Pharmacological research最新文献

{"title":"SLMO2 promotes chemoresistance in glioblastoma by regulating BNIP3-dependent mitophagy via the NF-κB/HIF-1α axis.","authors":"Ning Yang, Yuan Qiao, Jing Wu, Chao Niu, Jianpeng Wang, Shiming Sun, Chunyan Liu, Jingtao Chen, Shan Zhu","doi":"10.1016/j.phrs.2026.109688","DOIUrl":"10.1016/j.phrs.2026.109688","url":null,"abstract":"<p><p>Glioblastoma (GBM) is a highly aggressive malignancy, with chemoresistance acting as a major hurdle that severely limits clinical efficacy and long-term prognosis. Mitophagy, a core mechanism of mitochondrial quality control, enables tumor cells to adapt to chemotherapy-induced stress and maintain survival. However, its regulatory mechanism in GBM chemoresistance remains poorly understood. Here, we identify SLMO2 as a key factor mediating chemoresistance in GBM. Low-dose TMZ induces protective mitophagy, whereas SLMO2 knockdown abrogates this autophagic defense, thereby sensitizing GBM cells to TMZ-induced apoptosis. Mechanistically, TMZ treatment upregulates SLMO2, which potently activates HIF-1α signaling to transcriptionally drive BNIP3-mediated mitophagy, a process dependent on ROS-NF-κB signaling. Notably, this SLMO2-mediated cascade is also engaged under cisplatin-induced stress, indicating a broader role in chemoresistance. Collectively, our findings reveal that SLMO2 promotes chemoresistance in GBM by regulating BNIP3-mediated mitophagy. Targeting SLMO2 disrupts mitochondrial homeostasis by this process, offering a novel therapeutic strategy for enhancing chemosensitivity in GBM.</p>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":" ","pages":"109688"},"PeriodicalIF":12.2,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149183845","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":"Prenatal exposure to maternal SARS-CoV-2 infection leads to altered neuro-immune biomarker profiles at birth.","authors":"Giulia Bertoni, Alessandro Rossi, Patrizia Colapietro, Cecilia Zen, Gabriella Gaudioso, Rosamaria Silipigni, Angelo Iannielli, Marco Rasile, Nicola Persico, Grazia Volpe, Michela Matteoli, Silvia M Tabano, Giuliana Fossati, Elisabetta Menna","doi":"10.1016/j.phrs.2026.109682","DOIUrl":"https://doi.org/10.1016/j.phrs.2026.109682","url":null,"abstract":"<p><p>Maternal infection during pregnancy can induce immune-mediated biological adaptations that influence fetal neurodevelopment. Although vertical transmission of SARS-CoV-2 is uncommon, the impact of maternal infection on fetal neuroimmune signaling remains poorly characterized. We investigated whether prenatal exposure to maternal SARS-CoV-2 infection is associated with alterations in circulating neuroimmune biomarkers detectable at birth. In this case-control study, 28 women with SARS-CoV-2 infection during pregnancy and 61 uninfected controls were enrolled. Maternal and cord blood samples were collected at delivery. Following an initial inflammatory screening, neuro-specific biomarkers (NfL, Tau, P-Tau217, GFAP, S100β, α-Synuclein) and PTX3 were measured. Correlation network analyses, PTX3 promoter methylation assessment, and haplotype stratification analyses were also performed. Systemic inflammatory mediators did not differ significantly between groups. In contrast, neonates exposed to maternal SARS-CoV-2 infection exhibited significantly lower cord blood concentrations of GFAP, NfL, and P-Tau217 and increased α-Synuclein levels compared with controls. Tau showed a decreasing trend, whereas S100β and PTX3 remained unchanged. Network analyses revealed reduced cytokine connectivity but enhanced interactions among neuro-specific biomarkers. Although PTX3 promoter methylation was unchanged, the PTX3 h2/h2 haplotype appeared to modulate biomarker interaction patterns. To our knowledge, this is the first study to characterize a circulating neuro-specific biomarker signature in neonates prenatally exposed to maternal SARS-CoV-2 infection. This supports the utility of neuroimmune biomarker networks as translational tools to investigate the biological consequences of maternal immune activation during pregnancy.</p>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":" ","pages":"109682"},"PeriodicalIF":12.2,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149183820","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":"From Toxicity to Therapy: Probiotics and Novel Adsorbents in Aflatoxin Detoxification.","authors":"Ziying Huang, Chun Xie, Guang Yang, Siqin Li, Huanling Wu, Yinglan Nie, Hongmei Li, Bingbing Liu, Mengyao Du, Linjie Zhang, Zhengyun Jiang, Xin He, Elaine Lai-Han Leung, Jiang Ma, Ji Yang","doi":"10.1016/j.phrs.2026.109661","DOIUrl":"https://doi.org/10.1016/j.phrs.2026.109661","url":null,"abstract":"<p><p>Aflatoxins (AFs), toxic secondary metabolites primarily produced by Aspergillus flavus and A. parasiticus, remain a serious global health challenge due to both acute and particularly