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}
Pub Date : 2026-01-31DOI: 10.1016/j.bcp.2026.117767
Maria Grazia Signorello
The effects of three polyamines, spermine, spermidine, and putrescine, on thrombin-induced platelet activation and function were investigated. Our findings demonstrate that polyamines significantly influence platelet activity, with spermine exhibiting the most pronounced effects. Polyamines dose-dependently were able to inhibit platelet aggregation and CD62P exposure induced by thrombin, as well as the rise in intracellular calcium concentration, indicating the involvement of polyamines in platelet activation signaling pathways. Beyond their effects on platelet function, polyamines show potent antioxidant activity. In thrombin-stimulated platelets, polyamines, and spermine in particular, inhibit reactive oxygen species and superoxide anion production, as well as the consequent lipid peroxidation, demonstrating a protective effect against oxidative stress. Furthermore, polyamines restored mitochondrial function by improving oxidative phosphorylation efficiency. Polyamines can restore the oxygen consumption rate and ATP production, indicating a role in maintaining cellular energy homeostasis under pro-thrombotic conditions. These findings suggest that polyamines, particularly spermine, could have an interesting therapeutic role since they can modulate platelet activation, oxidative stress, and oxidative phosphorylation efficiency. The restoration of platelet function through treatment with polyamines could have a protective effect against a pro-thrombotic state, which is involved in venous and arterial thrombosis, which contributes to cardiovascular diseases.
{"title":"Modulation of thrombin-induced human platelet activation and oxidative stress by polyamines","authors":"Maria Grazia Signorello","doi":"10.1016/j.bcp.2026.117767","DOIUrl":"10.1016/j.bcp.2026.117767","url":null,"abstract":"<div><div>The effects of three polyamines, spermine, spermidine, and putrescine, on thrombin-induced platelet activation and function were investigated. Our findings demonstrate that polyamines significantly influence platelet activity, with spermine exhibiting the most pronounced effects. Polyamines dose-dependently were able to inhibit platelet aggregation and CD62P exposure induced by thrombin, as well as the rise in intracellular calcium concentration, indicating the involvement of polyamines in platelet activation signaling pathways. Beyond their effects on platelet function, polyamines show potent antioxidant activity. In thrombin-stimulated platelets, polyamines, and spermine in particular, inhibit reactive oxygen species and superoxide anion production, as well as the consequent lipid peroxidation, demonstrating a protective effect against oxidative stress. Furthermore, polyamines restored mitochondrial function by improving oxidative phosphorylation efficiency. Polyamines can restore the oxygen consumption rate and ATP production, indicating a role in maintaining cellular energy homeostasis under pro-thrombotic conditions. These findings suggest that polyamines, particularly spermine, could have an interesting therapeutic role since they can modulate platelet activation, oxidative stress, and oxidative phosphorylation efficiency. The restoration of platelet function through treatment with polyamines could have a protective effect against a pro-thrombotic state, which is involved in venous and arterial thrombosis, which contributes to cardiovascular diseases.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"247 ","pages":"Article 117767"},"PeriodicalIF":5.6,"publicationDate":"2026-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146103709","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 : 2026-01-30DOI: 10.1016/j.bcp.2026.117756
Tsigereda Weldemichael, Md Abdul Hye Khan, John D. Imig
Nephrotoxicity is a significant adverse effect of many cancer chemotherapies, often limiting treatment success and complicating clinical management. The kidneys are essential for removing antineoplastic drugs and their metabolites through glomerular filtration and tubular secretion. Unfortunately, both traditional cytotoxic agents and newer targeted therapies can harm various parts of the nephron, including the renal vasculature. This damage can present clinically as proteinuria, hypertension, electrolyte imbalances, glomerulopathies, acute and chronic interstitial nephritis, acute kidney injury (AKI), and often progression to chronic kidney disease (CKD). Among cytotoxic drugs, anthracyclines, potent natural antibiotics, are widely used to treat a broad range of cancers. Doxorubicin (DOX), the most common anthracycline, is particularly effective but also linked to notable nephrotoxic effects. Doxorubicin-induced kidney damage is multifactorial, involving oxidative stress, inflammation, and apoptosis, which collectively impair renal structure and function. This review discusses the mechanisms behind doxorubicin-induced nephrotoxicity and emphasizes the urgent need for nephroprotective strategies. It also reviews current therapies under investigation to reduce renal damage caused by DOX, including natural compounds and pharmacological agents that target oxidative and inflammatory pathways, aiming to preserve renal function and improve the safety of chemotherapy treatments.
