Molecular and Cellular Endocrinology最新文献

{"title":"Corrigendum to \"The BRAF^V600E mutation maintains the aggressiveness of papillary thyroid cancers requiring downregulation of primary cilia\" [Mol. Cell. Endocrinol. 581 (2024) 112113].","authors":"Cheng-Xu Ma, Xiao-Ni Ma, Jin-Jin Liu, Cong-Hui Guan, Ying-Dong Li, Nan Zhao, Dídac Mauricio, Song-Bo Fu","doi":"10.1016/j.mce.2025.112626","DOIUrl":"https://doi.org/10.1016/j.mce.2025.112626","url":null,"abstract":"","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":" ","pages":"112626"},"PeriodicalIF":3.6,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144765088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The effect of Semaglutide on mitochondrial function and insulin sensitivity in a myotube model of insulin resistance","authors":"Emmalie R. Spry,&nbsp;Kipton B. Travis,&nbsp;Kayla J. Ragland,&nbsp;Alexa J. Klein,&nbsp;John M. Zimmerman,&nbsp;Roger A. Vaughan","doi":"10.1016/j.mce.2025.112629","DOIUrl":"10.1016/j.mce.2025.112629","url":null,"abstract":"<div><h3>Aims</h3><div>Semaglutide (SEMA) is a glucagon-like peptide-1 receptor agonist (GLP-1RA) that has recently emerged as a popular pharmacological treatment for type 2 diabetes and insulin resistance due to its weight loss properties. Previous studies have examined the metabolic effects of SEMA using supra-pharmacokinetically (but not pharmacokinetically attainable) concentrations. The aim of the present study was to determine the metabolic effects of pharmacokinetically attainable levels of SEMA on mitochondrial function and metabolism, which are often reduced during insulin resistance.</div></div><div><h3>Methods</h3><div>C2C12 myotubes were treated for 24 h with SEMA at 10 nM which approximates pharmacokinetically attainable blood concentrations in vivo. Metabolic gene expression was measured using qRT-PCR. pAkt expression was assessed using Western blot. Seahorse metabolic assays were also used to measure mitochondrial and glycolytic metabolism. Fluorescent staining was used to assess mitochondrial and lipid content.</div></div><div><h3>Results</h3><div>Treatment with SEMA did not alter mitochondrial function, content, or related gene expression. Similarly, SEMA had no significant effect on glycolytic metabolism or related gene expression, nor did it alter cellular lipid content or lipogenic signaling.</div></div><div><h3>Conclusions</h3><div>High concentrations of SEMA may promote mitochondrial function during in vitro experiments, however the findings from the present report suggest pharmacokinetically attainable levels of SEMA do not alter myotube metabolism or expression of related molecular targets. Disparities in the present report and past observations may be a result of the lower concentrations of SEMA used in the present experiments. Further in vivo studies will be necessary to elucidate the full metabolic effects of SEMA on skeletal muscle.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"608 ","pages":"Article 112629"},"PeriodicalIF":3.6,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144766770","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The sex-chromosomes related cellular dimorphism in physiology and pathology","authors":"Cristina Antinozzi,&nbsp;Paolo Sgrò,&nbsp;Luigi Di Luigi","doi":"10.1016/j.mce.2025.112630","DOIUrl":"10.1016/j.mce.2025.112630","url":null,"abstract":"<div><div>Sex-based biological differences have a profound impact on health and disease. Historically, these disparities were primarily attributed to differences in gonadal hormones. Recent advances in biochemistry and molecular biology, however, have revealed additional contributing mechanisms—most notably, the critical role of genes located on the X and Y chromosomes. The expression of Y-linked genes, increased dosage of X-linked genes in XX compared to XY cells due to incomplete X-chromosome inactivation, genomic imprinting, and the presence of non-coding and micro-RNAs on the X chromosome are all factors that require consideration in the development of <em>in vitro</em> models addressing sex dimorphism.