The Journal Of Steroid Biochemistry And Molecular Biology[JOURNAL]
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200 papers
Polycystic ovary syndrome: The role of granulosa cell proliferation and apoptosis in disease development.
Yi Y, Zhong Y, Liang RN … +3 more , Liu CY, Zhang YF, Zhang YX
J Steroid Biochem Mol Biol · 2025 Nov · PMID 40721086 · Publisher ↗
Polycystic ovary syndrome (PCOS) is the most prevalent ovarian endocrine disorder in infertile women and significantly impacts their health. Granulosa cell (GC) is the largest functional cell type in follicular developme...
Polycystic ovary syndrome (PCOS) is the most prevalent ovarian endocrine disorder in infertile women and significantly impacts their health. Granulosa cell (GC) is the largest functional cell type in follicular development and plays a crucial role in follicle growth, differentiation, and maturation. Studies have shown that women with PCOS experience abnormal GC proliferation and apoptosis, which contribute to symptoms such as inflammation, irregular estrous cycles, hormonal imbalances, and follicular development arrest. These findings suggest that altered GC quantity is a key factor in the pathogenesis and progression of PCOS. Nevertheless, substantial inconsistencies exist in studies regarding GC number changes in PCOS follicles. To explore the underlying causes, we reviewed recent literature on GC proliferation and apoptosis in PCOS over the past years. This review identifies several potential causes contributing to these discrepancies, including overlooked follicular-phase-dependent effects on GC quantity, variations in GC sources (PCOS vs. non-PCOS, human vs. animal models, and human immortalized granulosa cells), and the lack of animal model validation, inadequate detection of relevant indicators, and unclear identification of vital influential factors. To address these issues, we propose several potential solutions to provide valuable insights into elucidating the roles of GC proliferation and apoptosis, their regulatory mechanisms, and potential therapeutic strategies in PCOS.
Vitamin D3 (cholecalciferol) is more efficacious than Vitamin D2 (ergocalciferol) at regulating calcium absorption and bone quality in rats.
Dutta S, Sudharma AA, Aboo S … +7 more , Jatavath S, Siginam S, Patil PB, Vadakattu SS, Surekha MV, Reddy GB, Ismail A
J Steroid Biochem Mol Biol · 2025 Nov · PMID 40712802 · Publisher ↗
Differential efficacy of vitamin D2 (D2) versus vitamin D3 (D3) in improving classical functions in target organs remain incompletely understood. Previous studies show contradictory results, with limited comprehensive as...
Differential efficacy of vitamin D2 (D2) versus vitamin D3 (D3) in improving classical functions in target organs remain incompletely understood. Previous studies show contradictory results, with limited comprehensive assessment of functional and molecular outcomes across classical target organs namely intestine, bone and kidney. This study investigated the comparative effects of D2 and D3, administered independently or in combination at different dosages, on these organs using a rat model. Weanling male Sprague-Dawley rats were subjected to a depletion-repletion study design with diets containing D2, D3, combination (D2 +D3), or vitamin D deficient (VDD) diet. Our results demonstrated that vitamin D3 supplementation elevated serum 25(OH)D levels more efficiently compared to vitamin D2, while concurrent D2 administration reduced the potential of D3 to increase 25(OH)D3 levels. Both D2 and D3 maintained serum Ca and PTH in the normal range. Intestinal Ca absorption was higher in groups receiving D3-based diets in a dose-dependent manner. Furthermore, D3 supplementation had superior effects on bone length, width and strength compared to D2. Vitamin D3 more effectively reduced trabecular bone area in the rehabilitation phase. Additionally, the expression of genes involved in renal calcium reabsorption (Trpv5, Calbindin-D28k, Pmca1b) and vitamin D metabolism/function (Cubilin, Vdr) were significantly altered in VDD group and better corrected with D3 than D2 during rehabilitation. These findings suggest that vitamin D3 is more efficacious than vitamin D2 in improving blood levels of 25(OH)D and majority of the classical functions. Hence vitamin D3 appears to be the superior choice for both prevention and rehabilitation purposes.
Very high-dose vitamin D₃ supplementation reduces the expression of genes and proteins engaged in β-oxidation in healthy pigs.
Steg A, Smołucha G, Świątkiewicz M … +1 more , Oczkowicz M
J Steroid Biochem Mol Biol · 2025 Nov · PMID 40680899 · Publisher ↗
Vitamin D plays a multifaceted role in the body, influencing a wide range of physiological processes. While its benefits in deficiency states are well recognized, the effects of high-dose vitamin D₃ supplementation in vi...
