Biochemical pharmacology最新文献

{"title":"Disruption of gut bacteria-derived hydrogen sulfide signaling mediates antibacterial-induced acute anorexia.","authors":"Han Zhang, Ling-Li Lu, Hua-Jie Wang, Pei Wang, Jian-Guo Chen, Fang Wang, Yang Liu, Hong-Sheng Chen, Peng-Fei Wu","doi":"10.1016/j.bcp.2026.118413","DOIUrl":"10.1016/j.bcp.2026.118413","url":null,"abstract":"<p><p>Numerous commonly used antibacterial agents frequently induce acute anorexia as a clinical side effect, yet the underlying mechanism remains poorly understood. Here, we investigated the role of gut bacteria-derived hydrogen sulfide (H₂S) signaling in the regulation of feeding behavior and its involvement in antibiotic-associated anorexia. Using methylene blue colorimetric and fluorescent probe-based detection, we found that 24-h fasting elevated H₂S levels in rat feces and serum, which robustly stimulated feeding behavior. 16S rRNA sequencing revealed that fasting reshaped the gut microbiota and enriched certain H₂S-producing bacterial taxa. Through fecal microbiota transplantation and pharmacological manipulations, our findings suggest a contribution of microbiota-derived H₂S to fasting-induced feeding behavior. Mechanistically, fasting-induced H₂S promoted feeding by activating AMP-activated protein kinase (AMPK) in the hypothalamic arcuate nucleus, a key center for feeding regulation, via an S-sulfhydration-dependent mechanism, which in turn enhanced the activity of neuropeptide Y-positive neurons. Furthermore, we showed that impaired gut bacterial H₂S signaling contributed to metronidazole-induced acute anorexia, a common adverse clinical effect. Given that H₂S-producing taxa, especially Desulfovibrio, are sensitive to a broad range of antibacterial agents, our findings suggest an important role for gut bacterial H₂S signaling in gut-brain communication and appetite control, and point to a microbiota-host feedback mechanism underlying antibacterial-induced acute anorexia.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"118413"},"PeriodicalIF":6.5,"publicationDate":"2026-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148856937","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":"Mammalian nitrate transport: emerging roles of sialin, chloride channels, aquaporin-6, and the sodium-iodide symporter.","authors":"Asghar Ghasemi, Sajad Jeddi, Khosrow Kashfi","doi":"10.1016/j.bcp.2026.118412","DOIUrl":"https://doi.org/10.1016/j.bcp.2026.118412","url":null,"abstract":"<p><p>Nitrate (NO₃^-) has emerged as an important physiological reservoir of nitric oxide (NO) and as a nutritional strategy for enhancing NO bioavailability through the nitrate-nitrite-NO pathway. Despite increasing recognition of the biological and therapeutic significance of nitrate, the mechanisms governing its transport across mammalian cell membranes remain incompletely understood. As a charged anion, NO₃^- cannot freely diffuse across lipid bilayers and therefore requires membrane transport proteins to mediate its cellular uptake, distribution, and storage. This review critically examines the current evidence for membrane proteins implicated in mammalian nitrate transport, including solute carriers (sialin and the sodium-iodide symporter, NIS), chloride transport proteins, and aquaporin-6 (AQP6). We discuss their structural and functional properties, tissue distribution, transport mechanisms, and emerging physiological roles in nitrate homeostasis. Recent evidence indicates that nitrate not only serves as a substrate for these transport systems but also regulates their expression and function, including the proteolytic cleavage of plasma membrane sialin to generate sialin2, an intracellular nitrate sensor that activates metabolic signaling pathways. Collectively, current evidence suggests that mammalian nitrate transport is mediated by multiple, mechanistically distinct membrane proteins that function cooperatively to maintain nitrate homeostasis and nitric oxide bioavailability. A better understanding of these transport mechanisms may facilitate the optimization of dietary nitrate interventions and the development of nitrate-based therapeutic strategies.