Journal of Steroid Biochemistry and Molecular Biology最新文献

{"title":"Pentadecanoic acid as a potential endogenous mTOR modulator for age-related female infertility: Mechanistic insights, molecular docking evidence, and therapeutic perspectives.","authors":"Reni Kalfin, Sidharth Mehan, Rajaram Samant, Manoj Tongra, Harsh Patil, Rohit Kumar Singh","doi":"10.1016/j.jsbmb.2026.107100","DOIUrl":"10.1016/j.jsbmb.2026.107100","url":null,"abstract":"<p><p>Age-related female infertility is a major reproductive health challenge that accelerates sharply after the age of 34, primarily due to declining oocyte quality, increased chromosomal abnormalities, and impaired embryonic developmental competence. Emerging evidence identifies chronic hyperactivation of the mechanistic target of rapamycin (mTOR) signalling pathway as a central molecular driver of ovarian aging, promoting excessive ribosome biogenesis, impaired proteostasis, suppressed autophagy, mitochondrial dysfunction, and oxidative stress within oocytes and surrounding cumulus cells. Although rapamycin, the prototypical mTOR inhibitor, has demonstrated promising effects in improving ovarian function and in vitro fertilization outcomes, its teratogenic potential, immunosuppressive properties, metabolic side effects, and prolonged pre-conception washout requirements limit its clinical applicability in fertility management. This review synthesises current evidence on the role of mTOR in ovarian aging and is complemented by an original molecular docking analysis performed by the authors to evaluate the interaction between pentadecanoic acid and the mTOR kinase domain, an endogenous odd-chain saturated fatty acid, as a potential fertility-safe mTOR modulator. A comprehensive review of the literature was conducted using PubMed and related databases, encompassing pentadecanoic acid biochemistry, molecular mechanisms, mTOR signalling architecture, ovarian aging biology, rapamycin pharmacology, and molecular docking studies. Available evidence indicates that pentadecanoic acid activates AMP-activated protein kinase (AMPK), modulates PPAR-α/δ signalling, supports cellular antioxidant defence, and collectively attenuates anabolic mTOR activity while promoting autophagic recycling and metabolic homeostasis. Molecular docking analysis against the mTOR kinase domain (PDB ID: 4JSV) demonstrated that pentadecanoic acid binds within the active site with a binding energy of -4.4 kcal/mol through interactions with key hydrophobic residues, including Leu1936, Ile1939, Tyr2144, Val2227, and Gly2142, whereas rapamycin exhibited a stronger affinity (-10.1 kcal/mol). Unlike rapamycin, pentadecanoic acid is endogenously produced, compatible with pregnancy, and requires no washout period. Collectively, these findings position pentadecanoic acid as a promising endogenous mTOR modulator with potential therapeutic relevance for age-related female infertility, warranting further mechanistic investigations and well-designed human clinical trials.</p>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":" ","pages":"107100"},"PeriodicalIF":3.1,"publicationDate":"2027-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148714283","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}

{"title":"Exploring the putative role of EGFR in prostate cancer: Interactions with androgen and estrogen receptors.","authors":"G M Gonçalves, D S Souza, C R M Costa, M E G Oliveira, C S Porto, C M Vicente","doi":"10.1016/j.jsbmb.2026.107101","DOIUrl":"10.1016/j.jsbmb.2026.107101","url":null,"abstract":"<p><p>The epidermal growth factor receptor (EGFR) is a transmembrane tyrosine kinase receptor that plays a critical role in regulating cell proliferation, survival, and differentiation. Aberrant activation or overexpression of EGFR has been observed in several cancers, including prostate cancer (PCa), and is associated with aggressive tumor behavior and poor prognosis. The development and progression of PCa largely depend on the involvement of androgen receptor (AR) pathways, which are directly related to EGFR signaling. Research indicates that EGFR can affect AR activity, increasing transcriptional activity or promoting ligand-independent activation, which may lead to castration-resistant prostate cancer (CRPC). Furthermore, emerging evidence suggests that estrogen receptors (ERs) may also interact with EGFR signaling in prostate tissue. These may influence tumor growth, interactions with cellular plasticity, and therapy resistance, but their exact mechanisms require further investigation. Identifying and improving treatment strategies for advanced and treatment-resistant PCa requires understanding the interplay between the EGFR, AR, and ER pathways. However, clinical trials have shown limited success in targeting EGFR alone, possibly through compensatory mechanisms via steroid hormone receptors. Therefore, therapies that simultaneously target EGFR and AR/ER activity may be more effective. Continued research into the molecular interplay between these pathways will broaden our understanding of prostate cancer biology and support the development of more personalized and effective treatments. In this review will focus on EGFR/HER1 and its putative role in prostate cancer. Furthermore, we discuss the potential interaction between EGFR, androgen receptor (AR), and estrogen receptor (ER) signaling pathways.</p>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":" ","pages":"107101"},"PeriodicalIF":3.1,"publicationDate":"2027-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148708523","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}