Vitamin D plays a multifaceted role in the body, influencing a wide range of physiological processes. While its benefits in deficiency states are well recognized, the effects of high-dose vitamin D₃ supplementation in vitamin D-sufficient individuals remain poorly understood. In this study, we applied an integrative transcriptomic and proteomic approach to assess the dose-dependent effects of long-term dietary vitamin D₃ supplementation (5000 and 10,000 IU/kg feed) in healthy pigs. Despite the absence of phenotypic alterations in fattening characteristics, we observed significant molecular changes in liver tissue, particularly in pathways related to fatty acid β-oxidation, amino acid catabolism, and oxidative stress response. High-dose vitamin D₃ supplementation led to consistent downregulation of key genes and proteins involved in mitochondrial and peroxisomal β-oxidation, including ACSL5, ACADVL, HADHA, ACAA1 (gene expression), and ACADM, ECHDC1, and ECHDC2 (protein level). These findings suggest a reduced hepatic capacity for activating and degrading long-, very long-, and medium-chain fatty acids, potentially resulting in the accumulation of lipid intermediates and a shift toward alternative metabolic pathways. Our findings indicate that very high-dose vitamin D₃ supplementation in non-deficient states may lead to adverse metabolic shifts in the liver, including lipid accumulation and compromised energy metabolism. These effects appear to be dose-dependent, and while they may not manifest phenotypically in short-lived species, they offer important insights into non-classical toxicological effects of high-dose vitamin D₃ supplementation. Importantly, this study highlights the context-dependent nature of vitamin D's effects and provides a new direction for research focused on its metabolic roles beyond classical pathways.
Phytosterols as modulators of gut-brain axis and neuroinflammation in Alzheimer's disease: A novel therapeutic avenue in aging research.
Ganamurali N, S B V, Sabarathinam S
J Steroid Biochem Mol Biol · 2025 Nov · PMID 40680898 · Publisher ↗
Alzheimer's disease (AD) is characterized by amyloid-β deposition and neuroinflammation. Emerging evidence implicates gut microbiota dysbiosis and gut-brain axis dysfunction in AD pathogenesis, while phytosterols-plant s...
Alzheimer's disease (AD) is characterized by amyloid-β deposition and neuroinflammation. Emerging evidence implicates gut microbiota dysbiosis and gut-brain axis dysfunction in AD pathogenesis, while phytosterols-plant sterols similar to cholesterol-modulate microbiota composition, lipid metabolism, and inflammatory pathways. To review evidence of phytosterols as modulators of the gut-brain axis and neuroinflammation in AD, outlining mechanisms, therapeutic potential, and delivery approaches. A literature search of PubMed, Scopus, and Web of Science identified studies on phytosterols, gut microbiota modulation, neuroinflammation, and AD. Mechanistic data on sterol structure-activity relationships, microbiota-derived metabolites, and in vivo AD outcomes were extracted and synthesized. Phytosterols lower systemic cholesterol, cross the blood-brain barrier, and accumulate in neural tissue. They enrich short-chain fatty acid-producing gut microbes, suppress pathogens, and increase secondary bile acids that activate FXR and TGR5 signaling, attenuating neuroinflammation. Preclinical AD models show reduced amyloid-β, decreased microglial activation, and improved cognition. Nanoencapsulation and esterification strategies enhance CNS bioavailability. Phytosterols modulate cholesterol, gut microbiota, and neuroinflammatory pathways through FXR- and TGR5-mediated signaling. Advanced delivery systems and microbiome-informed dosing strategies may enhance their therapeutic precision and uptake. Future studies should focus on stratified human trials to validate efficacy and enable personalized interventions in Alzheimer's disease.
Identification of cholesterol homeostasis related genes and potential pathogenesis mechanisms in ulcerative colitis.
Wan J, Zhang Y, Ge N … +2 more , Guan H, Liu J
J Steroid Biochem Mol Biol · 2025 Nov · PMID 40645380 · Publisher ↗
BACKGROUND AND AIMS: Cholesterol metabolism (CM) plays essential roles in human disease. Ulcerative colitis (UC) is a chronic inflammatory bowel disease associated with significant morbidity and healthcare burden. Howeve...
BACKGROUND AND AIMS: Cholesterol metabolism (CM) plays essential roles in human disease. Ulcerative colitis (UC) is a chronic inflammatory bowel disease associated with significant morbidity and healthcare burden. However, the role of CM in UC remains unclear. METHODS: Gene expression data of UC patients and control samples were retrieved and merged from GSE75214, GSE92415, GSE16879, and GSE48958. Differential analysis was performed for the identification of cholesterol homeostasis-related differentially expressed genes (DEGs), followed by machine learning for cholesterol homeostasis-related hub DEGs. Five cholesterol homeostasis related genes were identified. We further assessed the related pathways of 5 hub genes. RESULTS: Five overlapped cholesterol homeostasis related genes were identified by DEGs analysis. LIPC, LIPG, CETP, ABCB11, and APOH were identified as hub genes. CONCLUSIONS: The current study identified 5 cholesterol homeostasis related genes, LIPC, LIPG, CETP, ABCB11, and APOH, that might play key roles in the development of UC. These findings offer new insights for further exploring UC and its underlying mechanisms.
