&nbsp;Chao Jiang ,&nbsp;Liang Zhang ,&nbsp;Md Hasan Ali ,&nbsp;Yuanchuang Wang ,&nbsp;Kaiyue Zhang ,&nbsp;Zijun Zhao ,&nbsp;Qingqing Li ,&nbsp;Siqi Li ,&nbsp;Yongxiu Qian ,&nbsp;Mengwei Jiang ,&nbsp;Min Liu ,&nbsp;Shenghui Chu","doi":"10.1016/j.bcp.2025.117308","DOIUrl":"10.1016/j.bcp.2025.117308","url":null,"abstract":"<div><div>The etiology of alcoholic fatty liver (AFL) is complex, representing the early reversible stage of alcohol-associated liver disease (ALD). Alleviating oxidative stress, reducing inflammation, and preventing the development of liver fibrosis are considered the most effective strategies for treating AFL. Consequently, we selected isoliquiritigenin (ISL), a flavonoid compound recognized for its anti-inflammatory, antioxidant, and anticancer pharmacological properties. In this study, we investigated the role and mechanism of ISL in AFL. Mechanistic studies revealed that ISL reduces the expression of pro-inflammatory factors by inhibiting annexin A2 (ANXA2), which is involved in the inflammatory response, along with the downstream signaling pathways, activator of signal transducer and activator of transcription 3 (STAT3), and nuclear factor kappa-B (NF-κB). Additionally, ISL activates the nuclear factor erythroid 2 like 2 (Nrf2) antioxidant pathway and enhances antioxidant enzyme activity, thereby reducing liver inflammation and oxidative damage while promoting hepatocyte repair. We identified the significantly differentially expressed protein transgelin 2 (TAGLN2) using tandem mass tag (TMT) proteomics technology. Notably, ISL inhibits the expression of TAGLN2 both in vivo and in vitro, alleviating AFL by blocking the ANXA2/STAT3 signaling pathway. Furthermore, we demonstrated that TAGLN2 serves as a direct target for ISL in the treatment of AFL and regulates STAT3 through its interaction with ANXA2. In summary, this study provides a theoretical basis for considering ISL as a novel drug monomer for treating AFL and offers a promising therapeutic strategy for AFL.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117308"},"PeriodicalIF":5.6,"publicationDate":"2025-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145022773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Asiatic acid inhibits endothelial-to-mesenchymal transition in diabetic kidney disease by reducing acetyl-CoA production via targeting ACSS2","authors":"Ruo-hui Lin ,&nbsp;Ji-cong Chen ,&nbsp;Su-su Xu ,&nbsp;Yin-ying Xu ,&nbsp;Ke Pan ,&nbsp;Lei Wang ,&nbsp;Jian Zhang ,&nbsp;Zhi-qi Yin ,&nbsp;Ya-ping Huang","doi":"10.1016/j.bcp.2025.117311","DOIUrl":"10.1016/j.bcp.2025.117311","url":null,"abstract":"<div><div>Endothelial-to-mesenchymal transition (EndMT) is a critical contributor of renal fibrosis in diabetic kidney disease (DKD). Asiatic acid (AA), a natural triterpenoid compound, exhibits notable endothelial protective and anti-fibrotic properties; however, its impact on EndMT in DKD remains unclear. This study aimed to investigate the therapeutic effect of AA against EndMT in DKD and the underlying mechanisms. In vivo, AA effectively inhibited EndMT in the glomeruli of DKD mice, restored the expression of endothelial markers (CD31 and VE-cadherin), while reduced the expression of mesenchymal markers (α-SMA and Vimentin). Meanwhile, AA significantly reduced renal acetyl-CoA levels, which were elevated in DKD mice and strongly associated with EndMT progression. Mechanistically, acyl-CoA synthetase short-chain family member 2 (ACSS2) was identified as a key enzyme promoting acetyl-CoA production and histone acetylation, thereby facilitating EndMT. In vitro, exogenous acetate supplementation and siRNA mediated-ACSS2 knockdown confirmed ACSS2′s role in regulating EndMT. Pharmacological inhibition of ACSS2 further suppressed the progression of EndMT. Notably, molecular docking and cellular thermal shift assays revealed that AA directly binds to ACSS2. AA treatment reduced acetyl-CoA production, decreased H3K27 acetylation, restored endothelial characteristics, and suppressed mesenchymal features in both primary glomerular endothelial cells and endothelial cell lines. Overall, these findings demonstrate that AA inhibits EndMT in DKD by reducing acetyl-CoA production via targeting ACSS2. This study elucidates a novel mechanism by which AA attenuates renal fibrosis in DKD and highlights ACSS2 as a potential therapeutic target for intervention.