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"118412"},"PeriodicalIF":6.5,"publicationDate":"2026-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148856897","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":"One ligand, multiple fates: the multi-receptor signaling network of FSTL1 and receptor-selective intervention strategies.","authors":"Yuning Hou, Chunlu Fang, Wenqi Yang, Shujing Liu, Liangming Li","doi":"10.1016/j.bcp.2026.118403","DOIUrl":"10.1016/j.bcp.2026.118403","url":null,"abstract":"<p><p>Follistatin-like protein 1 (FSTL1) is a secreted glycoprotein involved in cardiovascular protection, tissue repair, inflammation, fibrosis, and tumor biology. Accumulating evidence indicates that FSTL1 exerts opposing effects across tissues and disease contexts, producing either protective or pathogenic outcomes. Although this functional duality is generally considered context dependent, its mechanistic basis remains incompletely understood. Recent studies suggest that FSTL1 does not signal through a single receptor but engages or modulates multiple functionally distinct receptor systems, including disco-interacting protein 2 homolog A (DIP2A), Toll-like receptor 4/cluster of differentiation 14 (TLR4/CD14), and bone morphogenetic protein (BMP) receptors. DIP2A predominantly mediates cell survival and tissue repair, whereas TLR4/CD14 primarily coordinates innate immune and inflammatory responses. FSTL1 also modulates BMP ligand-receptor signaling, thereby influencing development, differentiation, tissue remodeling, and context-dependent tumor responses. The net biological output of FSTL1 is therefore proposed to be shaped by cell-type-specific receptor expression, post-translational modifications, microenvironmental cues, and potential crosstalk or competition among coexisting receptor systems. From a translational perspective, non-receptor-selective targeting of FSTL1 carries inherent risks because it may simultaneously suppress protective and pathological signaling programs. Receptor-selective approaches, including the development of DIP2A-biased agonists to enhance tissue protection and the selective disruption of pathological TLR4 signaling to attenuate inflammation, may offer greater therapeutic precision. This review proposes a receptor-centered framework for understanding the functional complexity of FSTL1 and discusses receptor-selective intervention strategies for cardiovascular, fibrotic, inflammatory, and malignant diseases.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"118403"},"PeriodicalIF":6.5,"publicationDate":"2026-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148856922","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Drug failure in diabetic kidney disease: translational barriers, target validation and trial de-risking strategies.","authors":"Hongtu Hu, Suyue Hou, Wenjie Chen, Jijia Hu","doi":"10.1016/j.bcp.2026.118405","DOIUrl":"10.1016/j.bcp.2026.118405","url":null,"abstract":"<p><p>Diabetic kidney disease (DKD) remains a difficult therapeutic setting in nephrology, metabolism and clinical pharmacology. Standard care has moved from glucose- and blood-pressure-centred treatment toward disease-modifying therapy built around renin-angiotensin-aldosterone system (RAAS) blockade, sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 receptor agonists and nonsteroidal mineralocorticoid receptor antagonism. Yet DKD drug development is also defined by repeated translational failure. Many agents with strong mechanistic rationale have failed to improve hard kidney outcomes, have produced biomarker signals that did not mature into durable clinical benefit, or have been limited by hyperkalaemia, fluid retention, heart failure, acute kidney injury, anaemia or systemic immunosuppression. This Review treats failure as a source of translational information. We compare successful development paths for SGLT2 inhibitors, finerenone and semaglutide with constrained or unsuccessful programmes involving dual RAAS blockade, bardoxolone methyl, endothelin receptor antagonists, apoptosis signal-regulating kinase 1 (ASK1) inhibition, immunomodulation, sulodexide and pyridoxamine. Across these examples, recurring vulnerabilities emerge in human target validation, animal-to-human translation, renal exposure, target engagement, pharmacodynamic biomarker selection, patient enrichment, endpoint choice and safety-constrained dosing. We propose a de-risking framework that prioritizes human tissue evidence, renal cell-specific causal validation, pharmacokinetic and pharmacodynamic integration, mechanism-aligned biomarkers, adaptive trial design and biology-guided patient selection.