chronic toxicity. Unlike acute toxicity, chronic low-dose exposure to AFs is insidious and cumulative, leading to long-term effects such as immune dysfunction, growth retardation, and carcinogenesis. These outcomes are often underestimated, underscoring the importance of preventive strategies over therapeutic interventions. Although pharmacological agents have been investigated to inhibit CYP450-mediated bioactivation or enhance detoxification, their efficacy remains limited, particularly in reversing established damage. To address these limitations, recent efforts have shifted toward mechanism-based protective strategies, including interventions that block aflatoxin B1 (AFB₁) activation, enhance detoxification, and restore host defense. Recent evidence indicates that phytochemicals and probiotics exert promising multimodal activities, including attenuation of oxidative stress, inhibition of DNA adduct formation, and restoration of gut-microbiota-immune balance. For example, carnosic acid has a good free radical scavenging capacity, kolaviron could suppress abnormal DNA synthesis, and Bifidobacterium breve BAA-2849 may mitigate AFB₁-induced injury partly through gut microbiota remodeling and barrier protection. Furthermore, novel materials capable of adsorbing AFs can mitigate intoxication by reducing AFs levels. In this review, we critically synthesize advances in AFs toxicology and detoxification strategies, with particular emphasis on underlying mechanisms. We highlight probiotics and novel materials that detoxify or reduce AFs, proposing them as promising candidates for future research aimed at propelling therapeutic strategies. By identifying research gaps and outlining translational prospects, this review seeks to guide the development of effective and clinically applicable pharmacological strategies to mitigate AFs-associated health risks.</p>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":" ","pages":"109661"},"PeriodicalIF":12.2,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149113464","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":"Activation of the EPO-EPOR axis enhances dopamine agonist sensitivity in prolactinoma through mitochondrial STAT5A-mediated suppression of mtDNA transcription.","authors":"Xiang Guo, Linpeng Xu, Zihan Wang, Zisheng Yan, Biao Xing, Qian Jiang, Sihan Li, Quanji Wang, Jian Chen, Yuefeng Zhu, Chunlei Tian, Kai Shu, Ting Lei, Junwen Wang","doi":"10.1016/j.phrs.2026.109654","DOIUrl":"https://doi.org/10.1016/j.phrs.2026.109654","url":null,"abstract":"<p><strong>Background: </strong>Prolactinomas are among the most common pituitary neuroendocrine tumors (PitNETs). Although dopamine agonists (DAs) serve as the first-line medical treatment for prolactinomas, approximately 10-30% of patients exhibit DA resistance, underscoring the need for novel sensitization strategies.</p><p><strong>Methods: </strong>A clinical cohort was analyzed to determine the correlation between serum erythropoietin (EPO) levels and responsiveness to DAs in patients with prolactinomas. To evaluate the DA-sensitizing effect of recombinant EPO, we employed both in vitro and in vivo prolactinoma models. Integrated RNA sequencing and metabolomic profiling were performed to characterize the transcriptional alterations and metabolic reprogramming associated with EPO-mediated DA sensitization. Finally, immunofluorescence staining and subcellular fractionation were used to examine the subcellular localization of STAT5A, while ChIP-qPCR demonstrated its distinct enrichment at regulatory regions of mitochondrial DNA (mtDNA).</p><p><strong>Results: </strong>In our clinical cohort, we observed that serum erythropoietin (EPO) levels were positively correlated with DA responsiveness. Consistently, in vitro and in vivo prolactinoma models demonstrated that supplementation with the recombinant EPO epobis significantly enhanced DA efficacy. Mechanistically, epobis activated erythropoietin receptor (EPOR) signaling and exposed a metabolic vulnerability in prolactinomas by promoting the mitochondrial translocation of STAT5A and suppressing mtDNA transcription. This process impaired mitochondrial respiration and amplified mitochondrial reactive oxygen species (mitoROS) accumulation, ultimately exacerbating DA-induced apoptosis.</p><p><strong>Conclusion: </strong>Our findings reveal that EPO-EPOR signaling sensitizes prolactinomas to DAs by exploiting a mitochondrial metabolic vulnerability. The clinical association between serum EPO levels and DA responsiveness in patients highlights the clinical relevance of this pathway, while the co-administration of epobis with DAs represents a promising translational strategy for overcoming DA resistance.