{"title":"Renoprotective approaches against anthracycline nephrotoxicity","authors":"Tsigereda Weldemichael, Md Abdul Hye Khan, John D. Imig","doi":"10.1016/j.bcp.2026.117756","DOIUrl":"10.1016/j.bcp.2026.117756","url":null,"abstract":"<div><div>Nephrotoxicity is a significant adverse effect of many cancer chemotherapies, often limiting treatment success and complicating clinical management. The kidneys are essential for removing antineoplastic drugs and their metabolites through glomerular filtration and tubular secretion. Unfortunately, both traditional cytotoxic agents and newer targeted therapies can harm various parts of the nephron, including the renal vasculature. This damage can present clinically as proteinuria, hypertension, electrolyte imbalances, glomerulopathies, acute and chronic interstitial nephritis, acute kidney injury (AKI), and often progression to chronic kidney disease (CKD). Among cytotoxic drugs, anthracyclines, potent natural antibiotics, are widely used to treat a broad range of cancers. Doxorubicin (DOX), the most common anthracycline, is particularly effective but also linked to notable nephrotoxic effects. Doxorubicin-induced kidney damage is multifactorial, involving oxidative stress, inflammation, and apoptosis, which collectively impair renal structure and function. This review discusses the mechanisms behind doxorubicin-induced nephrotoxicity and emphasizes the urgent need for nephroprotective strategies. It also reviews current therapies under investigation to reduce renal damage caused by DOX, including natural compounds and pharmacological agents that target oxidative and inflammatory pathways, aiming to preserve renal function and improve the safety of chemotherapy treatments.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"247 ","pages":"Article 117756"},"PeriodicalIF":5.6,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146099867","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 : 2026-01-30DOI: 10.1016/j.bcp.2026.117761
Ao Guo , Bijun Yang , Aolin Xiao Huang , Jie Ni , Yanhui Zhang , Qinlin Jiang , Yunwen Yan , Qichao Luo , Jing Yang , Bin Yuan
Glutamine metabolism is a key driver of tumor progression, yet the molecular basis and prognostic relevance of glutamine metabolism–related genes in breast cancer (BC) remain incompletely defined. In this study, integrated analysis of public datasets identified Actin-like protein 8 (ACTL8) as a key prognostic gene significantly upregulated in BC tissue and associated with poor patient survival. In vitro, shRNA knockdown of ACTL8 reduced MYC expression and its downstream targets SLC1A5 and GLS1, suppressing cell proliferation, migration and invasion. This disruption led to impaired redox homeostasis as evidenced by reduced GSH/GSSG and NADPH/NADP+ ratios. Mechanistically, MYC overexpression restored metabolic enzymes and phenotypes but failed to rescue p-AKT levels, confirming ACTL8 acts upstream of the PI3K/AKT/mTOR axis. Virtual screening identified Momordin Ic as a small molecule that directly interacts with ACTL8. Surface plasmon resonance (SPR) and Thermal shift assay (TSA) confirmed this high-affinity binding, which destabilized ACTL8 and promoted its ubiquitin–proteasome degradation. Moreover, ACTL8 knockdown significantly attenuated the sensitivity of BC cells to Momordin Ic treatment, confirming ACTL8 as the specific therapeutic target. In vivo, suppression of ACTL8 markedly reduced tumor growth. Together, these findings establish ACTL8 as a key oncogenic driver of BC progression. Targeting ACTL8 offers a novel strategy to disrupt glutamine-dependent metabolic reprogramming, and Momordin Ic represents a promising lead agent to combat ACTL8-driven BC.