</div><div>In the present narrative review, we propose studies showing sex differences in vascular and cardiac cells, skeletal muscle cells, adipose tissue, liver, immune cells, cancer tissues and brain tissues. Given the absence of appropriate experimental methodologies for reproducing <em>in vitro</em> the sex differences observed <em>in vivo</em> and the limited research conducted at the cellular and molecular level to elucidate the mechanisms responsible for the observed dimorphism, the present review has two objectives. Firstly, it aims to emphasize the necessity of incorporating sex as a variable in preclinical research. Secondly, it highlights the importance of sex chromosome differences as a biological variable that can influence cell physiology and biological responses, which is crucial when conducting <em>in vitro</em> studies.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"608 ","pages":"Article 112630"},"PeriodicalIF":3.6,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144757830","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Role of the Mineralocorticoid Receptor in Skin.","authors":"Natalia Fossas De Mello, Wendy B Bollag","doi":"10.1016/j.mce.2025.112628","DOIUrl":"https://doi.org/10.1016/j.mce.2025.112628","url":null,"abstract":"<p><p>The mineralocorticoid receptor (MR) plays a pivotal role in skin homeostasis, inflammation, and repair, interacting closely with the glucocorticoid receptor (GR) to regulate various physiological and pathological processes. Dysregulation of MR signaling has been implicated in several skin disorders, including psoriasis, atopic dermatitis, and impaired wound healing. Furthermore, studies have shown that patients with primary hyperaldosteronism exhibit epidermal hyperplasia, impaired differentiation, increased immune cell infiltrates, and elevated pro-inflammatory cytokines due to MR overactivation. Pharmacological studies demonstrate that MR antagonists can mitigate glucocorticoid-induced skin barrier dysfunction, epidermal atrophy, and delayed wound healing. Additionally, skin sodium storage and water conservation mechanisms are emerging as key factors in systemic fluid balance and blood pressure regulation, with skin glycosaminoglycans (GAGs) thought to serve as sodium reservoirs. Mouse models of psoriasis further reveal how the disrupted skin barrier activates systemic protective mechanisms, including water retention processes in the skin that can lead to increased blood pressure; psoriasis in humans is also associated with hypertension. These findings and additional data are discussed in this review and underscore the dual role of cutaneous MR in both maintaining epidermal integrity and contributing to inflammatory skin disorders, and potentially hypertension, when dysregulated. Targeting MR signaling pathways may offer novel therapeutic strategies for skin diseases while enhancing our understanding of the skin's role in systemic homeostasis.</p>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":" ","pages":"112628"},"PeriodicalIF":3.6,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144760555","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Liraglutide induces enhanced suppression of food intake in mice lacking the growth hormone secretagogue receptor","authors":"Daniela A. Cassano ,&nbsp;Julieta Aguggia ,&nbsp;Lucía Giovanini ,&nbsp;Florencia Heredia ,&nbsp;Pablo N. De Francesco ,&nbsp;María F. Andreoli ,&nbsp;Helgi B. Schöth ,&nbsp;Abdella M. Habib ,&nbsp;Gimena Fernandez ,&nbsp;Mario Perello","doi":"10.1016/j.mce.2025.112627","DOIUrl":"10.1016/j.mce.2025.112627","url":null,"abstract":"<div><div>The glucagon-like peptide-1 receptor (GLP-1R) and the growth hormone secretagogue receptor (GHSR) exert opposing effects on food intake. GLP-1R activation produces potent appetite-suppressing effects, whereas GHSR activation strongly stimulates food intake. Here, we tested the hypothesis that blocking GHSR could affect the anorectic and weight-reducing effects of liraglutide, a GLP-1R agonist widely used to treat diabetes and obesity. We first found that liraglutide induced a stronger reduction in food intake in <em>ad libitum</em>-fed GHSR-deficient mice compared to wild-type (WT) controls, regardless of sex. Liraglutide treatment also resulted in greater gastric content mass in <em>ad libitum</em>-fed GHSR-deficient mice than in WT mice. Interestingly, GLP-1R immunolabeling was elevated in the paraventricular