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"118405"},"PeriodicalIF":6.5,"publicationDate":"2026-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148856917","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":"Inflammatory-metabolic coupling in glia: LCN2-PDK axis as molecular mechanism and therapeutic paradigm.","authors":"Kyoungho Suk","doi":"10.1016/j.bcp.2026.118407","DOIUrl":"10.1016/j.bcp.2026.118407","url":null,"abstract":"<p><p>Neuroinflammation and metabolic dysfunction converge in diverse neurological disorders, yet the molecular mechanisms linking these processes remain incompletely defined. This review integrates current evidence that the lipocalin-2 (LCN2) - pyruvate dehydrogenase kinase (PDK) axis represents a candidate mechanistic pathway, most directly established to date in diabetic peripheral neuropathy, coupling glial inflammatory activation to pathological metabolic reprogramming. LCN2, a pro-inflammatory mediator upregulated in reactive glia, drives PDK expression through two convergent mechanisms: PPARβ/δ-dependent transcription of PDK2/4, and iron-dependent HIF-1α stabilization inducing PDK1/3. PDK-mediated pyruvate dehydrogenase inhibition redirects metabolism from oxidative phosphorylation toward aerobic glycolysis, causing lactate accumulation whose functional consequences range from beneficial neuronal fuel support at physiological concentrations to potential neurotoxicity at higher, context-dependent levels (often cited around 5-10 mM), with the transition shaped by pH, tissue compartment, duration of exposure, and disease context rather than a single universal threshold. The axis operates across central and peripheral nervous system disorders with disease-specific patterns: in diabetic peripheral neuropathy, satellite glial cell LCN2 drives PPARβ/δ-PDK2-mediated lactate accumulation with Lcn2 knockout providing robust protection; in traumatic brain injury and stroke, acute astrocytic LCN2 surges are associated with secondary damage; and in Alzheimer disease, chronic microglial LCN2 elevation is associated with impaired metabolic function. Evidence for axis involvement is currently most direct and mechanistically established in diabetic peripheral neuropathy, whereas its role in traumatic brain injury, stroke, and Alzheimer disease is comparatively less characterized and remains largely correlative. Multi-level therapeutic opportunities include PDK inhibition with dichloroacetate, PPARβ/δ antagonism, LCN2 neutralization, and metabolic support strategies, although disease-specific dosing, timing, efficacy, and long-term safety (including the risk of peripheral neuropathy with dichloroacetate) require further clinical evaluation. Plasma LCN2 and hyperpolarized ¹³C-pyruvate magnetic resonance imaging represent promising, though still emerging, candidate biomarkers for patient stratification and target engagement monitoring. This mechanistic convergence across disorders positions the LCN2-PDK axis as a promising candidate therapeutic target, with diabetic neuropathy - where supporting evidence is currently strongest - representing the lead indication for clinical translation.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"118407"},"PeriodicalIF":6.5,"publicationDate":"2026-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148849703","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 macrophage mitochondrial metabolism in tuberculosis: from pathogen-driven biochemical reprogramming to host-directed pharmacotherapy.","authors":"Jianhao Xu, Xinran Ding, Jiahui Tang, Yongwei Qin","doi":"10.1016/j.bcp.2026.118408","DOIUrl":"https://doi.org/10.1016/j.bcp.2026.118408","url":null,"abstract":"<p><p>Mycobacterium tuberculosis (Mtb) remains a leading global health threat. The fate of the Mtb-infected macrophage is critically governed by host mitochondrial metabolism. In this review, we propose a unifying biochemical \"threshold model\" of tuberculosis pathogenesis: Mtb functions as an intracellular \"mitochondrial parasite,\" deploying multiple effectors-including ESAT-6, PtpA, and TNT-that perturb host mitochondrial or mitochondria-linked metabolic pathways, spanning oxidative phosphorylation, NAD⁺ homeostasis, TCA cycle remodeling, and ATP synthesis. This cumulative biochemical damage is predicted to progressively lower the macrophage threshold for TNF-induced programmed necrosis, a cell death modality executed through reverse electron transport (RET) and reactive oxygen species (ROS) generation at mitochondrial complex I. This metabolic-necrotic axis may therefore present druggable vulnerabilities. We evaluate emerging small-molecule host-directed therapies (HDTs) that counter these pathogenic mechanisms by targeting specific mitochondrial nodes, including succinate dehydrogenase (SDH), mitochondrial complex I, pyruvate dehydrogenase kinase (PDK), SIRT3, and the ACOD1/itaconate axis. For each pharmacological class, we discuss its biochemical mechanism of action and translational potential. Our threshold model predicts that restoring selected mitochondrial functions may reduce macrophage susceptibility to lytic death and bacterial dissemination; whether individual interventions actively redirect infected macrophages toward apoptosis, rather than simply preserving cell viability, requires direct experimental testing.