Biochemical pharmacology最新文献

{"title":"Altered gene expression and activity of human placental drug-metabolizing cytochrome P450 enzymes across gestation","authors":"Saba N. Albetawi ,&nbsp;Ashley S. Meakin ,&nbsp;Yu-Chin Lien ,&nbsp;Michael D. Wiese ,&nbsp;Rebecca A. Simmons ,&nbsp;Janna L. Morrison","doi":"10.1016/j.bcp.2026.117786","DOIUrl":"10.1016/j.bcp.2026.117786","url":null,"abstract":"<div><div>Most medications administered during pregnancy will enter the fetal circulation through the placenta. The activity of placental drug-metabolizing cytochrome P450 (CYP) enzymes modulates the extent of this transfer. However, many gaps exist in understanding how CYP expression and activity vary across gestation and how placental sex influences these changes. Therefore, we aimed to characterize the expression and activity of placental CYPs throughout gestation stratified by sex. Placentas were collected from participants who provided informed consent and received care at the University of Pennsylvania hospital between 18–23.5 weeks gestational age (GA; Tri2, n=27), 20–36^6/7 weeks GA for preterm delivery (preterm, n=40), or 37 to 41 weeks GA for uncomplicated delivery (term, n=40). The DESeq2 R package was used to perform differential expression analysis of CYP gene expression. CYP2C8 and 2D6 activity was measured in vitro using established mass spectrometry assays and analyzed using Kruskal Wallis-ANOVA. Placental expression of <em>CYP1A2, CYP2C8, CYP3A5</em>, and <em>CYP3A7</em> decreased towards the end of pregnancy, whereas<!--> <em>CYP2C9</em> and <em>CYP2D6</em> expression increased toward the end of pregnancy. When considering placental sex, <em>CYP2D6</em> expression was lower in Tri2 vs term in males (log₂ fold change (logFC)=-1.1123) and females (logFC=-1.3750), whereas <em>CYP2C8</em> was higher in the same comparisons (male logFC=1.4940, female logFC=1.2659). In females only, CYP2D6 and CYP2C8 activity increased in term vs Tri2 placentae (<em>P</em>=0.0004 and <em>P</em>=0.0281, respectively). Consistent with this, female placental CYP2D6 and CYP2C8 activity was positively associated with gestational age (<em>P</em>=0.0020 and <em>P</em>=0.0009, respectively). Placental activity of two CYPs responsible for metabolizing 25% of drugs increases from Tri2 to term in a sex-specific manner, which may affect fetal exposure to maternally administered medications metabolized by these isoforms.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"247 ","pages":"Article 117786"},"PeriodicalIF":5.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146177698","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":"Prenatally elevated glucocorticoid disrupts social behavior via GR-Id3/E47-dependent astroglial dysfunction in LPS-induced autism-like rats","authors":"Binlin Yuan,&nbsp;Xueli Xiang,&nbsp;Ting Yang,&nbsp;Fang Lin,&nbsp;Junyan Yan,&nbsp;Bei Tong,&nbsp;Tingyu Li,&nbsp;Jie Chen","doi":"10.1016/j.bcp.2026.117784","DOIUrl":"10.1016/j.bcp.2026.117784","url":null,"abstract":"<div><div>Maternal infection during pregnancy may contribute to autism spectrum disorder (ASD) through dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, however, the precise mechanisms disrupting fetal neurodevelopment remain unclear. By integrating human cohort analyses with experimental models, this study identifies prenatal infection as a significant maternal risk factor associated with elevated glucocorticoid (GC) exposure in offspring. In animal model, maternal lipopolysaccharide (LPS) exposure induced fetal GC surges, leading to GC receptor (GR)-dependent upregulation of inhibitor of DNA binding 3(Id3). Elevated Id3 formed complexes with E47, impairing its suppression of the astrocytic gene S100b and promoting aberrant astroglial differentiation. This astrocytic dysfunction disrupted synaptic glutamate/GABA homeostasis, resulting in core autistic-like behavioral phenotypes. Importantly, prenatal pharmacologic inhibition of GR signaling or downregulation of Id3 rescued Id3-E47 functional equilibrium, normalized astrocytic differentiation, and attenuated behavioral deficits. Our findings establish the GC-GR-Id3/E47 pathway as a mechanistic link between prenatal environmental insults and neurodevelopmental pathology, providing novel etiological insights into an ASD subtype of gestational infection.