nucleus of the hypothalamus (PVH) in GHSR-deficient mice, whereas the number of proopiomelanocortin (POMC) neurons and liraglutide-induced c-Fos activation—either in the entire arcuate nucleus or specifically within POMC neurons—remained unchanged compared to WT controls. Liraglutide-induced c-Fos expression in the lateral septum and PVH was reduced in GHSR-deficient mice. Conversely, pharmacological GHSR blockade using either JMV2959 or the endogenous antagonist/inverse agonist liver-expressed antimicrobial peptide 2 did not enhance liraglutide-induced food intake reduction. In conclusion, our findings reveal that genetic GHSR deficiency amplifies liraglutide's anorectic effects and provide new insight into the neurobiological mechanisms underlying this interaction. These results suggest that dual modulation of the GHSR and GLP-1R systems may represent a promising strategy for obesity treatment, though careful selection of GHSR-targeting agents and therapeutic protocols will be essential to optimize clinical outcomes.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"608 ","pages":"Article 112627"},"PeriodicalIF":3.6,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144753834","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Breaking immune evasion in breast cancer by targeting COX-2/PGE2 pathway","authors":"Xuewei Zheng ,&nbsp;Junxiang Wang ,&nbsp;Yanan OuYang ,&nbsp;Kaiyuan Yao ,&nbsp;Jiayu Zheng ,&nbsp;Li Zeng ,&nbsp;Jingjing Wang ,&nbsp;Hetao Chen ,&nbsp;Haoming Du ,&nbsp;Dongliao Fu ,&nbsp;Linlin Shi ,&nbsp;Anshun Zhao ,&nbsp;Qinan Yin","doi":"10.1016/j.mce.2025.112617","DOIUrl":"10.1016/j.mce.2025.112617","url":null,"abstract":"<div><div>The cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) pathway plays a pivotal role in breast cancer (BC) progression by promoting immune suppression, tumor growth, and metastasis. PGE2 mediates these effects through EP receptors (EP1–EP4), suppressing anti-tumor immunity while fostering an immunosuppressive tumor microenvironment (TME). This includes the recruitment and activation of tumor-associated macrophages (TAMs), dendritic cells (DCs), cancer-associated fibroblasts (CAFs), myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs), ultimately impairing cytotoxic T lymphocyte and natural killer (NK) cell function. Targeting the COX-2/PGE2 axis presents a promising strategy for BC treatment. Dual inhibition of EP2 and EP4 has demonstrated superior efficacy in reversing immune suppression compared to single-receptor blockade. Additionally, combining EP4 antagonists with immune checkpoint inhibitors (ICIs) such as anti-PD-1 and anti-CTLA-4 enhances T cell infiltration and tumoricidal activity, leading to improved therapeutic outcomes. Another emerging approach involves enhancing the activity of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), the key enzyme responsible for PGE2 degradation, to counteract PGE2-driven immune evasion. PTGES1 inhibitors have shown great potential in overcoming the immunosuppressive TME in BC patients. Elevated TIL levels in TNBC and HER2-positive BC are associated with improved prognosis; however, COX-2 inhibitors such as celecoxib failed to enhance survival and carry potential cardiovascular risks, highlighting the need for TIL-stratified trials to refine immunotherapeutic strategies. This review highlights the immunosuppressive mechanisms of the COX-2/PGE2 pathway in BC and explores novel therapeutic strategies targeting this axis. Understanding the intricate crosstalk between PGE2 signaling and immune modulation may lead to the development of more effective BC treatments, particularly in combination with immunotherapies.