Pub Date : 2026-01-29DOI: 10.1016/j.jsbmb.2026.106948
Xiaomeng Zha , Liang Chen , Zhaoping Tan , Tiancheng Wu , Qiaohua Xiong , Haihua Wang , Yuanyuan Kuang , Fei Xing , Aihua Lu , Lili Sun , Yuanzhen Zhang
Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disease in women of reproductive age, characterized by hyperandrogenemia and obstruction of ovulation. However, the underlying mechanisms of ovarian abnormalities in PCOS remain to be investigated. In this study, we first identified altered levels of ovarian ferroptosis in the PCOS population by screening a web-based database. Further, we established a prasterone-exposed PCOS mouse model and a granulosa cell model to confirm that hyperandrogenism can lead to the development of ferroptosis in ovarian granulosa cells. The transcriptome sequencing and cellular experiments were conducted to explore the possible mechanisms. It was found that the ubiquitination pathway and P53 pathway are significantly enriched in the prasterone-exposed granulosa cells. The E3 ubiquitin ligase PELI1 gene is significantly highly expressed in PCOS ovaries and may contribute to ferroptosis by degrading FTH1. In addition, high expression of the P53 gene was associated with alterations in PELI1/FTH1. This study confirmed that hyperandrogenism can mediate the development of ovarian ferroptosis via the P53/PELI1/FTH1 pathway and the E3 ubiquitin ligase PELI1 plays an important regulatory role. In vivo, the iron death inhibitor deferoxamine mesylate could alleviate ferroptosis and follicular development disorder in the ovaries of PCOS mice. This study provides new insights into the pathological changes of PCOS ovaries and possible interventions for the treatment of PCOS.
{"title":"E3 ubiquitin ligase PELI1 promotes ferroptosis in granulosa cells in PCOS by degrading Fth1","authors":"Xiaomeng Zha , Liang Chen , Zhaoping Tan , Tiancheng Wu , Qiaohua Xiong , Haihua Wang , Yuanyuan Kuang , Fei Xing , Aihua Lu , Lili Sun , Yuanzhen Zhang","doi":"10.1016/j.jsbmb.2026.106948","DOIUrl":"10.1016/j.jsbmb.2026.106948","url":null,"abstract":"<div><div>Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disease in women of reproductive age, characterized by hyperandrogenemia and obstruction of ovulation. However, the underlying mechanisms of ovarian abnormalities in PCOS remain to be investigated. In this study, we first identified altered levels of ovarian ferroptosis in the PCOS population by screening a web-based database. Further, we established a prasterone-exposed PCOS mouse model and a granulosa cell model to confirm that hyperandrogenism can lead to the development of ferroptosis in ovarian granulosa cells. The transcriptome sequencing and cellular experiments were conducted to explore the possible mechanisms. It was found that the ubiquitination pathway and P53 pathway are significantly enriched in the prasterone-exposed granulosa cells. The E3 ubiquitin ligase PELI1 gene is significantly highly expressed in PCOS ovaries and may contribute to ferroptosis by degrading FTH1. In addition, high expression of the P53 gene was associated with alterations in PELI1/FTH1. This study confirmed that hyperandrogenism can mediate the development of ovarian ferroptosis via the P53/PELI1/FTH1 pathway and the E3 ubiquitin ligase PELI1 plays an important regulatory role. In vivo, the iron death inhibitor deferoxamine mesylate could alleviate ferroptosis and follicular development disorder in the ovaries of PCOS mice. This study provides new insights into the pathological changes of PCOS ovaries and possible interventions for the treatment of PCOS.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"259 ","pages":"Article 106948"},"PeriodicalIF":2.5,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146097526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-14DOI: 10.1016/j.jsbmb.2026.106939
Philipp Augsburger , Therina du Toit , Emre Murat Altinkiliç , Sabine Hannema , Christiaan de Bruin , Evangelia Charmandari , Erica L.T. van den Akker , Christa E. Flück
Thyroid hormones (THs) are critical regulators of human development, cellular differentiation, and metabolism. While their systemic effects are well established, their role in adrenal androgen production remains poorly defined. Moreover, potential feedback regulation of the hypothalamic–pituitary–thyroid (HPT) axis by adrenal androgens has not been thoroughly investigated. This study aimed to clarify the regulatory effects of THs on adrenal androgens and to investigate potential feedback mechanisms in patients with congenital adrenal hyperplasia (CAH). In an in-vitro experiment, treatment with 3,3′,5-triiodo-L-thyronine (T3) on adrenocortical carcinoma H295R cells significantly reduced dehydroepiandrosterone (DHEA) and DHEA-sulfate production while modestly increasing testosterone (T) and androstenedione (A4). These changes were associated with an increase in expression of HSD3B2 and AKR1C3, and a decrease of CYP17A1. Transcriptomic analysis additionally revealed enrichment of pathways related to steroidogenesis and adrenal development through T3 treatment. In the clinical part of the study, hormone levels in pediatric CAH patients were analyzed. Serum free thyroxine (fT4) and thyroid-stimulating hormone (TSH) showed weak negative correlations with the adrenal androgens DHEA and A4. However, no differences in fT4 or TSH concentrations were observed between well-controlled and hyperandrogenic patients, suggesting a lack of feedback regulation by adrenal androgens on the HPT axis. In conclusion, these findings suggest that THs regulate adrenal androgen production by modulating the activity of key steroidogenic enzymes. This relationship appears to be predominantly unidirectional, with THs influencing adrenal steroidogenesis but adrenal androgens not altering HPT axis function.