An in-silico investigation of protein-ligand interactions involving dietary flavonoids targeting the nucleotide-binding domain 1 (NBD1) of multidrug resistance-associated protein 1 (MRP1) to overcome multidrug resistance in cancer.
Padder KA
J Steroid Biochem Mol Biol · 2025 Nov · PMID 40633696 · Publisher ↗
Multidrug resistance (MDR) continues to pose a tough challenge in the successful chemotherapeutic management of various malignancies. A key contributor to MDR is the multidrug resistance-associated protein 1 (MRP1), a me...
Multidrug resistance (MDR) continues to pose a tough challenge in the successful chemotherapeutic management of various malignancies. A key contributor to MDR is the multidrug resistance-associated protein 1 (MRP1), a member of the ATP-binding cassette (ABC) transporter family comprising 1531 amino acids. MRP1 actively extrudes a broad spectrum of chemotherapeutic agents from cancer cells, thereby reducing their intracellular accumulation and attenuating their cytotoxic effects. In this study, we performed molecular docking analyses to investigate the binding interactions between a series of naturally occurring dietary flavonoids and the Nucleotide Binding Domain 1 (NBD1) of MRP1, aiming to identify structural determinants that enhance ligand affinity and inform the selection of effective MDR modulators. All docking simulations were conducted using the Glide v5.7 software suite (Schrödinger LLC., Portland, USA) in extra precision mode (GlideXP). The 14 naturally occuring flavonoids assessed, rutin, taxifolin, myricetin, isorhamnetin, apigenin, eriodictyol, chrysin, daidzein and genistein exhibited variable binding affinities toward MRP1-NBD1, with several compounds forming key hydrogen bonds with active site amino acid residues. Notably, rutin demonstrated the highest binding affinity (docking score: -10.1958), forming highly stable hydrogen bonds with SER686 and SER689. Taxifolin and myricetin also showed favorable interactions, primarily involving SER686. These findings highlight the potential of specific dietary flavonoids to serve as functional inhibitors of MRP1-mediated drug efflux. Overall, the structural insights gained underscore the utility of flavonoid based scaffolds as promising candidates for overcoming MDR, thereby improving the therapeutic efficacy of anticancer agents.
Nano-curcumin attenuates tamoxifen resistance and malignant progression in ER-positive breast cancer cells by inhibiting the PI3K/AKT/mTOR signaling pathway.
Zhang C, Wang H, Lei H … +1 more , Ou J
J Steroid Biochem Mol Biol · 2025 Nov · PMID 40617262 · Publisher ↗
Breast cancer (BC) is one of the most prevalent malignant tumors among women, with estrogen receptor (ER)-positive patients constituting approximately 70 % of all cases. Endocrine therapy is currently a treatment option...
Breast cancer (BC) is one of the most prevalent malignant tumors among women, with estrogen receptor (ER)-positive patients constituting approximately 70 % of all cases. Endocrine therapy is currently a treatment option for patients with ER-positive BC; however, the development of resistance significantly limits the effectiveness of this treatment. Nano-curcumin (Nano-CUR) possesses anticancer properties and enhances bioavailability by improving the hydrophobic character of curcumin (CUR). However, the underlying mechanism by which Nano-CUR affects tamoxifen (TAM) resistance in ER-positive BC remains unknown. Here, we found that Nano-CUR promoted apoptosis and cell cycle arrest, inhibited cell proliferation and reduced the levels of cancer stem cells (CSCs)-related markers, including octamer-binding protein (OCT4), Nanog homeobox (NANOG) and sex-determining region Y-box 2 (SOX2) in TAM-resistant BC cells. Additionally, Nano-CUR demonstrated the ability to inhibit tumor malignant progression in TAM-treated BC mice. Mechanistically, Nano-CUR blocked the activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway in MCF-7/TAM and T47D/TAM cells. The activation of this pathway by its activators (PI3K activator 740Y-P, AKT activator SC-79, and mTOR activator MHY1485) effectively alleviated the anti-tumor effect induced by Nano-CUR in TAM-resistant BC cells. Collectively, these findings reveal that Nano-CUR contributes to the reduction of tumorigenesis and TAM resistance in ER-positive BC cells by inhibiting the PI3K/AKT/mTOR signaling pathway.
Gastric mucosal differentially expressed genes after bariatric surgery: Effects on sterol-related pathways.
Mahjoubin-Tehran M, Eid AH, Jamialahmadi T … +4 more , Ahmad S, Rab SO, Kesharwani P, Sahebkar A
J Steroid Biochem Mol Biol · 2025 Nov · PMID 40609801 · Publisher ↗
Obesity is currently recognized as a serious global health problem, which accounts for a considerable morbidity and mortality burden. Bariatric surgery is widely accepted as one of the most effective treatments for sever...
