Korean Journal of Physiology & Pharmacology最新文献

{"title":"Similarity-based profiling of pharmacovigilance data for drug safety pattern discovery.","authors":"Seongjae Park, SeongJin Wi, Heeseon Jo, Yuseong Kwon, Nakyung Jeon, Haeseung Lee","doi":"10.4196/kjpp.26.080","DOIUrl":"https://doi.org/10.4196/kjpp.26.080","url":null,"abstract":"<p><p>Spontaneous adverse event (AE) reporting systems enable large-scale pharmacovigilance but are typically analyzed as isolated drug-event pairs. Here, we constructed a drug-drug similarity network at an ingredient-level, using 968,966 reports from the Korea Adverse Event Reporting System (KAERS; 2020-2024). After preprocessing, 382,530 reports involving 1,058 ingredients and 3,749 AE events in MedDRA preferred terms (PTs) were retained. Significant ingredient-event signals were identified using proportional reporting ratio, reporting odds ratio, χ², and information component. Pairwise similarity between ingredients was quantified using a hypergeometric test based on shared significant PTs with a false discovery rate ingredients and 1,111 PTs, resulting in a network of 150 ingredients and 1,267 edges. Community detection revealed modules that recapitulated known pharmacological classes, including antineoplastic agents and contrast media, and exhibited clinically coherent safety profiles. Notably, cross-class clustering, including statins with anti-infective and anti-inflammatory agents, suggested shared downstream biological effects beyond primary indications. These findings demonstrate that a signal-based drug similarity network derived from spontaneously reported data can capture clinically meaningful safety patterns and reveal latent relationships across therapeutic classes, thereby providing a scalable approach to pharmacovigilance and hypothesis generation.</p>","PeriodicalId":54746,"journal":{"name":"Korean Journal of Physiology & Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.2,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147846332","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of nortriptyline on inhibitory synaptic transmission within the substantia gelatinosa of the trigeminal subnucleus caudalis in mice.","authors":"Thi Quynh Nhu Tran, Seon Ah Park, Seon Hui Jang, Won Jung, Seong Kyu Han","doi":"10.4196/kjpp.26.010","DOIUrl":"https://doi.org/10.4196/kjpp.26.010","url":null,"abstract":"<p><p>Nortriptyline, a tricyclic antidepressant widely used for the treatment of neuropathic pain, produces antinociceptive effects that cannot be fully accounted for by monoamine reuptake inhibition alone. Increasing evidence indicates that tricyclic antidepressants directly influence neuronal excitability and synaptic transmission within central nociceptive pathways; their actions on inhibitory neurotransmission in the trigeminal system remain incompletely characterized. In the present study, we investigated the effects of nortriptyline on inhibitory synaptic transmission in substantia gelatinosa neurons of the trigeminal subnucleus caudalis using whole-cell patch-clamp recordings in mouse brainstem slices. Nortriptyline produced a concentration-dependent increase in the frequency of spontaneous inhibitory postsynaptic currents without altering event amplitude and in an action potential-independent manner, consistent with a presynaptic mechanism. This facilitation reflected enhanced release of both GABA and glycine from presynaptic terminals. Importantly, the nortriptyline-induced enhancement of inhibitory synaptic activity persisted under Ca²⁺-free extracellular conditions, indicating that extracellular Ca²⁺ influx is not required. Collectively, these findings demonstrate that nortriptyline enhances inhibitory synaptic transmission in trigeminal substantia gelatinosa neurons primarily through presynaptic mechanisms, likely involving intracellular Ca²⁺ mobilization, and provide a cellular framework for its modulatory effects on orofacial nociceptive processing.</p>","PeriodicalId":54746,"journal":{"name":"Korean Journal of Physiology & Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.2,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147846334","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cardioprotective effects of 3-N-Butylphthalide in diabetic cardiomyopathy: focus on balanced mitochondrial dynamics and pyroptosis pathways.","authors":"Huaning Xie, Shaik Althaf Hussain, Narendra Maddu, Jing An","doi":"10.4196/kjpp.25.294","DOIUrl":"https://doi.org/10.4196/kjpp.25.294","url":null,"abstract":"<p><p>Diabetic cardiomyopathy (DCM) is a severe complication of diabetes, marked by myocardial dysfunction due to mitochondrial dysfunction and pyroptosis. 