甲状腺激素（THs）是人类发育、细胞分化和代谢的关键调节因子。虽然它们对全身的影响已经确定，但它们在肾上腺雄激素产生中的作用仍不明确。此外，肾上腺雄激素对下丘脑-垂体-甲状腺（HPT）轴的潜在反馈调节尚未得到充分研究。本研究旨在阐明三萜类化合物对肾上腺雄激素的调节作用，并探讨其在先天性肾上腺增生症（CAH）患者中的潜在反馈机制。在一项体外实验中，用3,3 '，5-三碘- l -甲状腺原氨酸（T3）治疗肾上腺皮质癌H295R细胞可显著降低脱氢表雄酮（DHEA）和硫酸脱氢表雄酮（DHEA -sulfate）的产生，同时适度增加睾酮(T)和雄烯二酮（A4）。这些变化与HSD3B2和AKR1C3的表达增加以及CYP17A1的表达减少有关。转录组学分析还显示，通过T3治疗，与类固醇生成和肾上腺发育相关的途径丰富。在研究的临床部分，分析了儿科CAH患者的激素水平。血清游离甲状腺素（fT4）和促甲状腺激素（TSH）与肾上腺雄激素DHEA和A4呈弱负相关。然而，在控制良好的患者和高雄激素患者之间，fT4或TSH浓度没有差异，这表明肾上腺雄激素在HPT轴上缺乏反馈调节。综上所述，这些发现表明，三萜类化合物通过调节关键类固醇生成酶的活性来调节肾上腺雄激素的产生。这种关系似乎主要是单向的，这影响肾上腺甾体生成，但肾上腺雄激素不改变HPT轴功能。
{"title":"Androgen production in adrenocortical H295R cells is regulated by thyroid hormone T3 without reciprocal thyroid axis modulation in pediatric CAH","authors":"Philipp Augsburger , Therina du Toit , Emre Murat Altinkiliç , Sabine Hannema , Christiaan de Bruin , Evangelia Charmandari , Erica L.T. van den Akker , Christa E. Flück","doi":"10.1016/j.jsbmb.2026.106939","DOIUrl":"10.1016/j.jsbmb.2026.106939","url":null,"abstract":"<div><div>Thyroid hormones (THs) are critical regulators of human development, cellular differentiation, and metabolism. While their systemic effects are well established, their role in adrenal androgen production remains poorly defined. Moreover, potential feedback regulation of the hypothalamic–pituitary–thyroid (HPT) axis by adrenal androgens has not been thoroughly investigated. This study aimed to clarify the regulatory effects of THs on adrenal androgens and to investigate potential feedback mechanisms in patients with congenital adrenal hyperplasia (CAH). In an in-vitro experiment, treatment with 3,3′,5-triiodo-<span>L</span>-thyronine (T3) on adrenocortical carcinoma H295R cells significantly reduced dehydroepiandrosterone (DHEA) and DHEA-sulfate production while modestly increasing testosterone (T) and androstenedione (A4). These changes were associated with an increase in expression of <em>HSD3B2</em> and <em>AKR1C3</em>, and a decrease of <em>CYP17A1</em>. Transcriptomic analysis additionally revealed enrichment of pathways related to steroidogenesis and adrenal development through T3 treatment. In the clinical part of the study, hormone levels in pediatric CAH patients were analyzed. Serum free thyroxine (fT4) and thyroid-stimulating hormone (TSH) showed weak negative correlations with the adrenal androgens DHEA and A4. However, no differences in fT4 or TSH concentrations were observed between well-controlled and hyperandrogenic patients, suggesting a lack of feedback regulation by adrenal androgens on the HPT axis. In conclusion, these findings suggest that THs regulate adrenal androgen production by modulating the activity of key steroidogenic enzymes. This relationship appears to be predominantly unidirectional, with THs influencing adrenal steroidogenesis but adrenal androgens not altering HPT axis function.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"258 ","pages":"Article 106939"},"PeriodicalIF":2.5,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145981245","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
For an adrenal incidentaloma with indeterminate imaging characteristics, urine multisteroid profiling is suggested for diagnosing adrenocortical carcinoma (ACC). Data on the utility of serum steroid metabolomics in this context is limited to a few studies. Here, we present data of 62 adult patients with indeterminate unilateral adrenal masses (size ≥ 3 cm and basal attenuation ≥10HU) where baseline serum liquid chromatography-tandem mass spectrometry (LC-MS/MS) multisteroid profiling was available. Logistic regression was used to identify the key steroid signature for differentiating ACC from other non-ACC adrenal masses. Among 62 patients (median age: 41 years, 31 males), 37 (59.6 %) had ACC. The non-ACC cohort (n = 25) comprised pheochromocytoma (n = 9), adrenocortical adenoma (n = 8), metastases (n = 4), schwannoma (n = 2), ganglioneuroma (n = 1), and lymphoma (n = 1). Tumour size was significantly larger in the ACC cohort (9.9 vs 7.0 cm; p < 0.001) than the non-ACC cohort. Nine of 13 steroids were significantly elevated in ACC: 11-deoxycorticosterone (DOC), 17-hydroxyprogesterone (17OHP), 11-deoxycortisol (S), cortisone (E), androstenedione (A4), dehydroepiandrosterone (DHEA), and dehydroepiandrosterone sulphate (DHEAS) in both sexes, as well as testosterone (T) in females and progesterone (P4) in males. After excluding sex-dependent steroids, univariate analysis yielded six significant steroids (17OHP, S, E, A4, DHEA, and DHEAS). A multivariate logistic regression model with backward elimination identified A4, S, and DHEAS as the best discriminators (AUC:0.923), with a cutoff of 0.52 yielding 83.8 % sensitivity and 96 % specificity for diagnosing ACC. Our study results suggest serum LC–MS/MS profiling of three steroids (A4, S, and DHEAS) provides a non-invasive approach to distinguish ACC from other indeterminate adrenal masses.