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117311"},"PeriodicalIF":5.6,"publicationDate":"2025-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145018368","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PFGA12 ameliorates Hypoxic-Ischemic brain injury by directly regulating PRDX1 and inhibiting ferroptosis","authors":"Haocong Chen ,&nbsp;Jing Zhao ,&nbsp;Yu Kang ,&nbsp;Shuyan Wang ,&nbsp;Dani Qin ,&nbsp;Lingling Yu ,&nbsp;Yingmin Zhao ,&nbsp;Guangming Zhang ,&nbsp;Xiaohua Dong","doi":"10.1016/j.bcp.2025.117307","DOIUrl":"10.1016/j.bcp.2025.117307","url":null,"abstract":"<div><div>Hypoxic-ischemic brain damage (HIBD) is a severe condition leading to extensive neuronal loss and functional impairments, representing a significant challenge in neonatal care. PFGA12, a peptide derived from fibrinogen alpha chain (FGA), which is notably downregulated in the umbilical cord blood of hypoxic-ischemic encephalopathy (HIE) infants. We demonstrate that PFGA12 significantly enhances cell viability and mitigates oxygen-glucose deprivation/reperfusion (OGD/R)-induced neuronal cell death. PFGA12 treatment significantly alleviated cerebral edema, reduced infarct volume, and attenuated neuronal damage in HIBD rats, attributable to its stable presence within neurons. Additionally, PFGA12 attenuated neuroinflammation by inhibiting the activation of microglia and astrocytes. Moreover, Y-maze test demonstrated that PFGA12 effectively improved the spatial learning and memory abilities. Mechanistically, PFGA12 exerts potent neuroprotective effects by specifically targeting peroxiredoxin-1 (PRDX1). PFGA12 directly binds to PRDX1, effectively inhibiting phosphorylation at Tyr194 (p-PRDX1), thereby enhancing its peroxidase activity. This PRDX1-mediated antioxidant mechanism substantially reduces lipid reactive oxygen species (ROS) accumulation and provides protection against OGD/R-induced neuronal ferroptosis, as demonstrated by the upregulation of Glutathione peroxidase 4 (GPX4) and suppression of Acyl-CoA synthetase long-chain family member 4 (ACSL4). Notably, overexpression of PRDX1 mitigates ferroptotic damage induced by OGD/R, while knockdown of PRDX1 completely abolishes the protective effects of PFGA12 in OGD/R-treated HT22 cells, confirming PRDX1 as the critical molecular target through which PFGA12 inhibits ferroptosis. These results demonstrate that PFGA12, an active peptide, exhibits potential as a novel treatment option for HIBD.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117307"},"PeriodicalIF":5.6,"publicationDate":"2025-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145018369","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exendin-4 Prevents oxLDL-Induced upregulation of TREM2 and attenuates foam cell formation and inflammation in Macrophages","authors":"Xu Wang ,&nbsp;Mengting Jiang ,&nbsp;Hailong Bao ,&nbsp;Runze Huang ,&nbsp;Bingxiu Chen ,&nbsp;Changfang Wu ,&nbsp;Hongwei Wang ,&nbsp;Zhenhua Luo ,&nbsp;Wei Li","doi":"10.1016/j.bcp.2025.117306","DOIUrl":"10.1016/j.bcp.2025.117306","url":null,"abstract":"<div><div>Atherosclerosis (AS), a chronic inflammatory disease and a leading cause of cardiovascular morbidity and mortality. Macrophage-mediated lipid uptake and inflammation are central to plaque formation. TREM2, an immunoreceptor expressed in macrophages, has been reported to regulate lipid metabolism and inflammation, yet its role in atherosclerosis remains controversial. Exendin-4, a GLP-1 receptor agonist with its known cardiovascular protective effects, may influence immune signaling beyond glycemic control. However, whether the effect of Exendin-4 mitigating AS and the relations with TREM2 and its downstream JAK2/STAT3 pathway are unknown. We aimed to investigate the role of the Exendin-4-TREM2-JAK2/STAT3 axis in foam cell formation and inflammation during AS progression. OxLDL was used to stimulate THP-1-derived macrophages, and <em>ApoE^−/−</em> mice fed a high-fat diet were used to construct an in vivo AS model. TREM2 expression was manipulated using lentiviral vectors, and the role of JAK2 signaling was assessed with a specific inhibitor. We evaluated the effects of Exendin-4 on TREM2 expression, foam cell formation and inflammation. We found that lipid stimulation increased TREM2 expression and activated the JAK2/STAT3 pathway in macrophages, leading to enhanced foam cell formation and pro-inflammatory cytokine production. Also, TREM2 overexpression caused increasing levels of inflammatory cytokines and foam cells. Exendin-4 could alleviate AS progression under the anti-inflammatory and anti-foaming effects, with reducing TREM2 expressions. However, the inflammation and foam cell formation with JAK2/STAT3 pathway activation caused by TREM2 overexpression cannot be reversed by Exendin-4. All our findings indicate that Exendin-4 suppress foam cell formation and inflammatory responses, with inhibiting macrophage TREM2 expression up-regulation.