Obesity is currently recognized as a serious global health problem, which accounts for a considerable morbidity and mortality burden. Bariatric surgery is widely accepted as one of the most effective treatments for severe obesity. Roux-en-Y Gastric Bypass (RYGB) is a common type of bariatric surgery. Although the clinical impact of RYGB has been widely studied, the effects of this intervention at the molecular and genetic levels remain largely unknown. In this study, we aimed to identify differentially expressed genes in gastric mucosa after bariatric surgery vs. before in order to recognize genes and pathways influenced by surgery. Data of GSE76762 was downloaded from GEO (NCBI) database. Gene expression of after surgery samples were compared with before. Genes with a │Log fold change (LFC) │ > 1 and adjusted p-value < 0.05 were defined as differentially expressed genes. It was found that 11 genes were differentially upregulated and 6 genes were differentially downregulated after bariatric surgery. Protein-protein interactions assessed using STRNG online database was significant (p-value: 0.000202). SCD, INSIG1, CYP51A1, and LDLR have strong protein-protein interactions. Gene-gene interaction was investigated using GeneMANIA which showed the high co-expression score (97.78 %). GO and pathway enrichment analysis was investigated using EnrichR. Cholesterol Homeostasis, Sterol Homeostasis, and Cellular Response to Sterol are the best results of biological process. Metabolism of steroids, Steroid regulatory element binding proteins signaling, and Bile secretion are the best results of Reactome, WikiPathway, and KEGG, respectively. Importantly, associations of LDLR, KCNJ13, and PMP22 with Familial hypercholesterolemia, Hyperlipoproteinemia, Charcot-marie-tooth disease type 1 and 4, and Leber congenital amaurosis were discovered.
The role of cholesterol biosynthesis and metabolism causing medical complexity in patients with Smith-Lemli-Opitz Syndrome (SLOS).
Elias ER
J Steroid Biochem Mol Biol · 2025 Nov · PMID 40609800 · Publisher ↗
Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive genetic disorder associated with complex anatomic abnormalities, accompanied by medical, developmental and behavioral challenges. It was the first human disorde...
Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive genetic disorder associated with complex anatomic abnormalities, accompanied by medical, developmental and behavioral challenges. It was the first human disorder identified to be caused by an error in the complex cholesterol biosynthetic pathway, more than thirty years ago. This review will cover the clinical and developmental phenotype of patients with SLOS, and the understanding of how cholesterol deficiency, accumulation of the cholesterol precursors 7- and 8-dehydrocholesterol (7-DHC and 8-DHC), and the oxidation of these precursors into toxic oxysterols, are now known to cause this complex phenotype. There is a wide range of severity in patients with SLOS. The most severely affected babies may be miscarried or die in the newborn period due to lethal congenital anomalies. The most mildly impacted patients may show few anatomic abnormalities other than 2-3 toe syndactyly, but still display cognitive and behavioral challenges along the autism spectrum. The review will also cover the medical evaluation and interventions which are recommended in caring for patients with SLOS. There is no cure for this devastating disease, but certain interventions can lead to an improved quality of life, and stabilization of progressive problems for these complex patients.
Suppression of human and rat 17β-hydroxysteroid dehydrogenase 1 by salicylate preservatives: 3D quantitative structure-activity relationship and in silico docking analysis.
Zhang H, He J, Shen X … +6 more , Wen C, Xu Y, Wang F, Wang S, Ge RS, Li X
J Steroid Biochem Mol Biol · 2025 Nov · PMID 40602440 · Publisher ↗
The placenta contains 17β-hydroxysteroid dehydrogenase 1 (17β-HSD1), an enzyme critical for converting estrone to estradiol. Salicylates, widely used as preservatives, may inhibit 17β-HSD1, but their inhibitory strength...
The placenta contains 17β-hydroxysteroid dehydrogenase 1 (17β-HSD1), an enzyme critical for converting estrone to estradiol. Salicylates, widely used as preservatives, may inhibit 17β-HSD1, but their inhibitory strength and structure-activity relationships (SAR) remain unclear. This study evaluated 13 structurally diverse salicylates, identifying potent inhibitors of human and rat 17β-HSD1. Menthyl salicylate showed the strongest inhibition in humans (IC: 5.23 μM) and rats (IC: 14.85 μM). Inhibition correlated negatively with molecular weight, volume, carbon chain length, and LogP. Mechanistic studies revealed mixed/noncompetitive inhibition in both species. 3D-QSAR and molecular docking highlighted hydrophobic, van der Waals, and hydrogen-bonding interactions at the enzyme's active site. Key structural features, including carbon chain length and substituent patterns, determined inhibitory potency. These findings clarify SAR and suggest salicylates' potential as endocrine disruptors.