3-N-Butylphthalide (NBP), known for cardioprotective effects, remains unstudied in DCM. We evaluated NBP's therapeutic potential in a rat model of type 2 DCM, focusing on mitochondrial dynamics, mitophagy, and pyroptosis. Male Sprague-Dawley rats with DCM, induced by a high-fat diet and streptozotocin, were divided into five groups: control, DCM, DCM + NBP (100 mg/kg/day for 14 days' post-diabetes), DCM + Mdivi-1 (1.2 mg/kg/day), and DCM + NBP + Mdivi-1. Cardiac function was assessed by echocardiography; myocardial injury, histopathology, inflammasome-pyroptosis activation, mitophagy, mitochondrial dynamics, and function were analyzed via ELISA, hematoxylin and eosin staining, transmission electron microscopy, Western blot, and biochemical assays. DCM rats showed reduced ejection fraction and fractional shortening, increased left ventricular end-diastolic and systolic diameters, elevated cTnI and BNP, and histopathological damage. Inflammasome and pyroptosis markers (NLRP3, cleaved-caspase-1, ASC, GSDMD-N, IL-1β, LDH) increased, mitophagy (PINK1, Parkin) decreased, and mitochondrial function (ROS up, ATP down) worsened in DCM group. NBP improved cardiac function, reduced injury markers, and histopathology by suppressing inflammasome-pyroptosis, enhancing mitophagy, and restoring mitochondrial function and dynamics (Mfn2 up, Drp1 modulated). Co-treatment with Mdivi-1 attenuated these effects, indicating reliance on balanced mitochondrial dynamics. NBP mitigates DCM by enhancing mitochondrial homeostasis and inhibiting pyroptosis, but its efficacy diminishes with excessive fission inhibition. These findings suggest NBP's potential as a DCM therapy, meriting further clinical exploration.</p>","PeriodicalId":54746,"journal":{"name":"Korean Journal of Physiology & Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.2,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147846300","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Depletion of BIS in astrocytes aggravates reactive gliosis following photothrombotic brain injury.","authors":"Soon-Young Jung, Ji-Won Hwang, Hye Hyeon Yun, Kyunghyun Yoo, Hong Lim Kim, Yuna Oh, Sung Won Jung, Joo Youn Kim, Sun-Nyoung Hwang, Seong Yun Kim, Seung-Hyun Jung, Mun-Yong Lee, Jeong-Hwa Lee, Tae-Ryong Riew","doi":"10.4196/kjpp.25.361","DOIUrl":"10.4196/kjpp.25.361","url":null,"abstract":"<p><p>BIS (Bcl-2-interacting cell death suppressor, or BAG-3), is a multifunctional co-chaperone that maintains protein quality control via autophagy and proteostasis. Following the central nervous system (CNS) injury, BIS expression is markedly upregulated in reactive astrocytes, suggesting a regulatory role of reactive astrogliosis. To investigate this, we generated astrocyte-specific BIS knockout (BIS-aKO) mice for the first time. While BIS-aKO mice exhibited normal growth and survival, the injury-induced upregulation of BIS expression was abolished in reactive astrocytes following excitotoxic injury. Using a photothrombotic stroke model, we found that astrocytic BIS deficiency resulted in significantly increased GFAP expression in scar-forming astrocytes at the infarct border and altered morphology in the peri-infarct region. Furthermore, we observed increased infiltration of amoeboid Iba1-positive cells in the astroglial scar, indicating enhanced neuroinflammation. Correlative light-and electron-microscopy following both stroke and stab wound injury revealed BIS-aKO astrocytes exhibited a greater density of intermediate filament filling in their soma and processes, along with relatively fewer cytoplasmic organelles, such as mitochondria. Collectively, these findings highlight a previously unrecognized role of BIS in modulating reactive gliosis during brain injury and our model provides a valuable tool for investigating the astrocyte-specific functions of BIS in CNS pathophysiology.</p>","PeriodicalId":54746,"journal":{"name":"Korean Journal of Physiology & Pharmacology","volume":" ","pages":"251-264"},"PeriodicalIF":2.