对于影像学特征不确定的肾上腺偶发瘤，建议采用尿多类固醇谱分析诊断肾上腺皮质癌（ACC）。关于血清类固醇代谢组学在这方面的应用的数据仅限于少数研究。在这里，我们提供了62例患有不确定的单侧肾上腺肿块（大小≥3cm，基底衰减≥10HU）的成年患者的数据，其中基线血清液相色谱-串联质谱（LC-MS/MS）多类固醇分析可用。Logistic回归用于鉴别鉴别ACC与其他非ACC肾上腺肿块的关键类固醇特征。62例患者（中位年龄41岁，男性31例）中，37例（59.6%）患有ACC。非acc队列（n=25）包括嗜铬细胞瘤（n=9）、肾上腺皮质腺瘤（n=8）、转移瘤（n=4）、神经鞘瘤（n=2）、神经节神经瘤（n=1）和淋巴瘤（n=1）。ACC组的肿瘤大小明显大于非ACC组（9.9 vs 7.0cm; p < 0.001）。13种类固醇中有9种在ACC中显著升高：11-去氧皮质酮（DOC）、17-羟基孕酮（17OHP）、11-去氧皮质酮(S)、可的松(E)、雄烯二酮（A4）、脱氢表雄酮（DHEA）和脱氢表雄酮硫酸盐（DHEAS），以及女性睾酮(T)和男性孕酮（P4）。排除性别依赖性类固醇后，单变量分析得出6种显著类固醇（17OHP、S、E、A4、DHEA和DHEAS）。采用logistic回归模型进行反向消除，A4、S和DHEAS为最佳鉴别因子（AUC:0.923），截断值为0.52，诊断ACC的敏感性为83.8%，特异性为96%。我们的研究结果表明，血清LC-MS/MS分析三种类固醇（A4， S和DHEAS）提供了一种非侵入性方法来区分ACC和其他不确定的肾上腺肿块。
{"title":"Serum steroid profiling by LC-MS/MS in distinguishing adrenocortical carcinoma from other indeterminate adrenal masses","authors":"Archana Rao , Aditya Phadte , Anuj Ban , Saba Samad Memon , Manjiri Karlekar , Anurag Ranjan Lila , Vijaya Sarathi , Nimmi Kansal , Rohit Barnabas , Padma Vikram Badhe , Gwendolyn Fernandes , Sameer Rege , Gagan Prakash , Santosh Menon , Nalini Shah , Tushar Bandgar","doi":"10.1016/j.jsbmb.2026.106937","DOIUrl":"10.1016/j.jsbmb.2026.106937","url":null,"abstract":"<div><div>For an adrenal incidentaloma with indeterminate imaging characteristics, urine multisteroid profiling is suggested for diagnosing adrenocortical carcinoma (ACC). Data on the utility of serum steroid metabolomics in this context is limited to a few studies. Here, we present data of 62 adult patients with indeterminate unilateral adrenal masses (size ≥ 3 cm and basal attenuation ≥10HU) where baseline serum liquid chromatography-tandem mass spectrometry (LC-MS/MS) multisteroid profiling was available. Logistic regression was used to identify the key steroid signature for differentiating ACC from other non-ACC adrenal masses. Among 62 patients (median age: 41 years, 31 males), 37 (59.6 %) had ACC. The non-ACC cohort (n = 25) comprised pheochromocytoma (n = 9), adrenocortical adenoma (n = 8), metastases (n = 4), schwannoma (n = 2), ganglioneuroma (n = 1), and lymphoma (n = 1). Tumour size was significantly larger in the ACC cohort (9.9 vs 7.0 cm; p < 0.001) than the non-ACC cohort. Nine of 13 steroids were significantly elevated in ACC: 11-deoxycorticosterone (DOC), 17-hydroxyprogesterone (17OHP), 11-deoxycortisol (S), cortisone (E), androstenedione (A4), dehydroepiandrosterone (DHEA), and dehydroepiandrosterone sulphate (DHEAS) in both sexes, as well as testosterone (T) in females and progesterone (P4) in males. After excluding sex-dependent steroids, univariate analysis yielded six significant steroids (17OHP, S, E, A4, DHEA, and DHEAS). A multivariate logistic regression model with backward elimination identified A4, S, and DHEAS as the best discriminators (AUC:0.923), with a cutoff of 0.52 yielding 83.8 % sensitivity and 96 % specificity for diagnosing ACC. Our study results suggest serum LC–MS/MS profiling of three steroids (A4, S, and DHEAS) provides a non-invasive approach to distinguish ACC from other indeterminate adrenal masses.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"258 ","pages":"Article 106937"},"PeriodicalIF":2.5,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145991767","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-13DOI: 10.1016/j.jsbmb.2026.106938
Higor Souza Nascimento , Marcella Guerra Corrêa , Odonilton Lima Lemos , Hernando Nascimento Lima , Liliany Souza de Brito Amaral
