Experimental and molecular pathology最新文献

{"title":"Mechanism and importance of ferroptosis in clear cell renal cell carcinoma treatment","authors":"Manvi Agarwal Neeraj ,&nbsp;Songmi Noh ,&nbsp;JeeHoon Chae ,&nbsp;JunJeong Choi","doi":"10.1016/j.yexmp.2025.105004","DOIUrl":"10.1016/j.yexmp.2025.105004","url":null,"abstract":"<div><div>Metabolic reprogramming is a common phenomenon that is observed in diverse cancer types. Clear cell renal cell carcinoma (ccRCC) is termed a metabolic disease due to its dysregulated lipid and glucose metabolism. Among kidney cancers, ccRCC is the most malignant form of cancer, defined by the large accumulation of lipid droplets. These lipid droplets, although they provide energy and induction of metastasis, also act as a buffer by preventing ferroptosis. Ferroptosis is an iron-dependent type of regulated cell death, which is characterized by the accumulation of toxic lipid peroxides. Ferroptosis has emerged to play an important part in tumor progression and cancer therapy. Due to a lack of diagnostic markers and resistance towards therapy, ccRCC is a difficult cancer type to overcome. However, studies have shown the importance of ferroptosis in ccRCC treatment by targeting various pathways. This paper helps in understanding the mechanism of ferroptosis and the evidence observed in ccRCC. This paper aims to understand the current trend of ferroptosis in ccRCC and produce a potential therapy for ccRCC through ferroptosis.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"144 ","pages":"Article 105004"},"PeriodicalIF":3.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145312634","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":"Persistent renin-angiotensin system and inflammatory dysregulation following COVID-19 impairs ischemic stroke recovery","authors":"Amy May Lin Quek ,&nbsp;Ooiean Teng ,&nbsp;Ju-Hea Park ,&nbsp;Bernadette Guek Cheng Er ,&nbsp;Erle Chuen Hian Lim ,&nbsp;Raymond Chee Seong Seet","doi":"10.1016/j.yexmp.2025.105009","DOIUrl":"10.1016/j.yexmp.2025.105009","url":null,"abstract":"<div><div>Previous studies indicate that stroke recovery is worse in patients with prior COVID-19, suggesting persistent biological perturbations. We investigated lingering renin-angiotensin system (RAS) and inflammatory alterations after COVID-19 to uncover mechanisms driving impaired ischemic stroke recovery. We conducted a prospective observational cohort study comparing clinical and molecular profiles of ischemic stroke patients with and without recent COVID-19 infection to age-matched healthy controls. Plasma angiotensin-(1–7), angiotensin II, and soluble ACE2 were quantified, high-throughput proteomic profiling was performed using the Olink® Explore platform, and RNA sequencing was conducted to identify molecular mechanisms related to COVID-19-associated stroke and stroke outcomes (90-day modified Rankin Scale (mRS)). A total of 189 participants (38 COVID-19-associated stroke, 77 non-COVID-19 stroke, and 74 healthy controls) were enrolled. COVID-19-associated stroke patients exhibited significantly higher proportions of cryptogenic strokes (21.1 % vs 10.4 %), earlier hospital presentation (mean 185 vs 310 min), greater use of endovascular thrombectomy (97.4 % vs. 52.6 %), yet poorer functional outcomes (mRS ≥3) at 3 months (73 % vs. 47 %, all <em>p</em> &lt; 0.05). Both stroke groups showed elevated angiotensin-(1–7) levels compared to controls, but angiotensin II levels were notably higher only in non-COVID-19 stroke patients. Proteomic analysis revealed sustained elevation of interferon-gamma (IFN-γ) signaling in COVID-19-associated stroke patients. Reduced AKT3 levels emerged as a significant predictor of poor outcomes, independent of renin-angiotensin biomarkers (adjusted OR 0.40; 95 % CI 0.16–0.94). Stroke patients with low AKT3 levels and poor outcomes exhibited significant upregulation of ribosomal proteins (RPS15, RPS4X, RPS7, RPS18, RPSA, RPS27A, RPS13, RPS23), reflecting heightened translational stress. Persistent RAS and inflammatory dysregulation following COVID-19 may contribute to worse stroke recovery. Future studies should validate and investigate the therapeutic implications of these findings.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"144 ","pages":"Article 105009"},"PeriodicalIF":3.