Heart failure is a chronic condition with a poor prognosis, and the development of new treatments is an urgent necessity. Extracellular heat shock protein 90 (eHsp90) has been observed to increase in heart failure. However, the pathophysiological role of extracellular Hsp90 (eHsp90) in heart failure development remains unclear. Thus, this study aimed to examine the effects of the anti-Hsp90 antibody 1G6-D7, an eHsp90 inhibitor, on cardiac fibrosis induced by pressure overload. Eight-week-old male C57Bl/6N mice underwent transverse aortic constriction (TAC). Beginning 2 weeks after surgery, the anti-Hsp90 antibody or normal IgG was administered intravenously every 2 weeks. Mice treated with normal IgG developed chronic heart failure with severe myocardial fibrosis 8 weeks after TAC. By contrast, administration of the anti-Hsp90 antibody to the TAC mice partially attenuated myocardial fibrosis and improved cardiac function. The fibronectin level in the myocardial tissue and the interaction between Hsp90 and fibronectin increased in the TAC mice treated with normal IgG. Conversely, these pathophysiological changes were mitigated in the TAC mice treated with the anti-Hsp90 antibody. The results of this study suggest that eHsp90 contributes to cardiac fibrosis by mediating fibronectin in the extracellular space. Furthermore, treatment with the anti-Hsp90 antibody attenuated cardiac fibrosis, which is associated with decreased fibronectin levels. The results of this study indicate eHsp90 as a novel extracellular target molecule for treating heart failure. In addition, our findings also suggested that anti-Hsp90 antibody hold considerable promise as potential pharmaceutical agents for the treatment of heart failure by targeting eHsp90.
{"title":"Treatment with anti-Hsp90 antibody mitigates fibronectin-related cardiac fibrosis induced by pressure overload in mice","authors":"Tetsuro Marunouchi, Takuma Murakami, Kano Yamaguchi, Kotone Hiraga, Haruka Ban, Kouichi Tanonaka","doi":"10.1016/j.bcp.2026.117780","DOIUrl":"10.1016/j.bcp.2026.117780","url":null,"abstract":"<div><div>Heart failure is a chronic condition with a poor prognosis, and the development of new treatments is an urgent necessity. Extracellular heat shock protein 90 (eHsp90) has been observed to increase in heart failure. However, the pathophysiological role of extracellular Hsp90 (eHsp90) in heart failure development remains unclear. Thus, this study aimed to examine the effects of the anti-Hsp90 antibody 1G6-D7, an eHsp90 inhibitor, on cardiac fibrosis induced by pressure overload. Eight-week-old male C57Bl/6N mice underwent transverse aortic constriction (TAC). Beginning 2 <!--> <!-->weeks after surgery, the anti-Hsp90 antibody or normal IgG was administered intravenously every 2 weeks. Mice treated with normal IgG developed chronic heart failure with severe myocardial fibrosis 8 weeks after TAC. By contrast, administration of the anti-Hsp90 antibody to the TAC mice partially attenuated myocardial fibrosis and improved cardiac function. The fibronectin level in the myocardial tissue and the interaction between Hsp90 and fibronectin increased in the TAC mice treated with normal IgG. Conversely, these pathophysiological changes were mitigated in the TAC mice treated with the anti-Hsp90 antibody. The results of this study suggest that eHsp90 contributes to cardiac fibrosis by mediating fibronectin in the extracellular space. Furthermore, treatment with the anti-Hsp90 antibody attenuated cardiac fibrosis, which is associated with decreased fibronectin levels. The results of this study indicate eHsp90 as a novel extracellular target molecule for treating heart failure. In addition, our findings also suggested that anti-Hsp90 antibody hold considerable promise as potential pharmaceutical agents for the treatment of heart failure by targeting eHsp90.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"247 ","pages":"Article 117780"},"PeriodicalIF":5.6,"publicationDate":"2026-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146148954","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}
Pub Date : 2026-02-06DOI: 10.1016/j.bcp.2026.117772
Jiamin Xie, Xiaojuan Pan, Yan Xia
Hepatocellular carcinoma (HCC) is a lethal malignancy with limited therapeutic options. Cellular senescence exerts a critical role in tumor progression, but the regulatory mechanisms remain unclear. This study investigates the role of pyruvate dehydrogenase phosphatase 1 (PDP1) in modulating senescence-associated malignant progression in HCC. Our study suggests that PDP1 is upregulated in patients with HCC and is significantly associated with poor prognosis. Functionally, PDP1 induces cellular senescence, activates cyclic adenosine monophosphate (cAMP)/Ca2+ signaling, and promotes senescence-associated secretory phenotype (SASP)-driven epithelial-mesenchymal transition (EMT), stemness, and malignant progression. Xenograft models further demonstrate that PDP1 enhances tumor growth in vivo, accompanied by activation of senescence-associated pathways, including p16, p21, cAMP, and Ca2+. Adenylyl cyclase 5 (ADCY5), a membrane-associated enzyme responsible for catalyzing ATP into cAMP, is identified as a critical downstream mediator of these effects and serves as a major source of intracellular cAMP production. Mechanistically, PDP1 suppression enhances glycolysis and histone H3 lysine 18 lactylation (H3K18la), a recently identified lactate-derived epigenetic modification, leading to activation of DNA methyltransferase 1 (DNMT1), the primary enzyme maintaining DNA methylation patterns, and subsequent ADCY5 promoter hypermethylation and transcriptional silencing. Importantly, glycolysis inhibition restores senescence and reverses PDP1-driven malignant phenotypes. Collectively, these findings identify that PDP1 drives senescence-associated malignant progression in HCC by linking glycolytic regulation, histone lactylation, and DNA methylation to the control of ADCY5 expression and subsequent cAMP/Ca2+ signaling, underscoring its potential as a therapeutic target.