Mogroside-rich extract alleviates the inflammation state in polycystic ovary syndrome rats through modulating intestinal microbiota-metabolic axis and suppressing the NF-κB/NLRP3 pathway.
Li S, Lu R, Zhou B … +7 more , Wan R, Yan Y, He J, Wu J, Feng X, Yang X, Liang X
J Steroid Biochem Mol Biol · 2025 Oct · PMID 40581224 · Publisher ↗
Polycystic ovary syndrome (PCOS), a complex endocrine-metabolic disorder characterized by hyperandrogenism, polycystic ovarian morphology, and ovulatory dysfunction, is often associated with insulin resistance. Mogroside...
Polycystic ovary syndrome (PCOS), a complex endocrine-metabolic disorder characterized by hyperandrogenism, polycystic ovarian morphology, and ovulatory dysfunction, is often associated with insulin resistance. Mogroside-rich extract (MGE) from Siraitia grosvenorii possesses significant anti-inflammatory and antioxidant properties. However, its potential to restore intestinal microbial homeostasis and metabolic balance in PCOS and the underlying mechanisms remain unexplored. This study investigated MGE's protective effects and mechanisms in a letrozole-induced PCOS rat model. MGE administration significantly ameliorated estrous cycle irregularities, attenuated body weight gain, reduced cystic follicle formation in ovaries, and lowered serum testosterone and insulin levels. Integrated 16S rRNA sequencing and non-targeted metabolomics revealed that MGE enriched beneficial intestinal microbiota (Akkermansia, Parasutterella), associated with anti-inflammatory effects and metabolic improvement, while suppressing pro-inflammatory Corynebacterium. Notably, MGE partially reversed letrozole-induced alterations in colonic metabolites, restoring levels of anti-inflammatory metabolites like butyric acid and gamma-tocotrienol. Furthermore, MGE significantly reduced ovarian pro-inflammatory cytokines and downregulated the expression of p-NF-κB and NLRP3 proteins. Collectively, these findings demonstrate that MGE ameliorates PCOS symptoms by coordinately regulating ovarian inflammation via suppressing the NF-κB/NLRP3 pathway and restoring intestinal microbiota-metabolic axis balance, highlighting its therapeutic potential for PCOS.
Analysis of star promoter in common carp and catfish testis: Role of c-jun and its association with testicular function as a transcription factor.
Tenugu S, Senthilkumaran B
J Steroid Biochem Mol Biol · 2025 Oct · PMID 40553886 · Publisher ↗
Steroidogenic acute regulatory protein (Star) is a key factor that predominantly mediates the rate-limiting step of steroidogenesis which involved in the translocation of cholesterol from the outer to inner mitochondrial...
Steroidogenic acute regulatory protein (Star) is a key factor that predominantly mediates the rate-limiting step of steroidogenesis which involved in the translocation of cholesterol from the outer to inner mitochondrial membrane in most of the vertebrates. To understand the transcriptional regulation of star (star1) in fish, the 5' upstream region of the star was cloned from both common carp and catfish genomic libraries and in silico promoter motif analysis predicted putative binding sites of C-jun, AP-1, Gata2, and Oct1 in common carp while C-jun, Gata1, Gata2, and Oct1 binding sites were predicted in star promoter of catfish. Luciferase reporter assay through sequential deletion constructs in TM3 cells revealed significantly high promoter activity (P < 0.001) having C-jun site in both common carp and catfish but not with other motifs largely. Increased activity of star promoter was observed upon hCG induction, in vitro, indicating gonadotropin dependency. Site-directed mutagenesis and chromatin immunoprecipitation assays further confirmed the binding of C-jun to the upstream promoter region of star in both species. Expression of c-jun was significantly (P < 0.05) higher during the spawning phase of the testicular cycle in both species. Both c-jun and star were found to be gonadotropin inducible and androgen-dependent in both species. Further, transient gene silencing through c-jun-siRNA in both the species decreased expression of c-jun, star, and other AP-1 factors such as c-fos, junB, sox family genes, steroidogenic enzyme genes, sperm-related factor, testis-related genes, along with reduced testosterone and 11-ketotestosterone levels. The protein level of C-jun was decreased upon transient gene silencing in both species. This was the first report to show that C-jun binds to the upstream promoter motif of stars in both common carp and catfish and also adds valuable new insights that define the molecular mechanisms of c-jun regulating star transcription during steroidogenesis in teleost and probably testicular function.
Vitamin D receptor polymorphisms and their role in invasive breast cancer progression.
Sakhi Z, Najih M, Elghazali K … +3 more , Tadlaoui KA, Benhessou M, Ennaji MM
J Steroid Biochem Mol Biol · 2025 Oct · PMID 40553885 · Publisher ↗
Vitamin D plays a critical role not only in maintaining bone health and regulating calcium levels, but is also involved in several extra-skeletal functions, including cell physiology, proliferation, differentiation, anti...