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145573409","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":"Automated quantification of collagen proportionate area correlates with molecular and histological markers of fibrosis in CCl4-treated rats","authors":"Bernie Efole ,&nbsp;Mathilde Mouchiroud ,&nbsp;Alexandra Dubé ,&nbsp;Andréa Allaire ,&nbsp;Sébastien M. Labbé ,&nbsp;Cindy Serdjebi ,&nbsp;Olivier Barbier ,&nbsp;Alexandre Caron","doi":"10.1016/j.yexmp.2025.104996","DOIUrl":"10.1016/j.yexmp.2025.104996","url":null,"abstract":"<div><div>Liver fibrosis results from chronic liver injury and is characterized by excessive accumulation of extracellular matrix due to sustained wound-healing responses. Although histological evaluation remains the gold standard for fibrosis assessment, its subjectivity can limit reproducibility. In this study, we evaluated an automated image analysis software, MorphoQuant, for liver fibrosis quantification in a rat model of CCl4-induced liver injury. Male Wistar rats were treated with CCl4 or vehicle for six weeks, and fibrosis severity was assessed using both the conventional Ishak staging system and automated quantification of collagen proportionate area (CPA). Automated CPA strongly correlated with Ishak stage, liver index, and plasma aminotransferase levels. Additionally, CPA values were significantly associated with the expression of fibrosis-related genes and macrophage infiltration, highlighting the software's ability to assess both fibrosis progression and inflammatory responses. These findings support the use of MorphoQuant as a robust, reader-independent tool that enhance analytical consistency in preclinical models of liver fibrosis.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"144 ","pages":"Article 104996"},"PeriodicalIF":3.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145060865","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":"NVP-BEZ235 enhances autophagy and ameliorates cognitive deficits by targeting tauopathies","authors":"Ifat Alsharif","doi":"10.1016/j.yexmp.2025.104988","DOIUrl":"10.1016/j.yexmp.2025.104988","url":null,"abstract":"<div><div>Tauopathies are a class of neurodegenerative disorders characterized by the abnormal accumulation of hyperphosphorylated tau (p-tau) and the formation of neurofibrillary tangles. Autophagy, a fundamental cellular degradation pathway, plays a pivotal role in maintaining proteostasis by facilitating the clearance of misfolded and aggregated proteins. In tauopathies, however, autophagic processes are often impaired, contributing to the pathological buildup of p-tau. NVP-BEZ235, a dual inhibitor of the mammalian target of rapamycin (mTOR) and PI3K, has previously been evaluated in phase I clinical trials for solid tumors and lymphomas. In this study, we investigated the therapeutic potential of NVP-BEZ235 in tauopathy models, both in vitro and in vivo. In SH-SY5Y cells stably expressing human P301L-mutant tau (SH-Tau), NVP-BEZ235 treatment induced a time-dependent increase in LC3B-II and a decrease in p62 levels, consistent with enhanced autophagic activity. Autophagic flux analysis further confirmed the promotion of autophagy upon mTOR pathway inhibition. NVP-BEZ235 significantly reduced tau phosphorylation at multiple residues, including Ser262, Ser396, Ser404, and Thr231, without eliciting cytotoxic effects. In a transgenic mouse model of tauopathy (P301S), chronic treatment with NVP-BEZ235 (20 mg/kg/day for two months) resulted in a marked reduction of both RIPA-soluble and -insoluble p-tau species in the brain. Spatial learning and memory, assessed through Morris water maze and novel object recognition tests, were significantly improved in treated mice. Furthermore, NVP-BEZ235 administration reduced neuroinflammatory markers and pro-inflammatory cytokine levels (TNF-α, IL-1β, IL-6), while also enhancing autophagic markers in brain tissue. Hematological analysis and organ histology revealed no signs of systemic toxicity. Collectively, these findings demonstrate that NVP-BEZ235 facilitates tau clearance by enhancing autophagy through mTOR inhibition, thereby mitigating cognitive deficits and neuroinflammation in tauopathy models. This study supports the therapeutic potential of NVP-BEZ235 as a promising candidate for the treatment of tau-related neurodegenerative diseases.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"143 ","pages":"Article 104988"},"PeriodicalIF":2.