{"title":"PDP1 drives hepatocellular carcinoma progression by regulating senescence through the cAMP/Ca2+ signaling pathway","authors":"Jiamin Xie, Xiaojuan Pan, Yan Xia","doi":"10.1016/j.bcp.2026.117772","DOIUrl":"10.1016/j.bcp.2026.117772","url":null,"abstract":"<div><div>Hepatocellular carcinoma (HCC) is a lethal malignancy with limited therapeutic options. Cellular senescence exerts a critical role in tumor progression, but the regulatory mechanisms remain unclear. This study investigates the role of pyruvate dehydrogenase phosphatase 1 (PDP1) in modulating senescence-associated malignant progression in HCC. Our study suggests that PDP1 is upregulated in patients with HCC and is significantly associated with poor prognosis. Functionally, PDP1 induces cellular senescence, activates cyclic adenosine monophosphate (cAMP)/Ca<sup>2+</sup> signaling, and promotes senescence-associated secretory phenotype (SASP)-driven epithelial-mesenchymal transition (EMT), stemness, and malignant progression. Xenograft models further demonstrate that PDP1 enhances tumor growth <em>in vivo</em>, accompanied by activation of senescence-associated pathways, including p16, p21, cAMP, and Ca<sup>2+</sup>. Adenylyl cyclase 5 (ADCY5), a membrane-associated enzyme responsible for catalyzing ATP into cAMP, is identified as a critical downstream mediator of these effects and serves as a major source of intracellular cAMP production. Mechanistically, PDP1 suppression enhances glycolysis and histone H3 lysine 18 lactylation (H3K18la), a recently identified lactate-derived epigenetic modification, leading to activation of DNA methyltransferase 1 (DNMT1), the primary enzyme maintaining DNA methylation patterns, and subsequent ADCY5 promoter hypermethylation and transcriptional silencing. Importantly, glycolysis inhibition restores senescence and reverses PDP1-driven malignant phenotypes. Collectively, these findings identify that PDP1 drives senescence-associated malignant progression in HCC by linking glycolytic regulation, histone lactylation, and DNA methylation to the control of ADCY5 expression and subsequent cAMP/Ca<sup>2+</sup> signaling, underscoring its potential as a therapeutic target.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"247 ","pages":"Article 117772"},"PeriodicalIF":5.6,"publicationDate":"2026-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146140956","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}
Pub Date : 2026-02-06DOI: 10.1016/j.bcp.2026.117773
Anna Piotrowska , Joanna Starnowska-Sokół , Katarzyna Ciapała , Justyna Barut , Agata Ciechanowska , Klaudia Kwiatkowski , Ewelina Rojewska , Katarzyna Pawlik , Grzegorz Kreiner , Joanna Mika
The neuroimmune system is known to be pathologically activated after nerve injury and prolonged exposure to opioids. Whereas previous studies have predominantly focused on the involvement of individual chemokine receptors in this phenomenon, dual CCR2/CCR5 blockade with cenicriviroc represents a novel therapeutic strategy towards greater efficacy in alleviating hypersensitivity. In this study, the expression of opioid (MOR, DOR) and chemokine (CCR2, CCR5) receptors in the spinal cord was assessed by immunohistochemistry after chronic constriction injury (CCI) of the sciatic nerve. Analgesic effects of cenicriviroc were evaluated following intraperitoneal administration of cenicriviroc in behavioral tests (von Frey, cold plate) after single (both sexes) and repeated treatment (alone or with morphine in males). Motor coordination and spontaneous locomotor activity were also tested. Spinal protein levels (p-MOR^S363, p-DOR^S363, CCR2, CCR5, IBA1, GFAP) were analyzed by Western blot. Immunostaining showed that CCR5 and MOR were expressed exclusively by neurons, whereas CCR2 colocalized with neurons, astrocytes, microglia, and/or macrophages, and DOR with neurons and astrocytes. A single intraperitoneal cenicriviroc administration alleviated hypersensitivity in CCI-subjected mice. Unlike morphine, cenicriviroc did not induce tolerance over 16 days of repeated treatment. Moreover, cenicriviroc attenuated nerve injury-induced upregulation of IBA1 at all examined time points and reduced GFAP expression at day 16, which was accompanied by a decrease in CCR2 levels. Cenicriviroc exerts sustained analgesia by simultaneously blocking CCR2 and CCR5 - particularly CCR2 signaling in neurons and glia - which appears to be key to its efficacy. These findings highlight cenicriviroc as a promising, translational candidate for neuropathic pain therapy.