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"247 ","pages":"Article 117784"},"PeriodicalIF":5.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146177653","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":"ICAP-1 alternative splicing regulates Talin tension polarization in NSCLC durotaxis","authors":"Yunfeng Hu ,&nbsp;Wangxing Zhao ,&nbsp;Ying Zhao ,&nbsp;Lijun Zhang ,&nbsp;Yuqing Shi ,&nbsp;Shixiao Wan ,&nbsp;HuanHuan Zhao ,&nbsp;Jun Guo ,&nbsp;Ying Song","doi":"10.1016/j.bcp.2026.117762","DOIUrl":"10.1016/j.bcp.2026.117762","url":null,"abstract":"<div><div>The directional migration of cancer cells in response to tumor microenvironment stiffening is mediated through integrin-dependent mechanotransduction pathways, particularly involving integrin cytoplasmic domain-associated protein 1 (ICAP-1). In this study, we aimed to explore the role of Talin tension during directional migration of non-small cell lung cancer (NSCLC) cells, with a specific focus on the isoform-specific regulation by ICAP-1α and ICAP-1β. Our findings demonstrate that matrix stiffening triggers a significant shift in ICAP-1 isoform expression. ICAP-1α, but not ICAP-1β, reduces the aggressiveness and directionality of NSCLC cells on a cell-directed matrix (CDM) with a stiffness gradient. ICAP-1α exhibited an extensive subcellular distribution, which inhibits integrin activity and talin tension. Our results establish ICAP-1 as a critical mechanotransducer that relays signals from β1-integrin to Talin, and suggest that ICAP-1 alternative splicing could be harnessed as a potential therapeutic strategy for NSCLC.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"247 ","pages":"Article 117762"},"PeriodicalIF":5.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146077277","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":"Diacerein protects against Ovariectomy-Induced bone loss via reversal of NRF2 epigenetic suppression","authors":"Liang Qiao ,&nbsp;Tao Shen ,&nbsp;Yu Ben ,&nbsp;Jian Dong ,&nbsp;Bin Liu ,&nbsp;Xiang Chen ,&nbsp;Qing Jiang","doi":"10.1016/j.bcp.2026.117748","DOIUrl":"10.1016/j.bcp.2026.117748","url":null,"abstract":"<div><div>Osteoporosis (OP) is a prevalent degenerative musculoskeletal disorder in middle-aged and elderly populations, characterized by reduced bone mineral density and an increased risk of fragility fractures. Its pathogenesis is closely linked to oxidative stress imbalance; however, effective long-term therapeutic options remain limited. Here, we report that diacerein, a clinically used drug for osteoarthritis, significantly ameliorates OVX (ovariectomy)-induced bone loss and abnormal bone metabolism. Mechanistically, we demonstrate that diacerein activates the transcription and activity of NRF2 (nuclear factor erythroid 2–related factor 2), a central regulator of the antioxidant response, leading to the restoration of cytoprotective protein expression and thereby exerting protective effects against osteoporosis. The beneficial effects of diacerein on bone protection were largely abolished in <em>Nfe2l2</em> knockout mice, further underscoring the essential role of NRF2. Further investigation revealed that diacerein is metabolized <em>in vivo</em> into rhein, which exerts potent epigenetic activity. The upregulation of NRF2 appears to be primarily mediated through rhein’s inhibition of DNA methyltransferases (DNMTs) 1 and 3a. In summary, our study suggests that diacerein, a drug with a well-established safety profile and suitability for long-term use, represents a promising therapeutic candidate for the treatment of osteoporosis.