This narrative review explores the cardiovascular risks associated with the non-therapeutic use of anabolic-androgenic steroids (AAS) at supraphysiological doses. Initially indicated for clinical conditions like hypogonadism and anemia, AAS are increasingly misused for aesthetic and performance enhancement, often at doses far exceeding therapeutic recommendations. Through a literature review of 34 studies selected from PubMed (2015–2025), the review analyzes the molecular mechanisms and cardiovascular consequences of high-dose AAS use. Genomic and non-genomic pathways, along with modulation of the IGF-1 axis, underlie alterations in gene expression and cellular metabolism that lead to myocardial remodeling, hypertension, dyslipidemia, thrombosis, endothelial dysfunction, and systemic inflammation. These effects are further intensified by behavioral factors such as polypharmacy and substance abuse. Despite ethical limitations on clinical trials with supraphysiological doses, experimental and epidemiological data consistently suggest that excessive AAS use significantly elevates the risk of adverse cardiovascular events. This work highlights the urgent need for public health policies, educational initiatives, and longitudinal studies to assess real-world use patterns and mitigate harms associated with AAS abuse.
{"title":"Anabolic-androgenic steroids at supraphysiological doses: Cardiovascular impacts and pathophysiological mechanisms","authors":"Higor Souza Nascimento , Marcella Guerra Corrêa , Odonilton Lima Lemos , Hernando Nascimento Lima , Liliany Souza de Brito Amaral","doi":"10.1016/j.jsbmb.2026.106938","DOIUrl":"10.1016/j.jsbmb.2026.106938","url":null,"abstract":"<div><div>This narrative review explores the cardiovascular risks associated with the non-therapeutic use of anabolic-androgenic steroids (AAS) at supraphysiological doses. Initially indicated for clinical conditions like hypogonadism and anemia, AAS are increasingly misused for aesthetic and performance enhancement, often at doses far exceeding therapeutic recommendations. Through a literature review of 34 studies selected from PubMed (2015–2025), the review analyzes the molecular mechanisms and cardiovascular consequences of high-dose AAS use. Genomic and non-genomic pathways, along with modulation of the IGF-1 axis, underlie alterations in gene expression and cellular metabolism that lead to myocardial remodeling, hypertension, dyslipidemia, thrombosis, endothelial dysfunction, and systemic inflammation. These effects are further intensified by behavioral factors such as polypharmacy and substance abuse. Despite ethical limitations on clinical trials with supraphysiological doses, experimental and epidemiological data consistently suggest that excessive AAS use significantly elevates the risk of adverse cardiovascular events. This work highlights the urgent need for public health policies, educational initiatives, and longitudinal studies to assess real-world use patterns and mitigate harms associated with AAS abuse.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"258 ","pages":"Article 106938"},"PeriodicalIF":2.5,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145957880","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-12DOI: 10.1016/j.jsbmb.2026.106936
Kai Huang , Haili Cai , Cheng Jiang , Chunwei Zheng
Osteoarthritis (OA) is characterized by progressive cartilage degeneration and extracellular matrix (ECM) stiffening, yet effective disease-modifying therapies remain limited. This study evaluated the chondroprotective effect of dehydroepiandrosterone (DHEA) in early OA and elucidated its underlying mechanisms. Using rabbit and mouse models, we demonstrated that intra-articular DHEA administration attenuated cartilage damage, reduced catabolic enzyme expression, and preserved ECM elasticity. Mechanistically, DHEA downregulated lysyl oxidase (LOX), suppressed activation of the RhoA/ROCK/MLC signaling cascade, and thereby mitigated ECM stiffening. The protective effects were partly dependent on LOX inhibition, suggesting a dual regulatory mechanism. These findings identify DHEA as a potential disease-modifying agent that targets LOX-RhoA/ROCK/MLC signaling to maintain cartilage homeostasis in early OA, warranting further clinical investigation.