{"title":"CCR2/CCR5 antagonism with cenicriviroc relieves neuropathic pain induced by sciatic nerve injury and delays morphine tolerance in mice","authors":"Anna Piotrowska , Joanna Starnowska-Sokół , Katarzyna Ciapała , Justyna Barut , Agata Ciechanowska , Klaudia Kwiatkowski , Ewelina Rojewska , Katarzyna Pawlik , Grzegorz Kreiner , Joanna Mika","doi":"10.1016/j.bcp.2026.117773","DOIUrl":"10.1016/j.bcp.2026.117773","url":null,"abstract":"<div><div>The neuroimmune system is known to be pathologically activated after nerve injury and prolonged exposure to opioids. Whereas previous studies have predominantly focused on the involvement of individual chemokine receptors in this phenomenon, dual CCR2/CCR5 blockade with cenicriviroc represents a novel therapeutic strategy towards greater efficacy in alleviating hypersensitivity. In this study, the expression of opioid (MOR, DOR) and chemokine (CCR2, CCR5) receptors in the spinal cord was assessed by immunohistochemistry after chronic constriction injury (CCI) of the sciatic nerve. Analgesic effects of cenicriviroc were evaluated following intraperitoneal administration of cenicriviroc in behavioral tests (von Frey, cold plate) after single (both sexes) and repeated treatment (alone or with morphine in males). Motor coordination and spontaneous locomotor activity were also tested. Spinal protein levels (p-MOR^S363, p-DOR^S363, CCR2, CCR5, IBA1, GFAP) were analyzed by Western blot. Immunostaining showed that CCR5 and MOR were expressed exclusively by neurons, whereas CCR2 colocalized with neurons, astrocytes, microglia, and/or macrophages, and DOR with neurons and astrocytes. A single intraperitoneal cenicriviroc administration alleviated hypersensitivity in CCI-subjected mice. Unlike morphine, cenicriviroc did not induce tolerance over 16 days of repeated treatment. Moreover, cenicriviroc attenuated nerve injury-induced upregulation of IBA1 at all examined time points and reduced GFAP expression at day 16, which was accompanied by a decrease in CCR2 levels. Cenicriviroc exerts sustained analgesia by simultaneously blocking CCR2 and CCR5 - particularly CCR2 signaling in neurons and glia - which appears to be key to its efficacy. These findings highlight cenicriviroc as a promising, translational candidate for neuropathic pain therapy.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"247 ","pages":"Article 117773"},"PeriodicalIF":5.6,"publicationDate":"2026-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146140906","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}
This study aimed to systematically investigate the inhibitory effect and potential molecular mechanism of oridonin derivative U07 on gastric cancer cells. By combining in vitro cell experiments and in vivo animal experiments, techniques including Cell Counting Kit-8 (CCK-8) assay, colony formation assay, Annexin V-FITC/Propidium Iodide (Annexin V/PI) double-staining flow cytometry, Western blot, wound healing assay, Transwell invasion assay, fluorescence staining, surface plasmon resonance (SPR), isothermal titration calorimetry (ITC), and molecular docking were used to analyze the impact of U07 on the biological behavior of gastric cancer cells and related molecular pathways. The results showed that U07 exhibited concentration-dependent cytotoxicity against HGC-27 and MKN-45 gastric cancer cells (with IC50 values of 2.5 μM and 2.6 μM, respectively). It could inhibit cell proliferation and induce apoptosis by activating the caspase-3 pathway, while significantly reducing cell migration and invasion abilities. U07 concentration-dependently increased the levels of reactive oxygen species (ROS) and lipid peroxidation, decreased glutathione (GSH) content, and increased malondialdehyde (MDA) content, thereby triggering ferroptosis; this effect could be blocked by the ferroptosis inhibitor Fer-1. Molecular studies confirmed that U07 could specifically bind to PLK4 kinase (KD = 6.2 μM detected by SPR, Kd = 0.65 μM detected by ITC) and inhibit its activity. PLK4 negatively regulates frroptosis pathway by directly binding to and transcriptionally activating Glutathione Peroxidase 4 (GPX4) / ferritin heavy chain 1 (FTH1). By downregulating PLK4, U07 further reduced the expression of ferroptosis marker proteins GPX4 and FTH1, and promoted lipid peroxidation and ROS production; however, overexpression of PLK4 could reverse these effects. In vivo experiments demonstrated that U07 could inhibit tumor growth in a dose-dependent manner, with the high-dose group (6 mg) showing an anti-tumor effect comparable to that of cisplatin, and it could downregulate the expression of PLK4 and GPX4 in tumor tissues. In conclusion, the oridonin derivative U07 exerts anti-gastric cancer effects by inhibiting cell proliferation, inducing apoptosis, and mediating ferroptosis via PLK4, providing a new candidate drug and therapeutic target for gastric cancer treatment.