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13124745/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146068739","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MDH2 S246 phosphorylation protects mitochondria against hypoxia/reoxygenation injury due to acetate/lactate metabolism.","authors":"Jubert Marquez, Nammi Park, Maria Victoria Faith Garcia, Jessa Flores, Ippei Shimizu, Hyoung Kyu Kim, Jin Han","doi":"10.4196/kjpp.25.359","DOIUrl":"10.4196/kjpp.25.359","url":null,"abstract":"<p><p>Ischemic cardiomyopathy (ICM) is characterized by impaired myocardial function resulting from reduced coronary blood flow, resulting in heart failure. Emerging evidence from proteomic studies indicates that ischemic preconditioning confers cardioprotection against ICM through the regulation of mitochondrial proteins. Proteomic analyses have identified phosphorylation in mitochondrial proteins, including malate dehydrogenase 2 (MDH2), as mediators of cardioprotective mechanisms. However, the mechanism by which MDH2 phosphorylation contributes to cardioprotection in cardiovascular diseases remains poorly understood. This study investigates the role of MDH2 phosphorylation, particularly at S246, in regulating cardiac function. Analysis of patients with dilated cardiomyopathy indicated no significant change in <i>MDH2</i> expression, similar to a trend observed in ischemic patient data. Considering that a previous proteomic analysis of ischemic preconditioned rat hearts indicated phosphorylation at S246, we analyzed the functional role of this phosphorylation by introducing S246A phosphomutation. S246A phosphomutation significantly decreased MDH2 activity, accompanied by an increased accumulation of acetate and lactate as demonstrated by metabolomics. S246A phosphomutation also lowers mitochondrial membrane potential and ATP production. Under hypoxia/reoxygenation (H/R) conditions, S246A phosphomutation downregulates mitochondrial biogenesis and fusion proteins such as PGC1α and OPA1. Overall, these findings suggest that MDH2 phosphorylation at S246 is important in protecting against H/R injury through mitochondrial function regulation and activation of metabolic pathways. This discovery establishes a potential therapeutic strategy and a clear direction for drug development to specifically address conditions such as ICM.</p>","PeriodicalId":54746,"journal":{"name":"Korean Journal of Physiology & Pharmacology","volume":" ","pages":"241-249"},"PeriodicalIF":2.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13124744/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145913968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated analysis of scRNA-seq and bulk RNA-seq identifies matrisome-related biomarkers for prognostic stratification and immune landscape in lung adenocarcinoma.","authors":"Meifang Zhao, Yuanchao Xiao, Qunzhi Wang","doi":"10.4196/kjpp.25.293","DOIUrl":"10.4196/kjpp.25.293","url":null,"abstract":"<p><p>Lung adenocarcinoma (LUAD) displays significant biological heterogeneity, with matrisome-related genes (MRGs) playing key roles in tumor progression and immune regulation. Understanding the interplay between MRGs, the tumor microenvironment, and host immunity is critical for mechanistic insights. LUAD transcriptomic and clinical data were sourced from TCGA, GEO (GSE31210), and single-cell data (GSE189357). MRGs were analyzed <i>via</i> limma, with prognostic genes identified using univariate Cox. A LASSO-multivariate Cox model was built and validated using Kaplan-Meier, receiver operating characteristic, and external datasets. Functional enrichment (GO/KEGG/GSEA), immune infiltration (ssGSEA/ESTIMATE/CIBERSORT), tumor mutational burden, immunotherapy response, and drug sensitivity were assessed. Consensus clustering defined molecular subtypes. Single-cell analysis (Seurat/SCISSOR) identified risk-associated cells, with AUCell and CellChat evaluating activity and cell communication. A 7-gene risk model (ANGPTL4, C1QTNF6, CCL20, CLEC3B, FCN1, LAMA3, PRELP) stratified LUAD patients into distinct survival groups (area under the curve > 0.7). Low-risk patients showed higher immune infiltration, lower TIDE scores (suggesting better immunotherapy response), and reduced sensitivity to Axitinib/Gefitinib. Single-cell analysis implicated fibroblasts and myeloid cells in high-risk profiles, with activated MIF/TGF-β pathways. This integrated transcriptomic and single-cell model predicts LUAD prognosis and immune landscape, guiding personalized therapy.</p>","PeriodicalId":54746,"journal":{"name":"Korean Journal of Physiology & Pharmacology","volume":" ","pages":"199-218"},"PeriodicalIF":2.