{"title":"Therapeutic potential of dehydroepiandrosterone in early osteoarthritis: Modulating cartilage ECM stiffness through LOX-RhoA/ROCK/MLC signalling – An in vivo study","authors":"Kai Huang , Haili Cai , Cheng Jiang , Chunwei Zheng","doi":"10.1016/j.jsbmb.2026.106936","DOIUrl":"10.1016/j.jsbmb.2026.106936","url":null,"abstract":"<div><div>Osteoarthritis (OA) is characterized by progressive cartilage degeneration and extracellular matrix (ECM) stiffening, yet effective disease-modifying therapies remain limited. This study evaluated the chondroprotective effect of dehydroepiandrosterone (DHEA) in early OA and elucidated its underlying mechanisms. Using rabbit and mouse models, we demonstrated that intra-articular DHEA administration attenuated cartilage damage, reduced catabolic enzyme expression, and preserved ECM elasticity. Mechanistically, DHEA downregulated lysyl oxidase (LOX), suppressed activation of the RhoA/ROCK/MLC signaling cascade, and thereby mitigated ECM stiffening. The protective effects were partly dependent on LOX inhibition, suggesting a dual regulatory mechanism. These findings identify DHEA as a potential disease-modifying agent that targets LOX-RhoA/ROCK/MLC signaling to maintain cartilage homeostasis in early OA, warranting further clinical investigation.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"258 ","pages":"Article 106936"},"PeriodicalIF":2.5,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145981246","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-06DOI: 10.1016/j.jsbmb.2026.106935
Amy Li , Hideaki Tomita , Libin Xu
Smith-Lemli-Opitz syndrome (SLOS) is a cholesterol biosynthesis disorder caused by mutations in the DHCR7 gene, leading to reduced cholesterol production and accumulation of its precursor, 7-dehydrocholesterol. SLOS displays a wide range of neurodevelopmental defects, intellectual disability, and behavioral problems. However, an in-depth study of the temporal changes in gene expression in developing brains has not been conducted before. In this work, we carried out the transcriptomic analysis of whole brains from WT and Dhcr7-KO mice at embryonic day 12.5 (E12.5), E14.5, E16.5, and postnatal day 0 (PND0). First, we observed the expected downregulation of the Dhcr7 gene in the Dhcr7-KO brains, as well as changes in other genes involved in cholesterol biosynthesis at all time points. Pathway and GO term enrichment analyses revealed affected signaling pathways and biological processes that were shared amongst time points and unique to individual time points. Specifically, pathways important for embryonic and neural development, including Hippo, Wnt, and TGF-β signaling pathways, are most significantly affected at the earliest time point, E12.5. Additionally, neurogenesis-related GO terms were enriched at earlier time points, consistent with the timing of development. Conversely, pathways related to synaptogenesis, which occur later in development than neurogenesis, are significantly affected at the later time points, E16.5 and PND0, including cholinergic, glutamatergic, and GABAergic synapses. In vitro neurogenesis experiments using GABAergic neuronal precursors isolated from embryonic mouse brain confirmed that loss of Dhcr7 led to decreased proliferation and premature neurogenesis, consistent with the transcriptomic changes.
{"title":"Temporal transcriptomic changes during neurodevelopment in a mouse model of Smith-Lemli-Opitz syndrome","authors":"Amy Li , Hideaki Tomita , Libin Xu","doi":"10.1016/j.jsbmb.2026.106935","DOIUrl":"10.1016/j.jsbmb.2026.106935","url":null,"abstract":"<div><div>Smith-Lemli-Opitz syndrome (SLOS) is a cholesterol biosynthesis disorder caused by mutations in the <em>DHCR7</em> gene, leading to reduced cholesterol production and accumulation of its precursor, 7-dehydrocholesterol. SLOS displays a wide range of neurodevelopmental defects, intellectual disability, and behavioral problems. However, an in-depth study of the temporal changes in gene expression in developing brains has not been conducted before. In this work, we carried out the transcriptomic analysis of whole brains from WT and <em>Dhcr7</em>-KO mice at embryonic day 12.5 (E12.5), E14.5, E16.5, and postnatal day 0 (PND0). First, we observed the expected downregulation of the <em>Dhcr7</em> gene in the <em>Dhcr7</em>-KO brains, as well as changes in other genes involved in cholesterol biosynthesis at all time points. Pathway and GO term enrichment analyses revealed affected signaling pathways and biological processes that were shared amongst time points and unique to individual time points. Specifically, pathways important for embryonic and neural development, including Hippo, Wnt, and TGF-β signaling pathways, are most significantly affected at the earliest time point, E12.5. Additionally, neurogenesis-related GO terms were enriched at earlier time points, consistent with the timing of development. Conversely, pathways related to synaptogenesis, which occur later in development than neurogenesis, are significantly affected at the later time points, E16.5 and PND0, including cholinergic, glutamatergic, and GABAergic synapses. <em>In vitro</em> neurogenesis experiments using GABAergic neuronal precursors isolated from embryonic mouse brain confirmed that loss of <em>Dhcr7</em> led to decreased proliferation and premature neurogenesis, consistent with the transcriptomic changes.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"257 ","pages":"Article 106935"},"PeriodicalIF":2.5,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145936091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01DOI: 10.1016/j.jsbmb.2025.106932
Maryam Musavi , Farnaz Oghbaei , Mohammad Abavisani , Ahmad Ghasemi , Amir Abbas Momtazi-Borojeni
The hexosamine biosynthesis pathway (HBP) is a nutrient-sensitive branch of glucose metabolism that produces UDP-GlcNAc, a central substrate for protein glycosylation. Growing evidence links altered HBP activity to breast cancer (BC) progression and treatment response. However, the strength of evidence differs across tumor subtypes and across experimental versus patient data. This review summarizes current clinical and preclinical evidence on how HBP enzymes and HBP-derived glycosylation contribute to BC biology. Across BC cohorts and experimental models, increased expression of key HBP components has been associated with aggressive features, while mechanistic studies show that HBP activity can support oncogenic signaling through elevated O-GlcNAcylation of regulatory proteins. Work in BC models further indicates that HBP-related changes influence proliferation, survival, epithelial–mesenchymal transition, migration, and invasion, and may interact with pathways such as PI3K/AKT/mTOR, Wnt/β-catenin, and YAP. Evidence discussed in this review also links HBP output to stress-adaptation programs, including DNA damage responses and ER protein-folding capacity via N-linked glycosylation, which can promote survival under nutrient or therapy stress. Therapeutic studies described here include direct and indirect strategies to reduce HBP output, such as targeting pathway enzymes, modulating O-GlcNAc cycling, and using hexosamine analogs designed to disrupt flux or glycan function; these approaches reduce growth and metastatic behavior in several preclinical settings, but specificity and normal-tissue tolerance remain key constraints. Overall, the literature supports HBP as a plausible metabolic contributor to BC progression, but stronger patient-linked validation is needed. Future work should prioritize subtype-resolved clinical studies and direct measures of pathway activity to guide biomarker development and therapeutic targeting.