{"title":"U07, a novel oridonin derivative, targets polo-like kinase 4 (PLK4) to induce ferroptosis in gastric cancer cells.","authors":"Yingpeng Huang, Yujie Lin, Qishuo Zhou, Yingqi Liang, Mingdong Lu, Fang Wu, Qiantong Dong, Jun Cheng","doi":"10.1016/j.bcp.2026.117774","DOIUrl":"https://doi.org/10.1016/j.bcp.2026.117774","url":null,"abstract":"<p><p>This study aimed to systematically investigate the inhibitory effect and potential molecular mechanism of oridonin derivative U07 on gastric cancer cells. By combining in vitro cell experiments and in vivo animal experiments, techniques including Cell Counting Kit-8 (CCK-8) assay, colony formation assay, Annexin V-FITC/Propidium Iodide (Annexin V/PI) double-staining flow cytometry, Western blot, wound healing assay, Transwell invasion assay, fluorescence staining, surface plasmon resonance (SPR), isothermal titration calorimetry (ITC), and molecular docking were used to analyze the impact of U07 on the biological behavior of gastric cancer cells and related molecular pathways. The results showed that U07 exhibited concentration-dependent cytotoxicity against HGC-27 and MKN-45 gastric cancer cells (with IC<sub>50</sub> values of 2.5 μM and 2.6 μM, respectively). It could inhibit cell proliferation and induce apoptosis by activating the caspase-3 pathway, while significantly reducing cell migration and invasion abilities. U07 concentration-dependently increased the levels of reactive oxygen species (ROS) and lipid peroxidation, decreased glutathione (GSH) content, and increased malondialdehyde (MDA) content, thereby triggering ferroptosis; this effect could be blocked by the ferroptosis inhibitor Fer-1. Molecular studies confirmed that U07 could specifically bind to PLK4 kinase (KD = 6.2 μM detected by SPR, Kd = 0.65 μM detected by ITC) and inhibit its activity. PLK4 negatively regulates frroptosis pathway by directly binding to and transcriptionally activating Glutathione Peroxidase 4 (GPX4) / ferritin heavy chain 1 (FTH1). By downregulating PLK4, U07 further reduced the expression of ferroptosis marker proteins GPX4 and FTH1, and promoted lipid peroxidation and ROS production; however, overexpression of PLK4 could reverse these effects. In vivo experiments demonstrated that U07 could inhibit tumor growth in a dose-dependent manner, with the high-dose group (6 mg) showing an anti-tumor effect comparable to that of cisplatin, and it could downregulate the expression of PLK4 and GPX4 in tumor tissues. In conclusion, the oridonin derivative U07 exerts anti-gastric cancer effects by inhibiting cell proliferation, inducing apoptosis, and mediating ferroptosis via PLK4, providing a new candidate drug and therapeutic target for gastric cancer treatment.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"117774"},"PeriodicalIF":5.6,"publicationDate":"2026-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146140925","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}
Pub Date : 2026-02-05DOI: 10.1016/j.bcp.2026.117777
Jiahui Zhang , Yaojun Wang , Chunlai Yin , Xiangyu Shi , Zujia Chen , Yingying Wang , Yueyue Li , Changyuan Wang , Jie Li , Jingjing Wu , Yongshun Zhao
Carboxylesterase 2 (CES2), a member of the serine hydrolase superfamily, plays a crucial role in catalyzing the hydrolysis of numerous endogenous and exogenous compounds containing ester bonds. The commonly used clinical drug irinotecan (CPT-11) exerts its anti-tumor effect by being hydrolyzed by CES2 to generate SN-38. Epimedium, a widely used traditional Chinese herb with multiple pharmacological properties, has not yet been characterized for its effects on CES2. Our study systematically evaluated the three principal bioactive components of Epimedium for their effects on CES2 activity, revealing that icaritin significantly activated this enzyme. In vitro, Western blot and RT-PCR assays demonstrated that icaritin significantly upregulated CES2 expression at both mRNA and protein levels. Furthermore, icaritin further enhanced CES2 expression by activating the PXR pathway and increased the protein level of P53. Molecular docking simulations demonstrated that the interation energy between CES2 and icaritin was significantly higher than that with cisplatin (a reported CES2 activator), which might suggest that CES2 has a higher affinity for icaritin than cisplatin. In vivo studies confirmed that icaritin increased the hydrolytic activity and protein expression of Ces in mouse liver and intestinal tissues with a concentration-dependent manner. In conclusion, icaritin can enhance the hydrolysis of irinotecan in vitro and in vivo, and this enhancement is related to the activation of CES2 and the increase of CES2 gene and protein expression. These findings have important clinical significance for reducing chemotherapy drug resistance in cancer patients.