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"247 ","pages":"Article 117748"},"PeriodicalIF":5.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146050273","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":"Targeting the FAPα/Integrin αvβ1 complex attenuates hepatic stellate cell activation and liver fibrosis","authors":"Chun Guan ,&nbsp;Nuo Cheng ,&nbsp;Yu Tong ,&nbsp;Yifei Li ,&nbsp;Jiayi Liu ,&nbsp;Haishan Luo ,&nbsp;Shihao Liu ,&nbsp;Jihai Chen ,&nbsp;Cong Wang","doi":"10.1016/j.bcp.2026.117801","DOIUrl":"10.1016/j.bcp.2026.117801","url":null,"abstract":"<div><div>Hepatic stellate cell (HSC) activation is central to liver fibrosis. Fibroblast activation protein α (FAPα) is highly expressed in activated HSCs, yet its regulatory role remains unclear. This study investigates the function and mechanism of FAPα in HSC activation and fibrosis progression. Using TGF-β1-induced LX2 cells and CCl₄-induced mouse models, along with small-molecule inhibitors and multi-omics analyses, we found that inhibiting FAPα suppressed HSC activation, proliferation, migration, and ameliorated fibrosis. Notably, FAPα formed a functional complex with Integrin αvβ1 in activated HSCs. Dual inhibition of FAPα/Integrin αvβ1 more effectively attenuated HSC activation and fibrosis than single-agent treatment. Transcriptomic and proteomic studies revealed that the complex acts through the GPC3/FGF21 axis. This study identifies the FAPα/Integrin αvβ1 complex as a key regulator of liver fibrosis and provides a novel combinatory therapeutic strategy for anti-fibrotic drug development.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"247 ","pages":"Article 117801"},"PeriodicalIF":5.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146193769","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":"GLIS3, a novel regulator of eicosanoid gene expression and metabolism in normal kidney and polycystic kidney disease","authors":"Chitrangda Srivastava ,&nbsp;Hong Soon Kang ,&nbsp;Matthew L. Edin ,&nbsp;Tanushree Mukherjee ,&nbsp;Fred B. Lih ,&nbsp;Sara A. Grimm ,&nbsp;Justin B. Collier ,&nbsp;Darryl C. Zeldin ,&nbsp;Anton M. Jetten","doi":"10.1016/j.bcp.2026.117803","DOIUrl":"10.1016/j.bcp.2026.117803","url":null,"abstract":"<div><div>Loss of function of the Krüppel-like zinc finger transcription factor GLI-similar 3 (GLIS3) causes polycystic kidney disease (PKD) indicating that it plays a critical role in regulating normal kidney functions. The first postnatal month is accompanied with significant changes in gene expression and represents a key period in kidney development as well as the progression of PKD. In the current study, we examined the role of GLIS3 in the regulation of eicosanoid gene expression and metabolism during this period of kidney development. Transcriptome analysis showed that several eicosanoid metabolic genes are temporally regulated with the expression of some genes decreasing (lipoxygenase and cyclooxygenase arm) and others increasing (the cytochrome P450 pathways), suggesting that these changes are part of part of normal kidney maturation. Many of these temporal changes in eicosanoid gene expression are suppressed in GLIS3-deficient kidneys, consistent with our hypothesis that loss of GLIS3 function inhibits postnatal kidney maturation. Cistrome analyses revealed that several of these eicosanoid genes are directly regulated by GLIS3 and in coordination with hepatocyte nuclear factor 1 beta (HNF1B). Additionally, LC-MS-based eicosanoid metabolomics showed increased levels of PGD₂, PGE₂, TXB₂, and LTB₄ in PND28 GLIS3-deficient polycystic kidneys, consistent with elevated mRNA expression of <em>Ptgs1/2, Alox5ap, Lta4h,</em> and <em>Tbxas1</em>. The increased urinary excretion of PGE₂ and its metabolite PGEM in GLIS3-deficient mice correlates with increased renal production and metabolism of PGE₂ and higher <em>Slco2a1</em> and <em>Hpgd</em> mRNA expression. Elevated levels of these eicosanoid metabolites might contribute to cystogenesis, altered osmoregulation, inflammation, and fibrosis in GLIS3-deficient kidneys.