{"title":"The hexosamine biosynthesis pathway as a potent culprit in breast cancer progression","authors":"Maryam Musavi , Farnaz Oghbaei , Mohammad Abavisani , Ahmad Ghasemi , Amir Abbas Momtazi-Borojeni","doi":"10.1016/j.jsbmb.2025.106932","DOIUrl":"10.1016/j.jsbmb.2025.106932","url":null,"abstract":"<div><div>The hexosamine biosynthesis pathway (HBP) is a nutrient-sensitive branch of glucose metabolism that produces UDP-GlcNAc, a central substrate for protein glycosylation. Growing evidence links altered HBP activity to breast cancer (BC) progression and treatment response. However, the strength of evidence differs across tumor subtypes and across experimental versus patient data. This review summarizes current clinical and preclinical evidence on how HBP enzymes and HBP-derived glycosylation contribute to BC biology. Across BC cohorts and experimental models, increased expression of key HBP components has been associated with aggressive features, while mechanistic studies show that HBP activity can support oncogenic signaling through elevated O-GlcNAcylation of regulatory proteins. Work in BC models further indicates that HBP-related changes influence proliferation, survival, epithelial–mesenchymal transition, migration, and invasion, and may interact with pathways such as PI3K/AKT/mTOR, Wnt/β-catenin, and YAP. Evidence discussed in this review also links HBP output to stress-adaptation programs, including DNA damage responses and ER protein-folding capacity via N-linked glycosylation, which can promote survival under nutrient or therapy stress. Therapeutic studies described here include direct and indirect strategies to reduce HBP output, such as targeting pathway enzymes, modulating O-GlcNAc cycling, and using hexosamine analogs designed to disrupt flux or glycan function; these approaches reduce growth and metastatic behavior in several preclinical settings, but specificity and normal-tissue tolerance remain key constraints. Overall, the literature supports HBP as a plausible metabolic contributor to BC progression, but stronger patient-linked validation is needed. Future work should prioritize subtype-resolved clinical studies and direct measures of pathway activity to guide biomarker development and therapeutic targeting.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"257 ","pages":"Article 106932"},"PeriodicalIF":2.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145896926","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-31DOI: 10.1016/j.jsbmb.2025.106934
Nandani Dharwal, Deepshikha Rathore, Nirali Shukla, Heena V. Dave
Antiestrogen therapies, such as Tamoxifen (TAM), are widely used in managing estrogen receptor-positive (ER+) breast cancer (BC); however, resistance to these agents remains a significant clinical challenge. Triple-negative breast cancer (TNBC) represents the most aggressive subtype of breast cancer, lacking approved targeted therapies and exhibiting poor patient outcomes. Transforming growth factor-β (TGF-β), a dual-functional cytokine involved in tumor suppression and progression, has gained attention for its crucial role in breast cancer development and metastasis. Therefore, evaluating the impact of antiestrogens on TGF-β pathway components may help identify novel therapeutic targets for TNBC.
This study investigated the expressions of TGF-β1, TGF-β2, and SMAD-3 in four human BC cell lines (MCF-7, MDA-MB-231, MDA-MB-468, and SK-BR-3) following treatment with optimal cell-line-specific doses of TAM and its active metabolite, 4-Hydroxytamoxifen (4-OH-TAM). In TNBC cells, antiestrogen treatment resulted in elevated TGF-β1 expression, accompanied by increased TGF-β2 and SMAD-3, particularly in metastatic MDA-MB-231 cells. Gene expression analysis also revealed that TGF-β1 was upregulated in short-term TAM treatment in MDA-MB-231 cells, whereas 4-OH-TAM had minimal impact. Long-term exposure led to opposite patterns with TGF-β1 decreasing in TAM of MDA-MB-231 cells but increasing in MCF-7 cells, while TGF-β1 elevates in 4-OH-TAM in MDA-MB-231 cells, suggesting cell line and duration-specific responses. Functional assays further showed differential anti-migratory effects, with TAM more effective in MDA-MB-231 and 4-OH-TAM in MCF-7 cells. These findings highlight TGF-β1 as a potential biomarker for TNBC and for predicting responses to antiestrogen therapies, warranting further mechanistic and functional validation.