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144696821","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":"Twenty-eight-day perfluorooctanoate exposure does not affect immune cell populations in naïve mice","authors":"Candice Limper ,&nbsp;Crystal Silliman ,&nbsp;Ethan Cho ,&nbsp;Amanda Ng ,&nbsp;Steven Yang ,&nbsp;Zachary Hammer ,&nbsp;Isabella Ciocca ,&nbsp;Brian Imbiakha ,&nbsp;Amie Redko ,&nbsp;Colleen M. Lau ,&nbsp;Sue Chang ,&nbsp;Julie Sahler ,&nbsp;Avery August","doi":"10.1016/j.yexmp.2025.104990","DOIUrl":"10.1016/j.yexmp.2025.104990","url":null,"abstract":"<div><div>Perfluorooctanoate (C₇F₁₅CO₂⁻, PFOA) is a perfluorinated compound widely used in the production of industrial products, such as non-stick cookware and firefighting foams. Although its production has been phased out in the United States, PFOA remains prevalent in the environment due to its persistence and resistance to degradation. As a result, trace levels of PFOA is detectable in water, soil, biota, and the general population. Environmental and toxicological concerns have emerged due to potential health risks associated with PFOA exposure, including effects on the immune system. Basic underlying knowledge gaps exist for potential effects of PFOA on baseline immune cell maintenance in the absence of overt liver hypertrophy. In this study, we assessed the immune-related effects of 28-day daily PFOA exposure in adult naïve mice, using doses of 20 ng/kg/day, 200 ng/kg/day, 2 μg/kg/day, and 40 μg/kg/day, resulting in mean serum PFOA concentrations of non-detectable, 6.979 ng/mL, 80.03 ng/mL, and 1773 ng/mL respectively, representative of levels seen in the general human population (∼1.5 ng/mL), community-exposed residents (∼225 ng/mL), and occupational workers (∼2000 ng/mL). Evaluation of immune cell populations in bone marrow, thymus, spleen, liver, and lymph nodes, along with serum antibodies indicate that 28 days of PFOA exposure had no effect on proportion and number of immune cell populations nor serum antibodies, except for a slight decrease in serum IgE at the highest dose. By contrast, mice receiving CTX, a known immune suppressant, exhibited a wide array of biological responses, which were absent from PFOA-treated mice. These findings contribute to understanding the potential immune effects of environmentally relevant PFOA exposure.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"143 ","pages":"Article 104990"},"PeriodicalIF":3.7,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144723708","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":"Research progress of sarcopenia: Diagnostic advancements, molecular mechanisms, and therapeutic strategies","authors":"Hao-lin Wang ,&nbsp;Long-long Liu ,&nbsp;Ze-yu Tan ,&nbsp;Yuan Zhou ,&nbsp;Jing Zhang ,&nbsp;Lin Zhai ,&nbsp;Qian Xie ,&nbsp;Rong-hua Liu","doi":"10.1016/j.yexmp.2025.104992","DOIUrl":"10.1016/j.yexmp.2025.104992","url":null,"abstract":"<div><div>Muscle atrophy or loss is an important sign of human aging. As the aging society approaches and human lifespan prolongs, sarcopenia has emerged as one of the significant risks influencing the quality of life of the elderly. Sarcopenia is a progressive geriatric syndrome characterized by the deterioration of skeletal muscle mass and function, which can result in an increased risk of falls, fractures, restricted physical activity, disability, mortality, and a remarkable escalation in the risk of cardiovascular diseases among the elderly. This work synthesizes recent advances in sarcopenia research, critically evaluating diagnostic frameworks, histopathological hallmarks, and molecular pathways driving disease progression. Additionally, we provide an in-depth analysis of evidence-based exercise and nutritional interventions, identifying key research gaps. These insights offer valuable references for future research on sarcopenia and clinical management, as well as lifestyle interventions such as exercise and nutrition.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"143 ","pages":"Article 104992"},"PeriodicalIF":3.7,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144829736","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":"Daidzin suppresses melanogenesis through ERK and AKT signaling pathways mediated MITF proteasomal degradation","authors":"Jinpeng Lv ,&nbsp;Kun Zou ,&nbsp;Chuanwei Yin ,&nbsp;Wenhui Xu ,&nbsp;Duo Meng ,&nbsp;Huansha Zhang ,&nbsp;Wenhao Yu ,&nbsp;Peiwen Jiang ,&nbsp;Changjun Yun ,&nbsp;Hui Xue ,&nbsp;Nan Hu ,&nbsp;Rongyin Gao","doi":"10.1016/j.yexmp.2025.104986","DOIUrl":"10.1016/j.yexmp.2025.104986","url":null,"abstract":"<div><div>Daidzin, a prominent isoflavone found in soybeans, <em>Pueraria lobata</em>, and various legumes, has been extensively investigated for its diverse pharmacological activities, which include anticancer, antioxidant, anti-inflammatory, antiepileptic, and alcohol detoxification properties. Previous studies have shown that the dichloromethane fraction of <em>Pueraria lobata</em> stem (DCM-PLS) exhibits significant anti-melanogenic activity, with daidzin identified as the principal active compound. However, the precise role of daidzin in pigmentation