Vitamin D plays a critical role not only in maintaining bone health and regulating calcium levels, but is also involved in several extra-skeletal functions, including cell physiology, proliferation, differentiation, anti-cancer effects, modulation of immune responses, and inflammation control. Its biological effects are mediated by the nuclear vitamin D receptor (VDR), a member of the steroid hormone receptor family. Genetic variations in this VDR gene, such as the FokI (rs2228570) and TaqI (rs731236) single nucleotide polymorphisms (SNPs), may alter VDR expression levels, impair protein function, and potentially increase the risk of breast cancer. However, the relationship between these polymorphisms and breast cancer remains controversial. This study aims to assess the association between the FokI and TaqI polymorphisms of the VDR gene and breast cancer susceptibility in Moroccan women. For this study, breast cancer tissues and control samples were collected, and genomic DNA was extracted. Genotyping of FokI and TaqI SNPs was performed using TaqMan Real-Time Polymerase Chain Reaction (RT-PCR). Our findings revealed a significant difference in the distribution of FokI genotypes between breast cancer patients and controls (p = 0.031). The FokI polymorphism was significantly associated with histoprognostic grade (p < 0.001), tumor stage (p = 0.011), and progesterone receptor (PR) status (p = 0.004), while the TaqI polymorphism showed a significant association with estrogen receptor (ER) status (p = 0.016). These results suggest that the FokI polymorphism of the VDR gene may influence breast cancer susceptibility. Identifying these genetic variations could provide valuable insights into breast cancer pathogenesis and open avenues for personalized treatment strategies, including the use of VDR agonists as targeted therapies against breast cancer.
Cholesterol acyltransferase-1: A novel diagnostic biomarker and potential therapeutic target for cancer.
Mao S, Zhou W, Cheng A … +2 more , Cao H, Bei Y
J Steroid Biochem Mol Biol · 2025 Oct · PMID 40544892 · Publisher ↗
Aberrant lipid metabolism, particularly the dysregulation of cholesterol metabolism, is a hallmark of cancer cells, facilitating cancer progression. Targeting intracellular cholesterol homeostasis has emerged as a therap...
Aberrant lipid metabolism, particularly the dysregulation of cholesterol metabolism, is a hallmark of cancer cells, facilitating cancer progression. Targeting intracellular cholesterol homeostasis has emerged as a therapeutic strategy in cancer treatment. Esterification, a critical step for cholesterol storage, mitigates cytotoxicity induced by free cholesterol. Accumulation of cholesterol ester has been extensively revealed as a promoting factor for cancer progression. Elevated expression of acyl-coenzyme A: cholesterol acyltransferase-1 (ACAT-1), the primary enzyme responsible for cholesterol esterification, promotes cancer progression by activating multiple signaling pathways. ACAT-1 has garnered attention as a potential anti-cancer target, with many inhibitors developed and applied in cancer treatment. This review summarizes the effects and potential mechanisms of cholesterol ester accumulation on cancer cell proliferation, invasion, metastasis, chemotherapy resistance and immune evasion. Additionally, the role of ACAT-1 and the application of its inhibitors in various cancers are discussed, offering novel strategies for cancer therapy and diagnosis.
5α-reductase type 3 is a predictive marker for chemotherapy efficacy in breast cancer in an androgen-independent manner.
Nakamura K, Takagi K, Yamaguchi-Tanaka M … +6 more , Sato A, Inoue N, Ebata A, Miki Y, Miyashita M, Suzuki T
J Steroid Biochem Mol Biol · 2025 Oct · PMID 40541845 · Publisher ↗
Breast cancer is one of the most representative sex-steroid-dependent cancers and both estrogens and androgens are locally synthesized in breast cancer tissues by sex-steroid producing enzymes. 5α-reductase (5α-Red) is a...
Breast cancer is one of the most representative sex-steroid-dependent cancers and both estrogens and androgens are locally synthesized in breast cancer tissues by sex-steroid producing enzymes. 5α-reductase (5α-Red) is an enzyme which reduces testosterone to biologically active dihydrotestosterone (DHT), serving as a regulator of intratumoral DHT levels. To date, three 5α-Red isozymes have been identified: 5α-Red types 1-3. However, 5α-Red type 3 is not fully examined in breast cancer, and its contribution to DHT synthesis is yet to be elucidated. We therefore immunolocalized 5α-Red type 3 in breast cancer tissues and correlated its immunoreactivity with intratumoral DHT levels as well as clinicopathological parameters. In the present study, 5α-Red type 3 immunoreactivity was not correlated with intratumoral DHT level. Additionally, the immunoreactivity of 5α-Red type 3 was negatively correlated with that of 17β-hydroxysteroid dehydrogenase type 5, which converts androstenedione to testosterone. In the prognostic analysis, although 5α-Red type 3 immunoreactivity was not correlated with patients' clinical outcomes in the entire cohort of 172 breast cancer cases, it was significantly correlated with better clinical outcomes in the patients with non-luminal A type breast cancer or in those who received chemotherapy. These findings suggest that 5α-Red type 3 does not contribute to intratumoral DHT synthesis, while served as a potent predictive marker for efficacy of chemotherapy in breast cancer independent of androgen action.