{"title":"Increased TGF-β signaling during antiestrogen therapy in triple-negative breast cancer cells","authors":"Nandani Dharwal, Deepshikha Rathore, Nirali Shukla, Heena V. Dave","doi":"10.1016/j.jsbmb.2025.106934","DOIUrl":"10.1016/j.jsbmb.2025.106934","url":null,"abstract":"<div><div>Antiestrogen therapies, such as Tamoxifen (TAM), are widely used in managing estrogen receptor-positive (ER+) breast cancer (BC); however, resistance to these agents remains a significant clinical challenge. Triple-negative breast cancer (TNBC) represents the most aggressive subtype of breast cancer, lacking approved targeted therapies and exhibiting poor patient outcomes. Transforming growth factor-β (TGF-β), a dual-functional cytokine involved in tumor suppression and progression, has gained attention for its crucial role in breast cancer development and metastasis. Therefore, evaluating the impact of antiestrogens on TGF-β pathway components may help identify novel therapeutic targets for TNBC.</div><div>This study investigated the expressions of TGF-β1, TGF-β2, and SMAD-3 in four human BC cell lines (MCF-7, MDA-MB-231, MDA-MB-468, and SK-BR-3) following treatment with optimal cell-line-specific doses of TAM and its active metabolite, 4-Hydroxytamoxifen (4-OH-TAM). In TNBC cells, antiestrogen treatment resulted in elevated TGF-β1 expression, accompanied by increased TGF-β2 and SMAD-3, particularly in metastatic MDA-MB-231 cells. Gene expression analysis also revealed that TGF-β1 was upregulated in short-term TAM treatment in MDA-MB-231 cells, whereas 4-OH-TAM had minimal impact. Long-term exposure led to opposite patterns with TGF-β1 decreasing in TAM of MDA-MB-231 cells but increasing in MCF-7 cells, while TGF-β1 elevates in 4-OH-TAM in MDA-MB-231 cells, suggesting cell line and duration-specific responses. Functional assays further showed differential anti-migratory effects, with TAM more effective in MDA-MB-231 and 4-OH-TAM in MCF-7 cells. These findings highlight TGF-β1 as a potential biomarker for TNBC and for predicting responses to antiestrogen therapies, warranting further mechanistic and functional validation.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"257 ","pages":"Article 106934"},"PeriodicalIF":2.5,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145884507","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-31DOI: 10.1016/j.jsbmb.2025.106933
Siji Jose Pulluparambil , Subrahmanya Bhat
Accurate and timely diagnosis remains a challenge due to the complexity of Polycystic Ovary Syndrome (PCOS) symptoms and data imbalance issues in the existing datasets. This research aims to develop a robust PCOS detection model that addresses these challenges by introducing a novel hybrid methodology with effective feature prioritization while handling data balancing issues. The research involves three major phases: pre-processing, feature selection, and PCOS detection. In the pre-processing stage, dataset balancing is emphasized by the combination of Synthetic Minority Oversampling Techniques (SMOTE) and Edited Nearest Neighbor (ENN). Under this stage, replacing null values, balancing the dataset, and dropping unnecessary columns are accomplished to increase PCOS detection accuracy. The second stage is feature selection, where a distinct hybrid bionic strategy named the Gorilla Salp Swarm Troop Model (GS2TM) is proposed to pick the optimal set of dominant features. The GS2TM algorithm reduces the feature set by 51.1 %, retaining only 23 features while achieving a state-of-the-art accuracy of 98.7 %. In addition, the Densely Connected Attention-Based Squeeze Convolutional Detection Model (DASCD) is proposed for the prediction of PCOS, in which multiple layers are adjusted in a feed-forward manner. The novelty of this work lies in the unified pipeline that simultaneously addresses three major challenges in PCOS detection, such as dataset imbalance (SMOTE-ENN), feature redundancy (GS2TM), and overfitting (DASCD with attention), providing both high accuracy and enhanced interpretability. As a result, the proposed detection model greatly improves accuracy compared to other existing ML-based strategies. Specifically, by utilizing 23 characteristics with GS2TM, the proposed model outperforms with an accuracy of 98.7 % in categorizing PCOS and non-PCOS.