remains incompletely understood. This study aimed to investigate the effects of daidzin on pigmentation and to elucidate the underlying mechanisms. Our findings revealed that daidzin not only inhibited basal melanin production but also reduced melanin synthesis induced by α-MSH, ACTH, and UV exposure. The effects of daidzin were primarily mediated through the activation of the extracellular signal-regulated protein kinase (ERK) and protein kinase B (AKT) pathways. Upon activation, these pathways facilitated the ubiquitination and degradation of Melanocytes Inducing Transcription Factor (MITF), resulting in decreased expression of tyrosinase, TRP-1, and TRP-2, ultimately inhibiting melanogenesis. Importantly, our research further demonstrated that daidzin reduced pigmentation in both zebrafish and human skin explants, highlighting its potential application as a therapeutic approach for disorders related to skin pigmentation.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"143 ","pages":"Article 104986"},"PeriodicalIF":2.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144680738","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":"Treatment with YKL-05-099, a salt inducible kinase (SIK) inhibitor, attenuates salt-sensitive hypertension: The molecular outcomes of SIK in the kidney","authors":"Dayene S. Gomes ,&nbsp;Bruna Visniauskas ,&nbsp;Prasad V.G. Katakam ,&nbsp;Rosilane Taveira-da-Silva ,&nbsp;Jennifer Lowe ,&nbsp;Zoe Vallotton ,&nbsp;Minolfa C. Prieto ,&nbsp;Lucienne S. Lara","doi":"10.1016/j.yexmp.2025.104977","DOIUrl":"10.1016/j.yexmp.2025.104977","url":null,"abstract":"<div><div>Salt-inducible kinase (SIK) is a serine/threonine kinase that acts as an intracellular Na⁺ sensor, playing a role in salt-sensitive hypertension. We aimed to evaluate the therapeutic potential of YKL-05-099, a selective SIK inhibitor, in protecting kidney function and attenuating salt-sensitive hypertension. Male adult C57BL/6 J mice were randomly assigned to either a normal sodium (0.5 % NaCl; NS) or high‑sodium diet (4 % NaCl; HS) and further divided into two subgroups – receiving either intraperitoneal injection of saline or SIK inhibitor (SIKi; YKL-05-099, 20 mg/Kg/day). Blood pressure was measured by radiotelemetry for 15 days. On days 7 and 14, mice were placed in metabolic cages for 24 h urine collection. At the end of the treatment, blood and kidneys were collected for renal function assessment, and the renal cortex was extracted for biochemical analysis. HS intake led to a salt-sensitive hypertension model, as seen by increased systolic blood pressure (SPB), kidney damage and impairment in renal function. In the HS, SIKi treatment blocked the elevated SIK activity in the renal cortex, preventing kidney damage, proteinuria, and increased SBP. The Na⁺ balance was positive due, partly, to a higher (Na⁺+K⁺)-ATPase activity in the HS. SIKi treatment exerted an anti-inflammatory effect by attenuating HS-dependent macrophage infiltration and ROS production and decreasing the metalloprotease activity. Consequently, the kidney damage biomarker monocyte chemotactic protein type 1 excretion was enhanced. In conclusion, SIK inhibition rescued HS mice from salt-sensitive hypertension and kidney insufficiency by blocking inflammation, metalloprotease activity, and oxidative stress.</div></div><div><h3>Significance</h3><div>Salt-sensitive hypertension is a major contributor to chronic kidney disease and cardiovascular morbidity worldwide. Despite its prevalence, the underlying mechanisms linking high salt intake to renal injury remain incompletely understood, and targeted therapies are lacking. This study identifies salt-inducible kinase (SIK) as a key mediator of salt-induced renal dysfunction and systemic hypertension. By using a selective SIK inhibitor (YKL-05-099), we demonstrate that pharmacological inhibition of SIK effectively prevents kidney damage, inflammation, oxidative stress, and high blood pressure in a preclinical model of salt-sensitive hypertension. These findings highlight SIK as a promising therapeutic target for preserving renal function and managing salt-induced hypertension, paving the way for novel interventions in salt-related cardiovascular and renal diseases.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"143 ","pages":"Article 104977"},"PeriodicalIF":2.