{"title":"Icaritin enhances the antitumor efficacy of irinotecan by dual-targeting carboxylesterase 2 and p53 in vitro and in vivo","authors":"Jiahui Zhang , Yaojun Wang , Chunlai Yin , Xiangyu Shi , Zujia Chen , Yingying Wang , Yueyue Li , Changyuan Wang , Jie Li , Jingjing Wu , Yongshun Zhao","doi":"10.1016/j.bcp.2026.117777","DOIUrl":"10.1016/j.bcp.2026.117777","url":null,"abstract":"<div><div>Carboxylesterase 2 (CES2), a member of the serine hydrolase superfamily, plays a crucial role in catalyzing the hydrolysis of numerous endogenous and exogenous compounds containing ester bonds. The commonly used clinical drug irinotecan (CPT-11) exerts its anti-tumor effect by being hydrolyzed by CES2 to generate SN-38. Epimedium, a widely used traditional Chinese herb with multiple pharmacological properties, has not yet been characterized for its effects on CES2. Our study systematically evaluated the three principal bioactive components of Epimedium for their effects on CES2 activity, revealing that icaritin significantly activated this enzyme. <em>In vitro</em>, Western blot and RT-PCR assays demonstrated that icaritin significantly upregulated CES2 expression at both mRNA and protein levels. Furthermore, icaritin further enhanced CES2 expression by activating the PXR pathway and increased the protein level of P53. Molecular docking simulations demonstrated that the interation energy between CES2 and icaritin was significantly higher than that with cisplatin (a reported CES2 activator), which might suggest that CES2 has a higher affinity for icaritin than cisplatin. <em>In vivo</em> studies confirmed that icaritin increased the hydrolytic activity and protein expression of Ces in mouse liver and intestinal tissues with a concentration-dependent manner. In conclusion, icaritin can enhance the hydrolysis of irinotecan in vitro and in vivo, and this enhancement is related to the activation of CES2 and the increase of CES2 gene and protein expression. These findings have important clinical significance for reducing chemotherapy drug resistance in cancer patients.</div><div>Abbreviations: CES2, Carboxylesterase 2; CRC, Colorectal cancer; CPT-11, Irinotecan; CYP3A, Cytochrome P450 3A; NR, Nuclear receptor; P53, Tumor protein p53; PPAR-α, Peroxisome proliferator-activated receptor α; PXR, Pregnane X receptor; SN-38, 7-Ethyl-10-hydroxycamptothecin; UGT1A1, UDP-glucuronosyltransferase 1A1.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"247 ","pages":"Article 117777"},"PeriodicalIF":5.6,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146137154","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}
ADP-ribosylation is a versatile post-translational modification that governs fundamental processes, including DNA repair, transcription, and stress adaptation. Its homeostasis relies on the dynamic interplay between poly(ADP-ribose) polymerases (PARPs), which assemble mono- or poly-ADP-ribose (PAR) chains on target macromolecules, and ADP-ribosyl hydrolases, which dismantle them. Disruption of this balance leads to the accumulation of toxic PAR and cell death, revealing vulnerabilities that can be therapeutically exploited. PARP inhibitors (PARPis) have revolutionised the treatment of homologous recombination-deficient cancers via synthetic lethality. Yet, emerging resistance limits their long-term efficacy, underscoring the need for novel targets within ADP-ribose signalling. The poly(ADP-ribose) glycohydrolase (PARG), the principal enzyme involved in hydrolysing PAR, has emerged as a compelling candidate: its inhibition amplifies replication stress, drives mitotic catastrophe, and selectively kills cancer cells, particularly those reliant on PAR turnover for survival. Elevated PARG expression correlates with aggressive tumours and poor prognosis, positioning it as both a prognostic biomarker and therapeutic target. This review integrates recent structural and biochemical insights into PARG, highlighting the mechanisms of PAR reversal, regulatory control, and potential synthetic lethal interactions. We also discuss the discovery and development of selective PARG inhibitors, which promise to expand the therapeutic landscape, overcome PARPis resistance, and exploit vulnerabilities in replication-stressed cancers. By bridging mechanistic understanding with translational potential, targeting PARG represents a frontier in precision cancer therapy.