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"608 ","pages":"Article 112617"},"PeriodicalIF":3.6,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144718174","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RUNX3 drives HTR-8/SVneo cell ferroptosis and spontaneous abortion: involvement of the suppression of GDF15 transcriptional activity","authors":"Lanlan Cheng,&nbsp;Jie Zhang,&nbsp;Yungai Xiang,&nbsp;Li Tan","doi":"10.1016/j.mce.2025.112618","DOIUrl":"10.1016/j.mce.2025.112618","url":null,"abstract":"<div><div>Spontaneous abortion (SA) refers to the loss of a pregnancy without external intervention. The runt-related transcription factor 3 (RUNX3) is associated with gestational disorders in view of previous studies. However, RUNX3 has not been reported in SA. RUNX3 is significantly upregulated in the placental villi of abortion patients based on the GSE123719 microarray data. Herein, we further validated and found that the expression of RUNX3 in placental villi of SA women was higher than those of induced abortion (IA) women. <em>In vitro</em>, we constructed human RUNX3 overexpression or interference adenovirus vectors to modulate RUNX3 expression in trophoblast cells. Our findings revealed that RUNX3 overexpression accelerated trophoblast cell ferroptosis, while RUNX3 knockdown alleviated erastin-induced ferroptosis. Subsequently, the dual luciferase reporter assay was performed to confirm that RUNX3 bound to the GDF15 promoter to transcriptionally repress GDF15 transcriptional activity. Importantly, GDF15 attenuated the pro-ferroptosis effects of RUNX3 on HTR-8/SVneo cells. <em>In vivo</em>, mouse RUNX3 interference adenovirus vectors were used to silence RUNX3 in mice. The results presented that the reduction of RUNX3 inhibited embryo adsorption rate in SA mice, involving ferroptosis and the interaction between RUNX3 and GDF15. Taken together, this study established that RUNX3 advanced SA progression by enhancing trophoblast ferroptosis via transcriptionally repressing GDF15. These findings may provide novel therapeutic strategies for SA management.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"608 ","pages":"Article 112618"},"PeriodicalIF":3.6,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144718188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Palmitate-induced downregulation of lipocalin prostaglandin D2 synthase accompanies hepatic lipid accumulation in HepG2 cells","authors":"Rhema Khairnar,&nbsp;Md Asrarul Islam,&nbsp;Divya K. Shetty,&nbsp;Vikas V. Dukhande,&nbsp;Sunil Kumar","doi":"10.1016/j.mce.2025.112615","DOIUrl":"10.1016/j.mce.2025.112615","url":null,"abstract":"<div><div>Metabolic dysfunction-associated steatotic liver disease (MASLD) is associated with multiple metabolic dysfunctions and poses a significant global health challenge. Our prior in vivo studies demonstrated that the absence of lipocalin prostaglandin D2 synthase (L-PGDS) leads to the development of fatty liver disease, and L-PGDS expression significantly decreased when C57BL/6 mice were kept on a high-fat diet. Briefly, L-PGDS belongs to the arachidonic acid pathway and enzymatically isomerizes prostaglandin H2 to prostaglandin D2, which imparts pharmacological effects via two receptors called DP1 and DP2. L-PGDS is an essential key player in fatty liver disease, but its mechanistic regulation still remains unknown. Therefore, we aimed to study the mechanistic regulation of L-PGDS using a palmitate-induced cellular MASLD model. We successfully recapitulated the MASLD phenotype in HepG2 cells with palmitate treatment. Our results showed significant lipid accumulation and increased lipidassociated protein and gene expression, along with palmitate concentration-dependent L-PGDS downregulation. To study the L-PGDS downregulation, we employed MG132, chloroquine, and cycloheximide to assess proteasomal degradation, autophagy, and translational activity, respectively. Our gene and protein expression data suggested the possible reason for L-PGDS downregulation via inhibiting transcription and subsequently translation. Additionally, our autophagy results also showed a role in LPGDS downregulation. In summary, it can be concluded that palmitate treatment downregulated L-PGDS, possibly involving transcription-translation and/or autophagy pathways. However, further studies are needed to delineate the precise molecular mechanism and apply this knowledge to MASLD pathogenesis and treatment.