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117306"},"PeriodicalIF":5.6,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145008114","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sappanone A, a potential natural inhibitor of PI3K, alleviates metabolic dysfunction-associated steatohepatitis in experimental models","authors":"Xi Qiao ,&nbsp;Qian Li ,&nbsp;Ruiqi Fan ,&nbsp;Yujie Cheng ,&nbsp;Qingxuan Zeng ,&nbsp;Huan Xue ,&nbsp;Xiaoli Zhang ,&nbsp;Yi Zhang ,&nbsp;Yunfeng Liu","doi":"10.1016/j.bcp.2025.117305","DOIUrl":"10.1016/j.bcp.2025.117305","url":null,"abstract":"<div><div>Metabolic dysfunction-associated steatohepatitis (MASH) affects a large proportion of the global population and is widely regarded as the fastest growing cause of hepatocellular carcinoma. Currently, approved therapeutic strategies for MASH are limited. Therefore, this study used the Connectivity Map (CMap) database to identify a candidate compound for MASH, evaluate its efficacy in experimental models, and explore its mechanism of action. Based on the gene expression profile of GSE126484, Sappanone A (SA) was screened using the CMap. In a palmitic acid-induced cell model, SA notably reduced the expression of fibrotic genes in LX-2 cells. In a methionine-choline-deficient (MCD) diet-induced MASH model, SA significantly attenuated liver injury, as evidenced by the reduction in serum alanine aminotransferase levels, alleviation of hepatic ballooning and inflammation. In a high-fat, methionine-restricted, choline-deficient (HFMRCD) diet-induced MASH model, SA remarkably improved lipid metabolism, ballooning, and inflammation. Importantly, SA markedly inhibited the progression of fibrosis. Network pharmacology results indicated that SA might alleviate MASH through the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/(Mechanistic target of rapamycin) mTOR signaling pathway. We performed molecular docking, cellular thermal shift assay, and western blotting to validate that SA bound to and inhibited PI3K activity, thereby reducing the downstream phosphorylation of AKT and mTOR. Notably, the PI3K activator Recilisib weakened the inhibitory effect of SA on PA-induced p-AKT and COL1a1 in LX-2 cells, further confirming the dependence of SA on PI3K activity. In conclusion, we identified SA as a potential natural PI3K inhibitor and promising compound for the treatment of MASH.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117305"},"PeriodicalIF":5.6,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145003983","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New insights into gut-liver axis in advanced liver diseases: A promising therapeutic target","authors":"Yunqi Xing,&nbsp;Yanghao Ou,&nbsp;Yujie Wang,&nbsp;Luming Hou,&nbsp;Junfeng Zhu","doi":"10.1016/j.bcp.2025.117284","DOIUrl":"10.1016/j.bcp.2025.117284","url":null,"abstract":"<div><div>The gut-liver axis constitutes a bidirectional communication network that integrates the microbial microenvironment, metabolism, and immune signals between the gut and the liver. Currently, there is compelling evidence indicating that the overall dysfunction of the gut-liver axis is a pivotal driver in the pathogenesis of advanced liver diseases. This review focuses on the latest research progress regarding various components of the intestinal barrier and how these components contribute to the onset and progression of cirrhosis and its complications. Chronic exposure to multifactorial stressors can result in irreversible damage to intestinal physical barriers, microbial dysbiosis, and immune dysregulation. These cumulative perturbations within the gut-liver axis promote pathogenic microbial translocation, initiate systemic inflammatory responses, and expedite disease progression. A more in-depth understanding of the gut-liver crosstalk mechanism is anticipated to offer novel therapeutic strategies for restoring microbiota-targeted intestinal homeostasis, which may lead to functional recompensation in decompensated cirrhosis.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117284"},"PeriodicalIF":5.6,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145005852","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}