{"title":"The PARG frontier: mechanisms of PAR turnover and opportunities in precision oncology","authors":"Giuliana Catara , Gaetano Gerace , Raffaella Lauro , Luca Palazzo","doi":"10.1016/j.bcp.2026.117770","DOIUrl":"10.1016/j.bcp.2026.117770","url":null,"abstract":"<div><div>ADP-ribosylation is a versatile post-translational modification that governs fundamental processes, including DNA repair, transcription, and stress adaptation. Its homeostasis relies on the dynamic interplay between poly(ADP-ribose) polymerases (PARPs), which assemble mono- or poly-ADP-ribose (PAR) chains on target macromolecules, and ADP-ribosyl hydrolases, which dismantle them. Disruption of this balance leads to the accumulation of toxic PAR and cell death, revealing vulnerabilities that can be therapeutically exploited. PARP inhibitors (PARPis) have revolutionised the treatment of homologous recombination-deficient cancers via synthetic lethality. Yet, emerging resistance limits their long-term efficacy, underscoring the need for novel targets within ADP-ribose signalling. The poly(ADP-ribose) glycohydrolase (PARG), the principal enzyme involved in hydrolysing PAR, has emerged as a compelling candidate: its inhibition amplifies replication stress, drives mitotic catastrophe, and selectively kills cancer cells, particularly those reliant on PAR turnover for survival. Elevated PARG expression correlates with aggressive tumours and poor prognosis, positioning it as both a prognostic biomarker and therapeutic target. This review integrates recent structural and biochemical insights into PARG, highlighting the mechanisms of PAR reversal, regulatory control, and potential synthetic lethal interactions. We also discuss the discovery and development of selective PARG inhibitors, which promise to expand the therapeutic landscape, overcome PARPis resistance, and exploit vulnerabilities in replication-stressed cancers. By bridging mechanistic understanding with translational potential, targeting PARG represents a frontier in precision cancer therapy.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"247 ","pages":"Article 117770"},"PeriodicalIF":5.6,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146131127","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}
Pub Date : 2026-02-04DOI: 10.1016/j.bcp.2026.117771
Jun Liu , Shunfei Liu , Qiannan Ma , Yilin Xie , Xinyue Zeng , Chunyang Zhang , Panhui Guo , Zhiwei Gao , Xiangpeng Hu
Ulcerative colitis (UC) is a recurrent inflammatory bowel disease characterized by mucosal inflammation. Recently, the incidence rate of UC increases year by year, and patients diagnosed with UC usually have the poor quality of life. The search for effective treatments of UC remains a crucial research priority. Since traditional Chinese medicine (TCM) is an important treatment for UC, the components of these TCMs were analyzed. Our data indicated that Mairin was the common core component of TCMs with UC therapeutic effects, including Licorice, Paeoniae Radix Alba and Aucklandiae Radix. Recently, only one study reported that the hydroxamate of Mairin prevented colonic inflammation and fibrosis, and the function and mechanism of Mairin on UC were still obscure. Dextran sulfate sodium (DSS)-induced UC mice were alleviated after Mairin treatment. Mechanistically, RNA sequencing data indicated that Mairin treatment increased the levels of Irf4 and Cd5l. Molecular docking, drug affinity responsive target stability (DARTS) and immunofluorescence experiments were used to verify that Mairin interacted with EGFR and SRC, promoted IRF4 nuclear import in macrophages. ChIP analysis was verified that IRF4, as a transcription factor, interacted with Cd5l promoter, and Mairin treatment increased the mRNA and protein levels of CD5L. CD5L+ macrophages exhibited the high level of M2 phenotype markers, and M2-phenotype macrophages alleviated UC. That was to say, Mairin activated IRF4-CD5L pathway, polarized macrophages into M2-phenotype, and alleviated UC. Our study contributes to the exploration the therapeutic mechanism of Mairin and it also may provide insights for new therapeutic medicine of UC.
{"title":"Mairin polarizes Macrophages into M2-phenotype and alleviates Ulcerative colitis through activating IRF4-CD5L pathway","authors":"Jun Liu , Shunfei Liu , Qiannan Ma , Yilin Xie , Xinyue Zeng , Chunyang Zhang , Panhui Guo , Zhiwei Gao , Xiangpeng Hu","doi":"10.1016/j.bcp.2026.117771","DOIUrl":"10.1016/j.bcp.2026.117771","url":null,"abstract":"<div><div>Ulcerative colitis (UC) is a recurrent inflammatory bowel disease characterized by mucosal inflammation. Recently, the incidence rate of UC increases year by year, and patients diagnosed with UC usually have the poor quality of life. The search for effective treatments of UC remains a crucial research priority. Since traditional Chinese medicine (TCM) is an important treatment for UC, the components of these TCMs were analyzed. Our data indicated that Mairin was the common core component of TCMs with UC therapeutic effects, including <em>Licorice</em>, <em>Paeoniae Radix Alba</em> and <em>Aucklandiae Radix</em>. Recently, only one study reported that the hydroxamate of Mairin prevented colonic inflammation and fibrosis, and the function and mechanism of Mairin on UC were still obscure. Dextran sulfate sodium (DSS)-induced UC mice were alleviated after Mairin treatment. Mechanistically, RNA sequencing data indicated that Mairin treatment increased the levels of <em>Irf4</em> and <em>Cd5l</em>. Molecular docking, drug affinity responsive target stability (DARTS) and immunofluorescence experiments were used to verify that Mairin interacted with EGFR and SRC, promoted IRF4 nuclear import in macrophages. ChIP analysis was verified that IRF4, as a transcription factor, interacted with <em>Cd5l</em> promoter, and Mairin treatment increased the mRNA and protein levels of CD5L. CD5L<sup>+</sup> macrophages exhibited the high level of M2 phenotype markers, and M2-phenotype macrophages alleviated UC. That was to say, Mairin activated IRF4-CD5L pathway, polarized macrophages into M2-phenotype, and alleviated UC. Our study contributes to the exploration the therapeutic mechanism of Mairin and it also may provide insights for new therapeutic medicine of UC.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"247 ","pages":"Article 117771"},"PeriodicalIF":5.6,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146131138","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}