Research progress of lipid metabolism reprogramming and related drug therapy in ovarian cancer.
Li X, Guo R, Yang G … +4 more , Zhu L, Liu R, Xia L, Zhang Q
J Steroid Biochem Mol Biol · 2025 Oct · PMID 40532958 · Publisher ↗
Ovarian cancer is the most malignant gynecological tumor. Dysregulation of lipid metabolism is not only associated with the formation of tumor cells, but also plays an important role in the invasion and drug resistance o...
Ovarian cancer is the most malignant gynecological tumor. Dysregulation of lipid metabolism is not only associated with the formation of tumor cells, but also plays an important role in the invasion and drug resistance of ovarian cancer. Dysregulation of lipid metabolism involves multiple aspects such as lipid uptake, storage, excretion, and fatty acids oxidation. Dysregulation of lipid metabolism affects tumor proliferation, migration, and drug resistance formation by generating more energy and synthesizing new lipid metabolites or activating related signaling pathways, leading to poor prognosis. This article reviews the role of fatty acid metabolism in ovarian cancer and the research progress in the field of drug therapy, suggesting that fatty acid and related lipid metabolism pathways are potential therapeutic targets for ovarian cancer.
Non-esterified fatty acids disrupt hepatic lipid metabolism and mitochondrial function via TLR4/MyD88/IRAK2 signaling in bovine hepatocytes.
Wen Y, Wang Y, Loor JJ … +2 more , Zhao C, Wang J
J Steroid Biochem Mol Biol · 2025 Oct · PMID 40518053 · Publisher ↗
Excessive non-esterified fatty acids (NEFA) in the blood often lead to ketosis and fatty liver in peripartal cows. The integrity of mitochondrial structure and function plays a key role in the development of lipid metabo...
Excessive non-esterified fatty acids (NEFA) in the blood often lead to ketosis and fatty liver in peripartal cows. The integrity of mitochondrial structure and function plays a key role in the development of lipid metabolism imbalance and inflammation. However, the precise molecular mechanisms of NEFA's impact on these processes remain unclear. To explore how NEFA (0, 0.3, 0.6, 1.2, and 2.4 mM) influence lipid metabolism, inflammation, and mitochondrial function in perinatal cow hepatocytes. Bovine primary hepatocytes were isolated from five 1-day-old Holstein calves using collagenase IV perfusion, hepatocytes were treated with various concentrations of NEFA for 12 h to systematically simulate the metabolic changes in the negative energy balance (NEB) environment. Oxidative stress levels, lipid metabolism gene and protein expression, inflammatory pathway activation, and mitochondrial structure and function were assessed. Compared with the control group, 1.2 and 2.4 mM NEFA significantly increased lipid accumulation (TAG, T-CHO, LDL-c) and oxidative stress (MDA), while reducing antioxidant levels (GSH, SOD, T-AOC). NEFA upregulated lipogenic genes (SREBP-1c, ACC, FASN) and downregulated lipid oxidation genes (PPARα, CPT1A). Lipid transport was impaired, with altered APOE, LDLR, CD36, and L-FABP expression. NEFA activated the TLR4/MyD88/IRAK2/NF-κB pathway, increasing pro-inflammatory cytokines (IL-1β, IL-6, TNF-α). Mitochondrial function was impaired, as evidenced by increased ROS, reduced mitochondrial membrane potential, decreased mtDNA levels, and downregulated expression of oxidative phosphorylation genes. NEFA enhanced IRAK2 mitochondrial translocation, inhibited the mitochondrial biogenesis process, and increased apoptosis. NEFA alters lipid metabolism, inflammation, and mitochondrial function in bovine hepatocytes via the TLR4/MyD88/IRAK2 pathway, providing a new target for preventing metabolic diseases in perinatal cows.
Multi-omics analysis reveals the impact of thrombotic diseases on the occurrence and prognosis of breast cancer.
Zhong Z, Wang Z, Fan T … +3 more , Xu L, Li Q, Dong C
J Steroid Biochem Mol Biol · 2025 Oct · PMID 40513964 · Publisher ↗
Venous thromboembolism (VTE) and breast cancer (BC) are two globally prevalent diseases that present significant public health challenges. Despite their impact, the potential genetic association between VTE and BC remain...