由于多囊卵巢综合征（PCOS）症状的复杂性和现有数据集的数据不平衡问题，准确和及时的诊断仍然是一个挑战。本研究旨在开发一个强大的PCOS检测模型，通过在处理数据平衡问题时引入一种具有有效特征优先级的新型混合方法来解决这些挑战。研究包括预处理、特征选择和PCOS检测三个主要阶段。在预处理阶段，通过结合合成少数派过采样技术（SMOTE）和编辑近邻（ENN）来强调数据集平衡。在此阶段，通过替换空值、平衡数据集和删除不必要的列来提高PCOS检测精度。第二阶段是特征选择，提出了一种独特的混合仿生策略，即大猩猩Salp蜂群模型（GS2TM），以选择最优的优势特征集。GS2TM算法将特征集减少了51.1%，仅保留了23个特征，同时达到了98.7%的最先进精度。此外，针对PCOS的预测，提出了一种多层前馈调整的基于密集连接注意力的挤压卷积检测模型（DASCD）。这项工作的新颖之处在于，统一的管道同时解决了PCOS检测中的三大挑战，即数据集不平衡（SMOTE-ENN）、特征冗余（GS2TM）和过拟合（DASCD with attention），提供了高精度和增强的可解释性。因此，与其他现有的基于ml的检测策略相比，所提出的检测模型大大提高了准确性。具体而言，通过利用GS2TM的23个特征，该模型在PCOS和非PCOS分类方面的准确率达到98.7%。
{"title":"Exploring the feature prioritization and data sampling of PCOS diagnosis via densely connected attention based squeeze deep learning detection model","authors":"Siji Jose Pulluparambil , Subrahmanya Bhat","doi":"10.1016/j.jsbmb.2025.106933","DOIUrl":"10.1016/j.jsbmb.2025.106933","url":null,"abstract":"<div><div>Accurate and timely diagnosis remains a challenge due to the complexity of Polycystic Ovary Syndrome (PCOS) symptoms and data imbalance issues in the existing datasets. This research aims to develop a robust PCOS detection model that addresses these challenges by introducing a novel hybrid methodology with effective feature prioritization while handling data balancing issues. The research involves three major phases: pre-processing, feature selection, and PCOS detection. In the pre-processing stage, dataset balancing is emphasized by the combination of Synthetic Minority Oversampling Techniques (SMOTE) and Edited Nearest Neighbor (ENN). Under this stage, replacing null values, balancing the dataset, and dropping unnecessary columns are accomplished to increase PCOS detection accuracy. The second stage is feature selection, where a distinct hybrid bionic strategy named the Gorilla Salp Swarm Troop Model (GS2TM) is proposed to pick the optimal set of dominant features. The GS2TM algorithm reduces the feature set by 51.1 %, retaining only 23 features while achieving a state-of-the-art accuracy of 98.7 %. In addition, the Densely Connected Attention-Based Squeeze Convolutional Detection Model (DASCD) is proposed for the prediction of PCOS, in which multiple layers are adjusted in a feed-forward manner. The novelty of this work lies in the unified pipeline that simultaneously addresses three major challenges in PCOS detection, such as dataset imbalance (SMOTE-ENN), feature redundancy (GS2TM), and overfitting (DASCD with attention), providing both high accuracy and enhanced interpretability. As a result, the proposed detection model greatly improves accuracy compared to other existing ML-based strategies. Specifically, by utilizing 23 characteristics with GS2TM, the proposed model outperforms with an accuracy of 98.7 % in categorizing PCOS and non-PCOS.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"258 ","pages":"Article 106933"},"PeriodicalIF":2.5,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145893463","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-31DOI: 10.1016/j.jsbmb.2025.106928
Shivali, Hitesh Kumar, Navneet Agnihotri
Cancer poses a major global health concern, with an alarming increase in incidence and associated mortality. Surgical resection of tumor, radiotherapy and chemotherapy remains the mainstay of therapeutic options available. Though these treatments do increase the life span of the patients but severely impact their quality of life due to their short term or long term adverse effects. The current research is therefore focused on exploring the natural compounds as an alternative and indeed many do exhibit anticancer activity. Complex metabolic reprogramming in cancer prompts the need for researchers to explore novel and innovative strategies to target such aberrant pathways by using safer and effective natural products. The present review focusses on Ergosterol, a mycosterol present in mushrooms which not only modulates the aberrant cholesterol homeostasis but also show independent anticancer activity due to its antioxidant, anti-inflammatory and lipid lowering properties. In addition, the challenges and limitations related to its utility as a drug molecule and advancements in improving its pharmacological properties using chemical and physical modifications has also been addressed.
{"title":"Molecular targets of ergosterol and its derivatives in cancer therapy: Recent trends and strategies to improve its bioavailability","authors":"Shivali, Hitesh Kumar, Navneet Agnihotri","doi":"10.1016/j.jsbmb.2025.106928","DOIUrl":"10.1016/j.jsbmb.2025.106928","url":null,"abstract":"<div><div>Cancer poses a major global health concern, with an alarming increase in incidence and associated mortality. Surgical resection of tumor, radiotherapy and chemotherapy remains the mainstay of therapeutic options available. Though these treatments do increase the life span of the patients but severely impact their quality of life due to their short term or long term adverse effects. The current research is therefore focused on exploring the natural compounds as an alternative and indeed many do exhibit anticancer activity. Complex metabolic reprogramming in cancer prompts the need for researchers to explore novel and innovative strategies to target such aberrant pathways by using safer and effective natural products. The present review focusses on Ergosterol, a mycosterol present in mushrooms which not only modulates the aberrant cholesterol homeostasis but also show independent anticancer activity due to its antioxidant, anti-inflammatory and lipid lowering properties. In addition, the challenges and limitations related to its utility as a drug molecule and advancements in improving its pharmacological properties using chemical and physical modifications has also been addressed.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"257 ","pages":"Article 106928"},"PeriodicalIF":2.5,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145884497","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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