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"118408"},"PeriodicalIF":6.5,"publicationDate":"2026-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148849721","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":"Thumpd1 preserves osteogenic TGF-β signaling by promoting USP4-dependent deubiquitination and stabilization of TGF-βRII.","authors":"Donglun Xiao, Houzhi Yang, Dongliang Zhang, Yubin Long, Xiangbin Wang, Shanshan Li, Tianwei Sun, Xin Jin","doi":"10.1016/j.bcp.2026.118400","DOIUrl":"10.1016/j.bcp.2026.118400","url":null,"abstract":"<p><p>Impaired osteogenic signaling contributes to defective bone formation, but the mechanisms that preserve receptor stability during skeletal development remain incompletely understood. We investigated the role of Thumpd1 in skeletal development and osteogenic differentiation and defined the downstream signaling mechanism. Thumpd1-deficient zebrafish were evaluated for embryonic development, craniofacial cartilage, skeletal mineralization, and bone microarchitecture, while bone marrow mesenchymal stem cells (BMSCs) were used to assess cell-intrinsic osteogenesis. Thumpd1 deficiency caused developmental delay, abnormal craniofacial cartilage morphology, reduced cartilage extracellular-matrix components expression, impaired ossification, and decreased bone mineral density and bone volume. In contrast, osteoclast differentiation and resorptive activity were not substantially increased. Thumpd1-deficient BMSCs showed reduced alkaline phosphatase activity, matrix mineralization, and osteogenic marker expression. Transcriptomic profiling identified ubiquitin-specific protease 4 (USP4) as a prominently downregulated factor. Mechanistically, Thumpd1 loss reduced USP4 expression, enhanced ubiquitination, and destabilized transforming growth factor-β receptor type II (TGF-βRII). TGF-βRII re-expression restored canonical SMAD2 signaling and osteogenic differentiation after USP4 depletion, while tgfb1a rescue partially reversed skeletal defects in vivo. These findings identify Thumpd1 as a regulator of skeletal development and define a Thumpd1-USP4-TGF-βRII proteostatic pathway contributing to impaired osteogenesis.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"118400"},"PeriodicalIF":6.5,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148824671","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 peptidylarginine deiminases 2 and 4 in diabetic kidney disease: mechanistic rationale and preclinical evidence.","authors":"Wiktoria Mallek, Aleksandra Wróblewska-Schmude, Adam Lesner, Agnieszka Piwkowska, Magdalena Wysocka","doi":"10.1016/j.bcp.2026.118396","DOIUrl":"https://doi.org/10.1016/j.bcp.2026.118396","url":null,"abstract":"<p><p>Many patients with diabetic kidney disease (DKD) continue to progress despite guideline-directed quadruple nephroprotective therapy, driven in part by sterile inflammation that current treatment does not target. Peptidylarginine deiminases 2 and 4 (PAD2/4) are calcium-dependent enzymes that convert peptidyl-arginine to peptidyl-citrulline, remodeling chromatin, shaping immune-cell function, and altering extracellular-matrix integrity. In the diabetic kidney, hyperglycemia-associated signaling activates PAD4, driving histone hypercitrullination, neutrophil extracellular trap (NET) formation, and innate-immune cell recruitment, while PAD2 contributes through macrophage-associated citrullination. This review examines PAD2/4 as candidate therapeutic targets in DKD, separating findings with direct evidence in diabetic renal tissue or DKD models from mechanisms extrapolated from rheumatoid arthritis, sepsis, or cancer. Available DKD studies provide early but limited support for a pathogenic role of PAD-mediated citrullination, particularly PAD4-associated NET formation and citrullinated-histone deposition. However, several proposed mechanisms, including citrullination of podocyte cytoskeletal proteins and glycosaminoglycan-driven amplification of PAD4 activity, remain indirect and require validation in diabetic renal tissue. We appraise the isoform-selective inhibitor landscape, candidate pharmacodynamic biomarkers, and translational barriers. In summary, PAD inhibition should therefore be framed as a mechanistically distinct, still-preclinical adjunct to the KDIGO 2024 standard of care, with its renal potential depending on isoform-resolved human data and pharmacokinetic characterization in chronic kidney disease.