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"608 ","pages":"Article 112615"},"PeriodicalIF":3.8,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144682810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptomic profiling of hypothalamic development in female rats","authors":"Emily N. Hilz ,&nbsp;Madeline Streifer ,&nbsp;Tyler M. Milewski ,&nbsp;Andrea C. Gore","doi":"10.1016/j.mce.2025.112616","DOIUrl":"10.1016/j.mce.2025.112616","url":null,"abstract":"<div><div>The hypothalamic arcuate nucleus (ARC) and anteroventral periventricular nucleus (AVPV) are critical regulators of reproductive function, energy balance, stress, and neuromodulation. These regions undergo substantial changes in neural and glial populations over development that enable the acquisition of adult functions. Although previous studies have examined developmental changes in specific hypothalamic cell populations or gene families, to our knowledge, none has comprehensively compared unbiased/bulk transcriptional profiles across key developmental stages in both the ARC and AVPV. In this study, we used 3′ targeted RNA sequencing to profile gene expression in the ARC and AVPV of female rats at infantile (P8), peripubertal (P30), and adult (P60) life stages. We conducted unbiased and <em>a priori</em> selected differential gene expression analyses, the latter genes selected for their roles in reproduction, metabolism, stress, and neuromodulation. We also measured serum hormones as an index of physiology. Developmental analyses revealed robust differential gene expression between the infantile and prepubertal periods in both the ARC and AVPV, with substantial transcriptional overlap between regions. Fewer and more region-specific transcriptional changes were observed during the transition to adulthood. Gene ontology (GO) analyses revealed coordinated developmental programming prior to puberty, including downregulation of developmental processes and upregulation of metabolic and regulatory pathways. In adulthood, the AVPV showed continued transcriptional remodeling, while the ARC remained comparatively stable. FSH emerged as the strongest hormonal correlate of <em>a priori</em> hypothalamic gene expression. These data provide a reference for understanding hypothalamic development and hormone–gene interactions across life stages in the female rat.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"608 ","pages":"Article 112616"},"PeriodicalIF":3.8,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144682811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association between BRAFV600E mutation and gene expression of CLDN1, TIMP1, and KRT19 in papillary thyroid cancer","authors":"Andrea Ross-Orozco ,&nbsp;Anette Roxana Gastelum-Quiroz ,&nbsp;Marco Alvarez-Arrazola ,&nbsp;Fred Luque-Ortega ,&nbsp;Alejandra Martínez-Camberos ,&nbsp;Karla Morales-Hernandez ,&nbsp;F. Lopez-Herrera y Cairo ,&nbsp;Noemí García-Magallanes","doi":"10.1016/j.mce.2025.112614","DOIUrl":"10.1016/j.mce.2025.112614","url":null,"abstract":"<div><div>The molecular mechanisms driving Papillary Thyroid Cancer (PTC) progression remain incompletely understood, although mutations in BRAF, are believed to affect the expression of key markers involved in PTC development. This study aimed to investigate the BRAFV600E mutation and its association with the expression of CLDN1, TIMP1, and KRT19 in PTC. A total of 93 thyroid samples were retrospectively analyzed: 42 cytologically diagnosed as PTC (Bethesda VI/V), 4 suspicious for malignancy (Bethesda V), and 47 as nodular hyperplasia (Bethesda II). The presence of the BRAFV600E mutation and the expression levels of CLDN1, TIMP1, and KRT19 were determined using qPCR. BRAFV600E genotypes included 70.2 % TT (wild-type), 17 % TA (heterozygous), and 12.8 % AA (mutant homozygous), with a mutated allele frequency of 0.210. The TA genotype was exclusive to the cancer group and significantly increased malignancy risk (OR 3.667; 95 % CI 2.473–5.437; p &lt; 0.001). Patients harboring the mutated A allele were significantly younger (p = 0.029) and exhibited higher expression of all three genes. Using Youden-derived cutoffs from ROC analysis, TIMP1 overexpression (cutoff 1.148) was most strongly associated with BRAFV600E (OR 4.34; 95 % CI 1.82–10.33; p &lt; 0.001). The BRAFV600E mutation and TIMP1 overexpression are strongly associated with malignant thyroid nodules, suggesting a role in the molecular pathogenesis of PTC.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"607 ","pages":"Article 112614"},"PeriodicalIF":3.8,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144649818","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}