Pub Date : 2026-02-02DOI: 10.1016/j.bcp.2026.117769
Anjana Sajeev, Mukesh Kumar Manickasamy, Ravichandran Vishwa, Mohammed S Alqahtani, Mohamed Abbas, Gautam Sethi, Ajaikumar B Kunnumakkara
Cancer comprises a diverse group of complex diseases driven by genetic and epigenetic alterations that disrupt cellular signaling, metabolism, and cell death mechanisms. Despite significant advances in therapy, challenges such as tumor heterogeneity, treatment resistance, and escape from regulated cell death continue to impede curative outcomes. Among the various modes of regulated cell death, ferroptosis, an iron-dependent mechanism characterized by excessive lipid peroxidation and oxidative stress, has emerged as a promising therapeutic avenue in oncology. Notably, ferroptosis is intricately linked to iron homeostasis, providing a vulnerability that can be exploited by ferroptosis-targeted strategies in cancer, where iron metabolism is often dysregulated. This review provides a coherent account of the molecular mechanisms governing iron regulation and highlights how its imbalance can trigger ferroptosis. Additionally, we detail the molecular mechanisms of ferroptosis and summarize key regulatory networks, including system xc-, GPx4, and the FSP1/CoQ10/NAD(P)H axis. Further, the role of natural and synthetic ferroptosis inducers is critically discussed, especially their synergistic potential when combined with chemotherapy, radiotherapy, and immunotherapy. Furthermore, this review explores emerging evidence on the regulation of ferroptosis by non-coding RNAs, hormonal regulation of ferroptosis sensitivity, and nanoparticle-based ferroptosis therapeutic strategies. Finally, the clinical relevance of ferroptosis in cancer therapy is discussed. Overall, this manuscript presents ferroptosis as a promising therapeutic avenue, offering new insights into its integration with existing cancer treatment strategies.
{"title":"Iron homeostasis and ferroptosis: a converging axis in cancer therapy.","authors":"Anjana Sajeev, Mukesh Kumar Manickasamy, Ravichandran Vishwa, Mohammed S Alqahtani, Mohamed Abbas, Gautam Sethi, Ajaikumar B Kunnumakkara","doi":"10.1016/j.bcp.2026.117769","DOIUrl":"https://doi.org/10.1016/j.bcp.2026.117769","url":null,"abstract":"<p><p>Cancer comprises a diverse group of complex diseases driven by genetic and epigenetic alterations that disrupt cellular signaling, metabolism, and cell death mechanisms. Despite significant advances in therapy, challenges such as tumor heterogeneity, treatment resistance, and escape from regulated cell death continue to impede curative outcomes. Among the various modes of regulated cell death, ferroptosis, an iron-dependent mechanism characterized by excessive lipid peroxidation and oxidative stress, has emerged as a promising therapeutic avenue in oncology. Notably, ferroptosis is intricately linked to iron homeostasis, providing a vulnerability that can be exploited by ferroptosis-targeted strategies in cancer, where iron metabolism is often dysregulated. This review provides a coherent account of the molecular mechanisms governing iron regulation and highlights how its imbalance can trigger ferroptosis. Additionally, we detail the molecular mechanisms of ferroptosis and summarize key regulatory networks, including system x<sub>c</sub>-, GPx4, and the FSP1/CoQ10/NAD(P)H axis. Further, the role of natural and synthetic ferroptosis inducers is critically discussed, especially their synergistic potential when combined with chemotherapy, radiotherapy, and immunotherapy. Furthermore, this review explores emerging evidence on the regulation of ferroptosis by non-coding RNAs, hormonal regulation of ferroptosis sensitivity, and nanoparticle-based ferroptosis therapeutic strategies. Finally, the clinical relevance of ferroptosis in cancer therapy is discussed. Overall, this manuscript presents ferroptosis as a promising therapeutic avenue, offering new insights into its integration with existing cancer treatment strategies.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"117769"},"PeriodicalIF":5.6,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146117585","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}
Pub Date : 2026-02-02DOI: 10.1016/j.bcp.2026.117768
Nina K. Blum, Rainer K. Reinscheid
Perception and processing of salient sensory input is vital for every animal. While sensory systems continuously receive a vast amount of information, animal brains are challenged to distinguish between relevant, i.e. salient, and neutral or unnecessary content. Stimulus salience can depend on intensity but also motivational and attentional states. Perception of salient information affects both immediate response behaviors and memory formation, which are both critical for survival. Conversely, aberrant salience processing may contribute to disorders such as schizophrenia or drug addiction. Research in recent decades has described several G protein-coupled receptor (GPCR) systems as important regulators of salience processing in the brain. They include receptors activated by monoamines, neuropeptides and lipid molecules. Although salience attribution is a critical brain function, a comprehensive survey of involved GPCRs and their endogenous transmitters has, to our knowledge, not been compiled. This review aims to close this gap by providing an overview of GPCRs involved in salience processing.