</p>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":" ","pages":"109654"},"PeriodicalIF":12.2,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149113492","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":"Corrigendum to \"CircBIRC6 facilitates the malignant progression via miR-488/GRIN2D-mediated CAV1-autophagy signal axis in gastric cancer\" [Pharmacol. Res. 202 (2024) 107127].","authors":"Zhiyuan Tang, Jieying Li, Bing Lu, Xiaojing Zhang, Lei Yang, Yue Qi, Sutian Jiang, Qianqian Wu, Yingjing Wang, Tong Cheng, Manyu Xu, Pingping Sun, Xudong Wang, Kai Miao, Han Wu, Jianfei Huang","doi":"10.1016/j.phrs.2026.109649","DOIUrl":"https://doi.org/10.1016/j.phrs.2026.109649","url":null,"abstract":"","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":" ","pages":"109649"},"PeriodicalIF":12.2,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149075592","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":"An FDA‑approved dicarboxylic acid allosterically targets PNPLA3 to resolve osteoarthritis.","authors":"Zhiyuan Guan, Ke Zhao, Wenyu Xiao, Zhiqiang Guan, Jin Xiao, Xuehan Jin, Shengfu Liu, Qin Yin, Liying Luo","doi":"10.1016/j.phrs.2026.109644","DOIUrl":"https://doi.org/10.1016/j.phrs.2026.109644","url":null,"abstract":"<p><p>Osteoarthritis (OA) lacks disease‑modifying therapies. The infrapatellar fat pad (IPFP) is hypothesized to regulate joint metabolism, but its molecular effectors are unknown. We investigated whether IPFP‑derived metabolites protect cartilage via lipid‑metabolizing enzymes.</p><p><strong>Methods: </strong>Non‑targeted metabolomics, IPFP excision/transplantation, single‑cell RNA‑seq, molecular dynamics, enzyme kinetics, and AAV‑mediated gene silencing were used in patient samples and the DMM mouse model.</p><p><strong>Results: </strong>Azelaic acid (AA) was the most significantly reduced metabolite in OA IPFP, and its levels correlated inversely with KL grade and WOMAC scores. IPFP excision substantially depletes joint AA (to ~8% of sham levels) and aggravates cartilage damage, while AA supplementation rescued the phenotype. Single‑cell sequencing identified a subset of metabolic chondrocytes (MetCs) that upregulate PNPLA3 upon IPFP loss. AA directly bound PNPLA3 with high affinity (Kd = 4.9μM) at a previously unrecognized allosteric site (>15Å from the catalytic triad), causing non-competitive inhibition (Ki = 12.4μM). Selectivity profiling against a panel of seven lipases, 50 kinases, and 50 GPCRs confirmed high selectivity for PNPLA3 within the tested panels (selectivity index >40). This inhibition was conserved in human primary OA chondrocytes and abolished by K42A mutation. PNPLA3 knockdown by AAV‑shPNPLA3 ameliorated OA, but its effect was lost in IPFP‑deficient mice, establishing an IPFP-AA-PNPLA3 axis.</p><p><strong>Conclusion: </strong>IPFP‑derived AA protects against OA by allosterically and selectively inhibiting PNPLA3‑driven lipolysis in MetCs. Because AA is already FDA‑approved for topical use, intra‑articular repurposing is immediately testable. Preserving IPFP integrity or delivering AA offers a first‑in‑class metabolism‑targeted therapy for OA.</p>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":" ","pages":"109644"},"PeriodicalIF":12.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149063693","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":"Corrigendum to \"Restoring lysosomal proteostasis reverses steatohepatitis and fibrosis in experimental MASH\" [Pharmacol. Res. 232 (2026) 108427].","authors":"Dylan Mastrippolito, Lauriane Gur, Malia Lasalo, Lara El Kaakour, Cindy Verdot, Franck Coste, Sébastien Blaise, Sylviane Muller","doi":"10.1016/j.phrs.2026.108480","DOIUrl":"https://doi.org/10.1016/j.phrs.2026.108480","url":null,"abstract":"","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":" ","pages":"108480"},"PeriodicalIF":12.2,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149025732","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":"Drug resistance in cancer radiotherapy: From mechanisms to overcoming strategies.","authors":"Yang Chen, Chao-Yun Cai, Xiao-Chen Xu, Zheng Yang, Jia Li, Qingming Pan, Lei Wang, Wei Luo, Zhe-Sheng Chen, Leli Zeng, Yihang Pan","doi":"10.1016/j.phrs.2026.108380","DOIUrl":"10.1016/j.phrs.2026.108380","url":null,"abstract":"<p><p>Radiotherapy is frequently combined with chemotherapy, targeted therapy and immunotherapy to improve the efficacy of cancer treatment. Nevertheless, some radioresistant cancer cells seem to possess higher drug resistance, leading to failure of cancer treatment. Thus, it is crucial to explore the mechanisms of drug resistance in cancer RT. This review outlines molecular, cellular, and microenvironmental adaptations in cancer RT. These adaptations confer enhanced chemotherapy resistance in cancer cells surviving from ionizing radiation (IR). In addition, RT also activates oncogene signaling pathways, induces epigenetic remodeling and alters post-translational modifications, collectively driving resistance to targeted therapy. RT alters tumor intrinsic properties, promotes immunosuppressive