Venous thromboembolism (VTE) and breast cancer (BC) are two globally prevalent diseases that present significant public health challenges. Despite their impact, the potential genetic association between VTE and BC remains insufficiently investigated. Mendelian randomization (MR) analysis was performed to evaluate the causal influence of VTE on BC. Summary-based Mendelian randomization (SMR) identified BC-induced cis-eQTLs in blood samples, while weighted correlation network analysis (WGCNA) identified VTE-related genes. Colocalization analysis was subsequently conducted to ascertain whether the intersecting genes identified through SMR and WGCNA are implicated in both diseases. MR analysis revealed that VTE conditions, particularly deep vein thrombosis (OR = 1.009, 95 % CI: 1.004-1.014, p = 0.0002) and pulmonary embolism (OR = 1.295, 95 % CI: 1.016-1.650, p = 0.037), may act as risk factors for BC. Colocalization analysis identified three VTE-related genes KCNN4 (PH4 = 0.638), SLC22A5 (PH4 = 0.946), and ZBTB38 (PH4 = 0.945) as being closely associated with BC development. Additionally, ssGSEA analysis demonstrated that both SLC22A5 and KCNN4 were enriched in the IL-17 signaling pathway and exhibited strong correlations with immune cells. Finally, a VTE-related risk score model was constructed, indicating better outcomes in the low-VTE risk score group. This study demonstrated that VTE is closely associated with BC development and identified potential molecular pathways linking the two conditions.
Epigenetics' responsibility in endometriosis: A comprehensive assessment.
Akano OP, Amos VO, Fawole IO … +2 more , Oyindamola AC, Ajayi AF
J Steroid Biochem Mol Biol · 2025 Oct · PMID 40513963 · Publisher ↗
Endometriosis is a chronic inflammatory disease characterized by the presence of endometrial-like tissue outside the uterus, affecting women of reproductive age. Despite extensive research, its pathophysiology remains un...
Endometriosis is a chronic inflammatory disease characterized by the presence of endometrial-like tissue outside the uterus, affecting women of reproductive age. Despite extensive research, its pathophysiology remains unclear, with genetic, hormonal, and environmental factors playing interconnected roles. Epigenetic processes, including non-coding RNAs, histone modifications, and DNA methylation, have been implicated in the genesis and progression of endometriosis. These modifications impact physiological functions such as inflammation, cell division, apoptosis, and hormone sensitivity. Recent findings on epigenetic alterations in endometriosis highlight their role in the abnormal behavior of ectopic endometrial-like cells. Aberrant DNA methylation patterns in genes related to immunological control and oestrogen metabolism contribute to the invasiveness and durability of lesions. Histone modifications, such as methylation and acetylation, regulate gene expression by altering chromatin structure. Non-coding RNAs, particularly microRNAs, influence tissue remodeling and inflammation. Given the reversible nature of epigenetic modifications, they present promising therapeutic targets for innovative treatment strategies. Epigenetic-based therapies aim to reverse pathological gene expression patterns, offering hope for more personalized and effective management of endometriosis. Further research is needed to fully utilize epigenetic processes in treating this debilitating disease.
Biological gender difference of bile acid metabolism in susceptibility to cholelithiasis in patients with nonalcoholic fatty liver disease.
Wang Y, Deng D, Mai M … +5 more , Song W, Yuan Q, Xie Y, Mo B, Guo H
J Steroid Biochem Mol Biol · 2025 Oct · PMID 40499663 · Publisher ↗
The incidence of gallstone disease (GSD) is often higher in female patients with nonalcoholic fatty liver disease (NAFLD) compared to their male counterparts; however, the underlying mechanisms remain unclear. This cross...
The incidence of gallstone disease (GSD) is often higher in female patients with nonalcoholic fatty liver disease (NAFLD) compared to their male counterparts; however, the underlying mechanisms remain unclear. This cross-sectional study aimed to investigate gender differences in susceptibility to GSD with a focus on the specificity of bile acid (BA) metabolism, while also considering the reciprocal influence between gut bacteria and BAs. A total of 16 female and 36 male NAFLD patients, identified as having a high risk of GSD, were included in the study. Serum and fecal BA profiles were analyzed, along with a correlation analysis of gut microbiota composition. Gender-specific divergence in hydrophobic BAs distribution was observed, with females exhibiting significantly higher serum retention. The concentrations of serum glycolithocholic acid, isolithocholic acid, and 12-ketolithocholic acid, as well as fecal lithocholic acid, were significantly higher in females than in males. Conversely, the levels of serum hyodeoxycholic acid, fecal 7-ketolithocholic acid (7-keto-LCA), chenodeoxycholic acid, glycocholic acid, and ursodeoxycholic acid were significantly lower in females. Additionally, the total abundance of Fusobacterium and Escherichia-Shigella in the gut microbiota was elevated in females. A statistically significant inverse correlation was observed in females between reduced fecal 7-keto-LCA levels and an increased abundance of butyrate-producing bacterial communities. Overall, BAs and gut microbiota exhibit gender dimorphism in NAFLD patients, which may be linked to the increased risk of secondary GSD in women.
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