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"247 ","pages":"Article 117803"},"PeriodicalIF":5.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146193798","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":"PACS2 deficiency ameliorates hepatic steatosis via inhibition of the JNK signaling pathway in diabetic mice","authors":"Hang Zou ,&nbsp;Shiying Qin ,&nbsp;Hongwei Lu ,&nbsp;Hong Xiang ,&nbsp;Ying Chen ,&nbsp;Zhihao Shu ,&nbsp;Xiao Zhang ,&nbsp;Jingjing Li ,&nbsp;Shuhua Chen","doi":"10.1016/j.bcp.2026.117794","DOIUrl":"10.1016/j.bcp.2026.117794","url":null,"abstract":"<div><div>Hepatic steatosis is a frequent complication of diabetes. To investigate the role of PACS2 in glucose and lipid metabolism in diabetic mice and to determine the underlying mechanisms. PACS2^-^/^- mice were used to establish diabetic models by a high-fat diet combined with intraperitoneal injection of STZ(HFD/STZ). Body weight, blood glucose, serum indexes, glucose tolerance test and insulin tolerance test were assessed. HepG2 cells were treated with high glucose and palmitic acid (HGPA). To investigate the specific mechanism of PACS2 silencing, HepG2 cells were transfected with the small interfering RNA (siRNA) of PACS2 or treated with an inhibitor of the JNK signaling (SP600125). Western blot was conducted to measure the JNK signaling pathway-related proteins. Our research findings indicate an upregulation of PACS2 expression in the liver tissues of diabetic mice. HFD/STZ induced dramatic exacerbation of higher blood glucose levels, insulin resistance, hepatic steatosis, MAMs formation, mitochondrial dysfunction and overactivation of the JNK signaling pathway in liver tissues, which was reversed by downregulation of PACS2. HepG2 cells treated with siRNA-PACS2 or SP600125 resulted in the inhibition of HGPA-mediated enhancement of JNK activation and the lipogenic enzymes expression (acetyl-CoA carboxylase 1 and fatty acid synthase), as well as the promotion of PPARα and fatty acid β-oxidation (FAO)-associated CPT1A expression. Collectively, our findings demonstrate that PACS2 deficiency alleviates hepatic steatosis and insulin resistance in diabetic mice by inhibition of JNK signaling pathway in hepatocytes.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"247 ","pages":"Article 117794"},"PeriodicalIF":5.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146193807","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":"Gamabufotalin impedes NSCLC progression by inhibiting the mitochondrial factor CHCHD2 and modulating XAF1 expression","authors":"Yisi Cai ,&nbsp;Xiaowei Wang ,&nbsp;Die Xu ,&nbsp;Yinghui Song ,&nbsp;Lemei Zhu ,&nbsp;Weijun Peng ,&nbsp;Bolin Chen","doi":"10.1016/j.bcp.2026.117809","DOIUrl":"10.1016/j.bcp.2026.117809","url":null,"abstract":"<div><div>Non-small cell lung cancer (NSCLC) continues to be the primary contributor to deaths associated with cancer. Current treatments are often limited by drug resistance and toxicity, highlighting the need for novel therapeutic approaches. Building on previous findings demonstrating that Gamabufotalin (CS-6) is effective against hepatocellular carcinoma, this study explores its mechanism of action in NSCLC. The findings indicate that CS-6 suppresses the proliferation and migratory capacity of NSCLC cells in a concentration-dependent manner, while significantly inducing apoptosis. The 48-hour half-maximal inhibitory concentration (IC₅₀) ranged from 30 to 80 nM. In xenograft models, CS-6 effectively suppressed tumor growth (<em>P</em> &lt; 0.05) without causing significant systemic toxicity at effective doses (25 mg/kg and 50 mg/kg). Mechanistically, coiled-coil-helix-coiled-coil-helix