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13128308/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145913960","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interleukin-1β-induced arthritis involves chondrocyte oxiapoptophagy.","authors":"Jeong-Yeon Seo, Do Kyung Kim, HyangI Lim, Kyeong-Rok Kang, Hong Sung Chun, Ji-Su Oh, Jae-Sung Kim","doi":"10.4196/kjpp.25.279","DOIUrl":"10.4196/kjpp.25.279","url":null,"abstract":"<p><p>Pro-inflammatory cytokine-induced chondrocyte death contributes to various types of arthritis, including osteoarthritis and rheumatoid arthritis. Recent studies have indicated that oxysterols induce oxiapoptophagy, a form of cell death characterized by oxidative stress, apoptosis, and autophagy. This study aimed to determine whether interleukin-1β (IL-1β)-induced articular cartilage degeneration is associated with chondrocyte oxiapoptophagy. Intra-articular injection of IL-1β into the knee joints of experimental animals induced progressive articular cartilage degeneration and promoted the expression of cholesterol-25-hydroxylase (CH25H), 25-hydroxycholesterol 7α-hydroxylase (CYP7B1), caspase-3, cyclooxygenase-2 (COX-2), and beclin-1. Consistently, IL-1β-stimulated cartilage explants showed proteoglycan loss, and chondrocytes exhibited increased expression and activation of matrix metalloproteinases (MMP-1, MMP-3, MMP-13). IL-1β upregulated the expression of CH25H and CYP7B1, thereby increasing 25-HC production in chondrocytes. Sequentially, IL-1β promoted chondrocyte apoptosis by triggering the caspase cascade, while levels of oxidative stress-related molecules, including reactive oxygen species (ROS), inducible nitric oxide synthase, COX-2, nitric oxide, and prostaglandin E₂, were elevated in chondrocytes. Additionally, IL-1β increased autophagosome formation and the expression of autophagy biomarkers, including beclin-1 and microtubule-associated protein 1A/1B-light chain 3, by increasing p53 and decreasing the phosphorylation of Akt and mTOR in chondrocytes. Furthermore, IL-1β increased the phosphorylation of NF-κB, which subsequently translocated from the cytosol to the nucleus in chondrocytes. CDDO-Me, an inhibitor of the NF-κB pathway, suppressed the IL-1β-induced expression of CH25H, CYP7B1, caspase-3, and beclin-1, as well as ROS production in chondrocytes. Collectively, these findings consistently indicate that IL-1β-induced articular cartilage degeneration is associated with chondrocyte oxiapoptophagy <i>via</i> the NF-κB signaling pathway.</p>","PeriodicalId":54746,"journal":{"name":"Korean Journal of Physiology & Pharmacology","volume":" ","pages":"185-197"},"PeriodicalIF":2.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13124743/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145919250","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Heart failure with preserved ejection fraction: current insights and emerging therapeutic directions.","authors":"Jeehyun Kim, Gwang Hyeon Eom, Somy Yoon","doi":"10.4196/kjpp.25.250","DOIUrl":"10.4196/kjpp.25.250","url":null,"abstract":"<p><p>Heart failure with preserved ejection fraction (HFpEF), defined by clinical heart failure with left ventricular ejection fraction ≥ 50%, represents more than half of heart failure cases in Asia and carries a one-year composite hospitalization and mortality rate of approximately 12.1%. Recent landmark trials have transformed the therapeutic landscape: Sodium-glucose cotransporter 2 inhibitors emerged as treatment for HFpEF, shown beneficial in EMPEROR-preserved and DELIVER. Empagliflozin significantly reduced the risk of cardiovascular death or heart failure hospitalization and dapagliflozin demonstrated comparable efficacy across regions. Furthermore, glucagon-like peptide-1 receptor agonist such as semaglutide have shown promising improvements in functional capacity and symptom burden in obesity-related HFpEF. Asian HFpEF phenotypes often exhibit high rates of hypertension and diabetes, alongside lower average body mass index compared to Western cohorts. In numerous respects, the clinical and pathophysiological features of HFpEF in Asian populations diverge from those traditionally observed in Western cohorts. In this brief review, we will focus on therapeutics approved for HFpEF and agents currently under clinical trial, as well as the distinctive characteristics of HFpEF patients observed in Asia and the key considerations for future therapeutic development in this region.</p>","PeriodicalId":54746,"journal":{"name":"Korean Journal of Physiology & Pharmacology","volume":" ","pages":"169-184"},"PeriodicalIF":2.