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144656118","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":"m6A demethylase FTO/ALKBH5 promotes diabetes-induced endothelial cell dysfunction by negatively regulating lncRNA H19","authors":"Yanli Luo ,&nbsp;Wanjun Luo ,&nbsp;Yanan Cao ,&nbsp;Zhanpeng Wang","doi":"10.1016/j.yexmp.2025.104970","DOIUrl":"10.1016/j.yexmp.2025.104970","url":null,"abstract":"<div><div>Endothelial cell dysfunction induced by glucose is the most important cause of diabetic vascular complications, which are the leading causes of blindness, disability, renal failure, heart failure, stroke, and even death in diabetic patients. RNA m6A modification is involved in the pathogenesis of human disease. However, the role and underlying mechanism of RNA m6A modification in high glucose-induced endothelial cell dysfunction is not well understood. Herein, this study first demonstrated that m6A levels were decreased and that the demethylases FTO and ALKBH5 were upregulated in diabetic patients and an STZ-induced diabetic mouse model. This study revealed that high glucose induced decreased m6A levels and increased expression of FTO and ALKBH5, and silencing of FTO and ALKBH5 restored high glucose-induced decreases in m6A levels and dysfunction of HUVECs. Next, this study systematically screened differentially expressed lncRNAs, including H19, in HUVECs under high glucose conditions. This study revealed that FTO-ALKBH5 inhibited H19 expression by decreasing m6A modification in H19 transcripts. In addition, this study demonstrated the role of the FTO/ALKBH5/H19 pathway in high glucose-induced cellular dysfunction of HUVECs. Ultimately, this study uncovered that silencing of H19 promoted the expression of cell cycle-related genes, including PTEN, p21 and p27 via interacting with EZH2 and affecting the H3K27me3 histone modification. Overall, this study is the first to dissect the regulation of lncRNA by m6A modification in hyperglycaemia, identifying a new regulatory pathway in high glucose-induced cellular dysfunction and providing biomarkers with the potential to serve as therapeutic targets for high glucose-induced cellular dysfunction.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"143 ","pages":"Article 104970"},"PeriodicalIF":2.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144069393","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":"Metabolic reprogramming during ineffective erythropoiesis in β-thalassemia/HbE disease","authors":"Chanyanat Sukhuma ,&nbsp;Donny Nauphar ,&nbsp;Khanita Nuamsee ,&nbsp;Wasinee Kheansaard ,&nbsp;Kittiphong Paiboonsukwong ,&nbsp;Alisa Wilantho ,&nbsp;Chumpol Ngamphiw ,&nbsp;Pornthip Chaichompoo ,&nbsp;Sissades Tongsima ,&nbsp;Saovaros Svasti ,&nbsp;Phatchariya Phannasil","doi":"10.1016/j.yexmp.2025.104980","DOIUrl":"10.1016/j.yexmp.2025.104980","url":null,"abstract":"<div><div>Ineffective erythropoiesis, the main cause of anemia in β-thalassemia disease, is characterized by dramatic expansion of erythroblasts and increased erythroblast cell death. The absence or reduction of β-globin chains causes an accumulation of excess α-globin chains and generates cytotoxic reactive oxidant species, resulting in erythroblast cell death. Metabolism provides energy, building blocks for macromolecule synthesis, and cofactors for antioxidative defense systems. We hypothesized that β-thalassemia erythroblasts might alter their metabolism to cope with increased proliferation and cellular stress. Herein, transcriptomic analysis of basophilic and polychromatic erythroblasts isolated from bone marrow obtained from β-thalassemia/HbE patients showed the global up-regulation of metabolic genes in glycolysis, TCA cycle, pentose phosphate pathway, ATP, and fatty acid synthesis pathway. The expression of metabolic genes during terminal erythropoiesis was further determined by PCR array and RT-qPCR in erythroblast culture obtained from β-thalassemia/HbE patients with mild and severe symptoms. The increased expression of enolase1, isocitrate dehydrogenase 1, and bisphosphoglycerate mutase was observed in mild cases compared to severe patients, suggesting that mild patients might modulate metabolic flux for cellular stress defense mechanisms, reducing disease severity. Moreover, the role of BPGM in regulating erythroid differentiation was demonstrated in K562 cells. Inhibition of BPGM promotes cell differentiation in K562 cells. Understanding metabolic reprogramming in thalassemia erythropoiesis opens new therapeutic approaches for β-thalassemia/HbE treatment. Further research is needed to explore how metabolism affects ineffective erythropoiesis and supports thalassemic erythroblasts' high proliferation and oxidative stress defense.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"143 ","pages":"Article 104980"},"PeriodicalIF":2.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144523192","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}