{"title":"Momordin Ic suppresses breast cancer growth by targeting ACTL8‑dependent glutamine metabolism and PI3K/AKT/mTOR–MYC","authors":"Ao Guo , Bijun Yang , Aolin Xiao Huang , Jie Ni , Yanhui Zhang , Qinlin Jiang , Yunwen Yan , Qichao Luo , Jing Yang , Bin Yuan","doi":"10.1016/j.bcp.2026.117761","DOIUrl":"10.1016/j.bcp.2026.117761","url":null,"abstract":"<div><div>Glutamine metabolism is a key driver of tumor progression, yet the molecular basis and prognostic relevance of glutamine metabolism–related genes in breast cancer (BC) remain incompletely defined. In this study, integrated analysis of public datasets identified Actin-like protein 8 (ACTL8) as a key prognostic gene significantly upregulated in BC tissue and associated with poor patient survival. In vitro, shRNA knockdown of ACTL8 reduced MYC expression and its downstream targets SLC1A5 and GLS1, suppressing cell proliferation, migration and invasion. This disruption led to impaired redox homeostasis as evidenced by reduced GSH/GSSG and NADPH/NADP<sup>+</sup> ratios. Mechanistically, MYC overexpression restored metabolic enzymes and phenotypes but failed to rescue p-AKT levels, confirming ACTL8 acts upstream of the PI3K/AKT/mTOR axis. Virtual screening identified Momordin Ic as a small molecule that directly interacts with ACTL8. Surface plasmon resonance (SPR) and Thermal shift assay (TSA) confirmed this high-affinity binding, which destabilized ACTL8 and promoted its ubiquitin–proteasome degradation. Moreover, ACTL8 knockdown significantly attenuated the sensitivity of BC cells to Momordin Ic treatment, confirming ACTL8 as the specific therapeutic target. In vivo, suppression of ACTL8 markedly reduced tumor growth. Together, these findings establish ACTL8 as a key oncogenic driver of BC progression. Targeting ACTL8 offers a novel strategy to disrupt glutamine-dependent metabolic reprogramming, and Momordin Ic represents a promising lead agent to combat ACTL8-driven BC.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"247 ","pages":"Article 117761"},"PeriodicalIF":5.6,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146099857","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 : 2026-01-29DOI: 10.1016/j.bcp.2026.117763
Xi Chen , Binhui Wang , Wanqian Li , Nan Jin , Guran Lu , Jiabing Wang
Hepatic ischemia–reperfusion injury (HIRI) represents a frequent and unavoidable complication following liver resection or liver transplantation, which can profoundly impair hepatic function and even cause irreversible tissue damage, precipitating multiple organ dysfunction and ultimately adversely influencing both the prognosis and overall patient survival. Inflammation demonstrates a robust association with HIRI and serves a crucial function across the entire pathological course of HIRI. In this context, pyroptosis constitutes a controlled inflammatory cell death mechanism that contributes substantially to the pathological progression of HIRI. Throughout HIRI development, gasdermin D (GSDMD) functions as the primary effector following caspase 1 activation. This review provides a concise summary and emphasizes the intricate cellular and molecular mechanisms underlying GSDMD-mediated pyroptosis, particularly focusing on its involvement in HIRI. Meanwhile, the potential therapeutic effect of the natural products that act on GSDMD was predicted, which would broaden the treatment options available for HIRI. However, existing research remains confined to laboratory-based investigations and lacks clinical studies to advance a comprehensive understanding of GSDMD-induced pyroptosis in the occurrence and progression of HIRI. Therefore, enhanced comprehension of GSDMD mechanisms and the development of GSDMD-targeting inhibitors may offer promising clinical application prospects for managing HIRI.
肝缺血再灌注损伤（Hepatic ischemia-reperfusion injury， HIRI）是肝切除或肝移植术后常见且不可避免的并发症，可严重损害肝功能，甚至造成不可逆的组织损伤，诱发多器官功能障碍，最终影响患者预后和总体生存。炎症与HIRI密切相关，在HIRI的整个病理过程中起着至关重要的作用。在这种情况下，焦亡构成了一种可控的炎症细胞死亡机制，在很大程度上促进了HIRI的病理进展。在HIRI的整个发展过程中，gasdermin D （GSDMD）是caspase 1激活后的主要效应物。这篇综述提供了一个简明的总结，并强调了gsdmd介导的焦亡的复杂的细胞和分子机制，特别关注它在HIRI中的参与。同时，预测了作用于GSDMD的天然产物的潜在治疗效果，这将拓宽HIRI的治疗选择。然而，现有的研究仍然局限于基于实验室的调查，缺乏临床研究来全面了解gsdmd诱导的焦亡在HIRI发生和发展中的作用。因此，加强对GSDMD机制的理解和开发GSDMD靶向抑制剂可能为治疗HIRI提供了良好的临床应用前景。