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13124746/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145671022","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aloin attenuates NMDA receptor by modulating calcium response on substantia gelatinosa neurons of the trigeminal subnucleus caudalis in mice.","authors":"Thi Quynh Nhu Tran, Seon Ah Park, Seon Hui Jang, Won Jung, Seong Kyu Han","doi":"10.4196/kjpp.25.317","DOIUrl":"10.4196/kjpp.25.317","url":null,"abstract":"<p><p>Aloe vera extracts, particularly aloin, have been widely used in traditional Chinese medicine for their anti-inflammatory and detoxifying properties. Recent studies suggest that aloin may also exert neuroprotective effects, though its specific mechanisms remain unclear. Glutamate excitotoxicity, a critical factor in neurodegenerative and pain-related disorders, is mediated primarily by <i>N</i>-methyl-D-aspartic acid (NMDA) receptors, which regulate calcium influx and neuronal excitability. Meanwhile, substantia gelatinosa (SG) of the trigeminal subnucleus caudalis (Vc) plays a central role in processing orofacial pain, where glutamate is a key excitatory neurotransmitter. Using whole-cell patch-clamp electrophysiology and calcium imaging techniques in mice SG neurons of the Vc, we examined aloin's effects on glutamate receptor-mediated responses. Aloin selectively inhibited NMDA-induced responses without affecting AMPA or kainate receptor activity. The suppression of NMDA-mediated currents by aloin was linked to changes in Ca²⁺ influx but occurred independently of voltage-gated sodium channels and action potential generation. Calcium imaging revealed that aloin reduced NMDA-induced intracellular calcium influx, supporting its role in mitigating NMDA-mediated excitotoxicity. Furthermore, aloin significantly suppressed the spontaneous firing activity of SG neurons, suggesting its broader regulatory effects on neuronal excitability. Our findings demonstrate that aloin attenuates NMDA receptor-induced excitatory signaling by regulating calcium response. This specificity highlights aloin's potential as a therapeutic candidate for conditions involving glutamate excitotoxicity and orofacial pain regulation.</p>","PeriodicalId":54746,"journal":{"name":"Korean Journal of Physiology & Pharmacology","volume":" ","pages":"231-239"},"PeriodicalIF":2.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13124741/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145913901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Circular RNA circSmad4 controls pulmonary fibrosis.","authors":"Anna Jeong, Taewon Kook, Yun-Gyeong Lee, Yongwoon Lim, Ayeong Han, Young-Kook Kim, Dongtak Jeong, Woo Jin Park, Duk-Hwa Kwon, Hyun Kook","doi":"10.4196/kjpp.25.123","DOIUrl":"10.4196/kjpp.25.123","url":null,"abstract":"<p><p>Pulmonary fibrosis is a progressive and irreversible lung disease characterized by excessive fibroblast activation and extracellular matrix (ECM) deposition, leading to respiratory failure. Despite recent advances in understanding its molecular mechanisms, effective therapies remain limited. Circular RNAs have emerged as key regulators of gene expression, yet their role in pulmonary fibrosis is poorly understood. Here, we investigated circSmad4 and its therapeutic potential. Our results demonstrate that circSmad4 expression was markedly upregulated in bleomycin-induced pulmonary fibrosis, suggesting a role in fibrotic progression. Silencing circSmad4 by siRNA significantly alleviated lung fibrosis, reducing lung weight, collagen deposition, and inflammatory cytokine expression. Mechanistically, we identified that circSmad4 exerted its pro-fibrotic effects through the miR-671-5p/<i>Fgfr2</i> axis, suppressing miR-671-5p and increasing <i>Fgfr2</i> expression, thereby enhancing fibroblast activation. Additionally, si-circSmad4 treatment also downregulated pro-inflammatory cytokines (IL-6, TNF-α, and TGF-β1) and inhibited ECM protein expression. Furthermore, <i>in vitro</i> experiments using TGF-β1-induced fibroblast activation models showed that circSmad4 knockdown mitigated fibroblast activation by lowering the expression of fibrosis-related genes (<i>Acta2, Col1a1, Col3a1, Ctgf</i>) and collagen secretion. Consistently, pharmacological inhibition of FGFR2 with FGFR2-IN-1 also suppressed the pro-fibrotic effects of TGF-β1, mimicking si-circSmad4. These findings suggest that circSmad4 functions as a central regulator of pulmonary fibrosis by modulating fibroblast activation, ECM deposition, and inflammation. In conclusion, circSmad4 represents a novel driver of pulmonary fibrosis, and targeting circSmad4 may offer a promising therapeutic strategy.</p>","PeriodicalId":54746,"journal":{"name":"Korean Journal of Physiology & Pharmacology","volume":" ","pages":"219-230"},"PeriodicalIF":2.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13128309/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146068833","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}