domain-containing protein 2 (CHCHD2) was identified as the direct molecular target of CS-6 through Limited Proteolysis-Mass Spectrometry (LiP-MS), validated by cell thermal shift assay (CETSA), MicroScale Thermophoresis (MST), and Surface Plasmon Resonance (SPR). CHCHD2, also known as mitochondrial nuclear retrograde regulator 1 (MNRR1), is a bi-organelle regulator located primarily in the mitochondrial intermembrane space, where it controls respiratory chain stability and cristae structure, thereby regulating cell survival and apoptosis<span><span>[1]</span></span>, <span><span>[2]</span></span>, <span><span>[3]</span></span>. CHCHD2 is essential for NSCLC cell survival, as both its knockdown and overexpression reduced the efficacy of CS-6. Furthermore, transcriptomic analysis revealed that targeting CHCHD2 with CS-6 activates interferon signaling and significantly upregulates the tumor suppressor X-linked inhibitor of apoptosis (XIAP)-associated factor 1 (XAF1). In conclusion, these findings establish the mitochondrial CHCHD2-XAF1 axis as a key mediator of CS-6 activity, thereby highlighting CS-6 as a promising candidate for targeted therapy in NSCLC.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"247 ","pages":"Article 117809"},"PeriodicalIF":5.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146199591","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":"Bivalent ligands targeting oxytocin receptor homodimers selectively activate distinct G protein and β-arrestin pathways","authors":"Marta Busnelli ,&nbsp;Alessandro Gori ,&nbsp;Bice Chini","doi":"10.1016/j.bcp.2026.117814","DOIUrl":"10.1016/j.bcp.2026.117814","url":null,"abstract":"<div><div>G protein-coupled receptors can assemble into both homodimers and heterodimers. While heterodimerization has been extensively characterized, the functional consequences of homodimerization on G protein coupling, signaling, and trafficking remain poorly understood.</div><div>Oxytocin receptors (OTRs) form homodimers, and we previously generated a series of homobivalent compounds composed of two modified oxytocin analogs (dOTK) linked by spacers of varying length. We already demonstrated that the bivalent ligands dOTK₂-C8 and dOTK₂-C10 possess an optimal spacer length that allows simultaneous binding of the dOTK moieties to each protomer of OTR homodimers, with an interface involving transmembrane domains 1 and 2 as well as helix 8, and act as superagonists at OTR/Gq-protein signaling. Moreover, dOTK₂-C8 exhibited approximately 100- and 40-fold increase in potency compared to OT in promoting social behavior in mice and zebrafish, respectively.</div><div>Here we used BRET biosensors to further explore the OTR signaling pathways activated by all bivalent ligands. We found that, in addition to Gq proteins, they activate Gi2 and Gi3, but not Gi1, GoA, or GoB, and that dOTK₂-C8 and dOTK₂-C10 were the only compounds capable of promoting the recruitment of β-arrestin 1 in addition to β-arrestin 2.</div><div>Altogether, these results indicate that dOTK₂-C8 and dOTK₂-C10, stabilizing a distinct OTR dimer conformation, can selectively promote G protein and β-arrestin coupling and provide a framework for the rational development of therapeutic agents with unprecedented selectivity and potency, highly relevant in the context of neurodevelopmental and psychiatric disorders characterized by social deficits, such as autism spectrum disorder and schizophrenia.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"247 ","pages":"Article 117814"},"PeriodicalIF":5.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146218490","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":"Renoprotective approaches against anthracycline nephrotoxicity","authors":"Tsigereda Weldemichael,&nbsp;Md Abdul Hye Khan,&nbsp;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":"2026-05-01","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}