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"118396"},"PeriodicalIF":6.5,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148824699","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":"Genistein inhibits colorectal cancer progression via regulating the LINC00355/miR-150/SGK1 axis and downstream EGFR/PI3K/AKT and MAPK signaling pathways.","authors":"Xing Zhou, Jian Qin, Zhongwen Feng, Shiran Qin, Quanzhi Qin, Chunxia Chen, Huan Huang, Xiaoyu Chen","doi":"10.1016/j.bcp.2026.118399","DOIUrl":"10.1016/j.bcp.2026.118399","url":null,"abstract":"<p><p>Colorectal cancer (CRC) is a major global malignant tumor with high morbidity and mortality, and current clinical therapies have limited curative effects and obvious adverse reactions. Genistein, a key bioactive isoflavone derived from soybeans, has shown prominent anti-tumor activity, whereas its exact molecular mechanism against CRC remains unclear. This study evaluated the anti-CRC effects of genistein using in vitro cell experiments and a nude mouse xenograft model, focusing on the LINC00355/miR-150/SGK1 axis and its downstream EGFR/PI3K/AKT and MAPK signaling pathways to explore the underlying regulatory mechanism. The results revealed that genistein dose-dependently inhibited CRC cell proliferation without obvious cytotoxicity to normal colon cells. It also induced cell cycle arrest and cancer cell apoptosis, and suppressed tumor migration and invasion. Mechanistically, genistein inhibited the activation of downstream oncogenic pathways by regulating the expression of the target molecular axis. In vivo assays further confirmed that genistein effectively repressed tumor growth with good safety. This study provides reliable experimental evidence for the development of genistein as a potential adjuvant therapeutic agent for CRC treatment.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"118399"},"PeriodicalIF":6.5,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148824682","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":"Integrin αVβ3-mediated focal adhesion signaling promotes fibroblast activation during renal fibrosis.","authors":"Dongdong Wu, Jing Zhao, Xinrui Chang, Yuman Lei, Chengcheng Mu, Donglin Yang, Ting Ye, Shouzhu Xu","doi":"10.1016/j.bcp.2026.118401","DOIUrl":"10.1016/j.bcp.2026.118401","url":null,"abstract":"<p><p>Renal fibrosis is a progressive pathological process underlying chronic kidney disease (CKD), characterized by persistent fibroblast activation and excessive extracellular matrix accumulation. Although integrin-dependent focal adhesion signaling has been implicated in tissue fibrosis, its role in renal fibroblast activation remains incompletely understood. In this study, publicly available single-cell and bulk transcriptomic datasets were integrated to characterize fibroblast-associated signaling alterations in fibrotic kidneys. Experimental validation was subsequently performed in a 5/6 nephrectomy rat model and TGF-β1-stimulated NRK-49F cells. Bioinformatic analyses revealed enrichment of extracellular matrix organization, focal adhesion, and cytoskeleton-related pathways in activated fibroblasts. Increased integrin αVβ3 expression and enhanced focal adhesion signaling were further confirmed in fibrotic renal tissues. Pharmacological inhibition of integrin αVβ3 with cyclo-RGDfK attenuated fibroblast adhesion, migration, and extracellular matrix production, accompanied by reduced FAK phosphorylation and RhoA expression. Furthermore, inhibition of FAK with PF-573228 impaired focal adhesion remodeling, disrupted F-actin stress fiber organization, and reduced fibroblast activation and extracellular matrix production. Pharmacological inhibition of ROCK with Y-27632 reduced MYPT1 phosphorylation, accompanied by impaired F-actin stress fiber organization and decreased fibroblast activation, supporting a functional role of ROCK signaling in focal adhesion remodeling and fibroblast activation. Collectively, these findings indicate that integrin αVβ3-associated FAK and RhoA/ROCK signaling contribute to focal adhesion remodeling and fibroblast activation during renal fibrosis, suggesting that this signaling network may represent a potential therapeutic target for renal fibrosis.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"118401"},"PeriodicalIF":6.5,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148824707","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}