effects and remodels TME, thus inducing immunotherapy resistance. Various emerging strategies including phytochemicals, small molecules, synthetic compounds, macromolecules, nanoparticles, photodynamic therapy (PDT), photothermal therapy (PTT), MicroRNA (miRNA) therapy, PROTACs, adoptive cell therapies, and engineered Salmonella, have been developed to overcome radioresistance and drug resistance in cancer RT. We highlight the importance of evaluating therapeutic effects and side effects of these emerging strategies. Through summarizing mechanisms and emerging strategies for drug resistance in cancer RT, this review aims to clarify obstacles in combined cancer treatment and guide future direction of research on cancer therapy.</p>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":" ","pages":"108380"},"PeriodicalIF":12.2,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148713460","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":"From indirect regulation to multi-layered metabolic control in MASLD: Multi-receptor agonism and microbiota-metabolite functional convergence.","authors":"Sini Zhou, Ling Dong","doi":"10.1016/j.phrs.2026.108369","DOIUrl":"10.1016/j.phrs.2026.108369","url":null,"abstract":"<p><p>Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown clinical efficacy in metabolic dysfunction-associated steatotic liver disease (MASLD), yet their therapeutic performance appears limited in several recurring settings, including advanced fibrosis, metabolically milder populations, and treatment discontinuation. These limitations suggest that treatment responses are shaped not only by pharmacological potency, but also by the regulatory systems through which GLP-1RAs act. Here, we propose a conceptual multi-layered framework in which GLP-1R-based therapies improve hepatic outcomes predominantly, although not exclusively, through indirect and systemic metabolic regulation. Within this framework, therapeutic responses may be influenced by the integrity of intrahepatic and systemic signaling networks, the magnitude of baseline metabolic perturbation, and the persistence of pharmacological input, which can be interpreted as structural, contextual, and temporal constraints. Multi-receptor agonists may partially mitigate these constraints by expanding regulatory inputs through glucose-dependent insulinotropic polypeptide receptor (GIPR) and glucagon receptor (GCGR) co-activation. However, receptor-level modulation alone may remain insufficient to ensure durable responses after treatment withdrawal. We further discuss the gut microbiota and its metabolites as a candidate system-level regulatory layer that integrates host metabolic, immune, and endocrine signaling. Across diverse interventions, convergence appears more consistent at the level of microbiota-associated metabolic functions than taxonomic composition, but its causal significance remains incompletely established. Cross-intervention convergence analysis may therefore serve as a hypothesis-generating strategy to identify recurrent microbiota-metabolite axes with potential mechanistic and therapeutic relevance.</p>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":" ","pages":"108369"},"PeriodicalIF":12.2,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148697609","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":"Multifaceted role of DEPP1: Linking oxidative stress with autophagy, and beyond.","authors":"Chuxin Zhang, Jiahao Wu, Jinhua Han, Sicheng Feng, Jiahui Gao, Fafeng Cheng, Qingguo Wang, Changxiang Li, Xueqian Wang","doi":"10.1016/j.phrs.2026.108381","DOIUrl":"10.1016/j.phrs.2026.108381","url":null,"abstract":"<p><p>Decidual protein induced by progesterone 1 (DEPP1), also known as DEPP or C10ORF10, was originally identified as a progesterone-induced protein in endometrial stromal cells. Over the past two decades, research has progressively elucidated its involvement in various biological processes such as energy metabolism, redox regulation, and cellular autophagy. Additionally, DEPP1 has been implicated in the pathogenesis of several diseases, including diabetes, atherosclerosis, ischemic cardiomyopathy, breast cancer, and colon cancer. In this review, we systematically summarise the research progress on DEPP1, with particular emphasis on its molecular mechanisms in the crosstalk between oxidative stress and autophagy. Its cellular localization and functional uniqueness are discussed within the context of the classical redox-autophagy regulatory network. Furthermore, key issues in DEPP1 research and its potential translational applications are discussed to provide insights and perspectives for future studies centred on DEPP1.</p>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":" ","pages":"108381"},"PeriodicalIF":12.2,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148713372","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}