{"title":"The role of gasdermin D-mediated pyroptosis in hepatic ischemia–reperfusion injury and prediction of the therapeutic natural products","authors":"Xi Chen , Binhui Wang , Wanqian Li , Nan Jin , Guran Lu , Jiabing Wang","doi":"10.1016/j.bcp.2026.117763","DOIUrl":"10.1016/j.bcp.2026.117763","url":null,"abstract":"<div><div>Hepatic ischemia–reperfusion injury (HIRI) represents a frequent and unavoidable complication following liver resection or liver transplantation, which can profoundly impair hepatic function and even cause irreversible tissue damage, precipitating multiple organ dysfunction and ultimately adversely influencing both the prognosis and overall patient survival. Inflammation demonstrates a robust association with HIRI and serves a crucial function across the entire pathological course of HIRI. In this context, pyroptosis constitutes a controlled inflammatory cell death mechanism that contributes substantially to the pathological progression of HIRI. Throughout HIRI development, gasdermin D (GSDMD) functions as the primary effector following caspase 1 activation. This review provides a concise summary and emphasizes the intricate cellular and molecular mechanisms underlying GSDMD-mediated pyroptosis, particularly focusing on its involvement in HIRI. Meanwhile, the potential therapeutic effect of the natural products that act on GSDMD was predicted, which would broaden the treatment options available for HIRI. However, existing research remains confined to laboratory-based investigations and lacks clinical studies to advance a comprehensive understanding of GSDMD-induced pyroptosis in the occurrence and progression of HIRI. Therefore, enhanced comprehension of GSDMD mechanisms and the development of GSDMD-targeting inhibitors may offer promising clinical application prospects for managing HIRI.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"247 ","pages":"Article 117763"},"PeriodicalIF":5.6,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146096787","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 : 2026-01-29DOI: 10.1016/j.bcp.2026.117765
Shuang-Zhou Bi, Xiang-Li Ni, Wei-Dong Sun, Chen-Ying Zhang, An Liu, Shi-Yan Lai, Jiang-Hua Li
Nicotinamide N-methyltransferase (NNMT) plays a critical role in the pathogenesis, progression, and treatment resistance of breast cancer (BC). This enzyme facilitates tumor progression through multiple mechanisms: it regulates NAD+ metabolism, thereby influencing the activity of key enzymes such as sirtuins (SIRTs) and Poly(ADP-ribose) polymerase (PARP), which drives metabolic reprogramming and enhances chemoresistance; it consumes the methyl donor S-adenosylmethionine (SAM), leading to histone hypomethylation and promoting the expression of genes associated with epithelial-mesenchymal transition (EMT) and metastasis; and its metabolite, 1-methylnicotinamide (MNA), acts as a signaling molecule within the tumor microenvironment (TME) to accelerate tumor development by facilitating cell cycle progression and suppressing protective autophagy. NNMT is frequently overexpressed in BC tissues and is correlated with poor prognosis, highlighting its potential as a diagnostic biomarker and therapeutic target. Studies have demonstrated that targeting NNMT effectively inhibits tumor growth and metastasis and may augment the efficacy of immunotherapy. Future research should prioritize the development of potent NNMT inhibitors and further elucidate the role of NNMT in modulating the TME and mediating drug resistance. As a pivotal molecule linking metabolism, epigenetics, and the TME, NNMT offers promising new avenues for BC treatment.
{"title":"The emerging role of nicotinamide N-methyltransferase in the pathogenesis and treatment of breast cancer","authors":"Shuang-Zhou Bi, Xiang-Li Ni, Wei-Dong Sun, Chen-Ying Zhang, An Liu, Shi-Yan Lai, Jiang-Hua Li","doi":"10.1016/j.bcp.2026.117765","DOIUrl":"10.1016/j.bcp.2026.117765","url":null,"abstract":"<div><div>Nicotinamide N-methyltransferase (NNMT) plays a critical role in the pathogenesis, progression, and treatment resistance of breast cancer (BC). This enzyme facilitates tumor progression through multiple mechanisms: it regulates NAD<sup>+</sup> metabolism, thereby influencing the activity of key enzymes such as sirtuins (SIRTs) and Poly(ADP-ribose) polymerase (PARP), which drives metabolic reprogramming and enhances chemoresistance; it consumes the methyl donor S-adenosylmethionine (SAM), leading to histone hypomethylation and promoting the expression of genes associated with epithelial-mesenchymal transition (EMT) and metastasis; and its metabolite, 1-methylnicotinamide (MNA), acts as a signaling molecule within the tumor microenvironment (TME) to accelerate tumor development by facilitating cell cycle progression and suppressing protective autophagy. NNMT is frequently overexpressed in BC tissues and is correlated with poor prognosis, highlighting its potential as a diagnostic biomarker and therapeutic target. Studies have demonstrated that targeting NNMT effectively inhibits tumor growth and metastasis and may augment the efficacy of immunotherapy. Future research should prioritize the development of potent NNMT inhibitors and further elucidate the role of NNMT in modulating the TME and mediating drug resistance. As a pivotal molecule linking metabolism, epigenetics, and the TME, NNMT offers promising new avenues for BC treatment.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"247 ","pages":"Article 117765"},"PeriodicalIF":5.6,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146096803","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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