{"title":"Why things get important: GPCRs in salience processing","authors":"Nina K. Blum, Rainer K. Reinscheid","doi":"10.1016/j.bcp.2026.117768","DOIUrl":"10.1016/j.bcp.2026.117768","url":null,"abstract":"<div><div>Perception and processing of salient sensory input is vital for every animal. While sensory systems continuously receive a vast amount of information, animal brains are challenged to distinguish between relevant, i.e. salient, and neutral or unnecessary content. Stimulus salience can depend on intensity but also motivational and attentional states. Perception of salient information affects both immediate response behaviors and memory formation, which are both critical for survival. Conversely, aberrant salience processing may contribute to disorders such as schizophrenia or drug addiction. Research in recent decades has described several G protein-coupled receptor (GPCR) systems as important regulators of salience processing in the brain. They include receptors activated by monoamines, neuropeptides and lipid molecules. Although salience attribution is a critical brain function, a comprehensive survey of involved GPCRs and their endogenous transmitters has, to our knowledge, not been compiled. This review aims to close this gap by providing an overview of GPCRs involved in salience processing.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"247 ","pages":"Article 117768"},"PeriodicalIF":5.6,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146117568","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}
Pub Date : 2026-02-01DOI: 10.1016/j.bcp.2026.117766
Xiaofei Wang , Xiao Hong , Wanting Liu , Yujun Xu , Roushi Chen , Fangyi Chen , Ke-Jian Wang , Luxi Wang
Pathogenic “non-cholera” Vibrio species of Vibrio parahaemolyticus (V. parahaemolyticus) and Vibrio vulnificus (V. vulnificus) frequently pose a serious threat to aquaculture security and public health by causing infectious diseases. In this study, we reported the discovery of a marine-sourced antimicrobial peptide (AMP) called Ajapocin, which identified through a sequence optimization strategy. Ajapocin exhibited potent activity against V. parahaemolyticus and V. vulnificus pathogens, with minimum inhibitory concentrations (MICs) of 6–12 μM—comparable to the clinical agent Polymyxin B (PMB). In vivo, a single administration of Ajapocin (1 mg/mL) displayed therapeutic efficacy in a zebrafish-Vibrio infection model. Multiple doses reduced bacterial burden and accelerated wound healing in a mouse model of V. vulnificus-infected skin wounds. Ajapocin showed no cytotoxicity in ZF4 cells and HaCaT cells at concentrations up to 32 μM. Notably, after intraperitoneal injection for 1 week, Ajapocin did not induce cumulative hepatic or renal toxicity, as confirmed by histopathology analysis and chemistry profiles. Mechanistically, membrane-interacting Ajapocin targeted negative cellular components, enhancing membrane permeation, inducing membrane depolarization, and ultimately causing membrane damage and bacterial dysfunction. Taken together, these results position Ajapocin as an appealing anti-Vibrio agent for combating vibriosis in both aquaculture and clinical settings.
{"title":"A Vibrio-susceptibility class of antimicrobial peptide Ajapocin via membranolytic pattern to combat “non-cholera” pathogens in vivo infection models","authors":"Xiaofei Wang , Xiao Hong , Wanting Liu , Yujun Xu , Roushi Chen , Fangyi Chen , Ke-Jian Wang , Luxi Wang","doi":"10.1016/j.bcp.2026.117766","DOIUrl":"10.1016/j.bcp.2026.117766","url":null,"abstract":"<div><div>Pathogenic “non-cholera” <em>Vibrio</em> species of <em>Vibrio parahaemolyticus</em> (<em>V. parahaemolyticus</em>) and <em>Vibrio vulnificus</em> (<em>V. vulnificus</em>) frequently pose a serious threat to aquaculture security and public health by causing infectious diseases. In this study, we reported the discovery of a marine-sourced antimicrobial peptide (AMP) called Ajapocin, which identified through a sequence optimization strategy. Ajapocin exhibited potent activity against <em>V. parahaemolyticus</em> and <em>V. vulnificus</em> pathogens, with minimum inhibitory concentrations (MICs) of 6–12 μM—comparable to the clinical agent Polymyxin B (PMB). <em>In vivo</em>, a single administration of Ajapocin (1 mg/mL) displayed therapeutic efficacy in a zebrafish-<em>Vibrio</em> infection model. Multiple doses reduced bacterial burden and accelerated wound healing in a mouse model of <em>V. vulnificus-</em>infected skin wounds. Ajapocin showed no cytotoxicity in ZF4 cells and HaCaT cells at concentrations up to 32 μM. Notably, after intraperitoneal injection for 1 week, Ajapocin did not induce cumulative hepatic or renal toxicity, as confirmed by histopathology analysis and chemistry profiles. Mechanistically, membrane-interacting Ajapocin targeted negative cellular components, enhancing membrane permeation, inducing membrane depolarization, and ultimately causing membrane damage and bacterial dysfunction. Taken together, these results position Ajapocin as an appealing anti-<em>Vibrio</em> agent for combating vibriosis in both aquaculture and clinical settings.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"247 ","pages":"Article 117766"},"PeriodicalIF":5.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146111975","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}
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