{"title":"Tissue-predominant estrogen metabolic remodeling in adenomyosis revealed by LC-MS/MS profiling.","authors":"Qing Wang, BoYang Liu, Lei Kuang, Lingke Wang, Yingying Chou, Bei Zhang, Guiping Wan, Tao Gui","doi":"10.1016/j.jsbmb.2026.107095","DOIUrl":"10.1016/j.jsbmb.2026.107095","url":null,"abstract":"<p><p>Adenomyosis (AM) is an estrogen-dependent gynecological disorder in which local steroid handling may contribute to clinical heterogeneity. To characterize estrogen metabolic features in AM, we used liquid chromatography-tandem mass spectrometry (LC-MS/MS) to quantify 13 estrogens and estrogen metabolites in endometrial tissue and serum. Tissue metabolite profiles showed marked increases in catechol estrogens, particularly 2-hydroxyestrone (2-OHE1) and 4-hydroxyestrone (4-OHE1), whereas serum changes were more limited, with 2-methoxyestrone (2-MeOE1) representing the main circulating difference. Pathway- and ratio-based analyses indicated enhanced hydroxylation in tissue without a proportionate increase in downstream methylation-related readouts. Correlation and regression analyses further showed that tissue 2-OHE1 and 4-OHE1 were independently associated with dysmenorrhea severity. In exploratory receiver operating characteristic analyses performed within the discovery cohort, tissue catechol estrogens showed stronger discriminatory ability than serum metabolites. These findings suggested that AM was associated with endometrial tissue-predominant remodeling of estrogen metabolism rather than with generalized elevation of parent estrogens. The present study identified candidate metabolic markers requiring further validation and provided a framework for future investigation of local steroid metabolism in AM.</p>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":" ","pages":"107095"},"PeriodicalIF":3.1,"publicationDate":"2027-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148631999","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}

{"title":"Three Decades of Liver X Receptor Agonist Chemistry: Structural Motifs, Structure-activity Relationship, and Therapeutic Prospects.","authors":"Norberta Delporte, Aurélie Lagarde, Pierre Chalard, Silvère Baron, Amalia Trousson, Jean-Marc A Lobaccaro, Isabelle Thomas","doi":"10.1016/j.jsbmb.2026.107137","DOIUrl":"https://doi.org/10.1016/j.jsbmb.2026.107137","url":null,"abstract":"<p><p>Liver X receptors (LXRs) are nuclear receptors that play an important role in the regulation of gene expression involved in lipid metabolism, cholesterol homeostasis and inflammation. Certain modifications in endogenous LXR activity have been associated with pathological conditions and diseases. The dysregulation of LXR activity can lead to vascular and metabolic diseases, neurological degeneration and formation of malignant tumors. One of the solutions to treat the diseases or at least to slow down the progression is the development of different strategies to modulate LXR signaling for the treatment or prevention of these pathological conditions. Many researchers and pharmaceutical companies are developing selective LXR modulators to precisely control receptor activity and achieve specific pharmacological effects. The activation of LXRs has been linked to the inhibition of cell proliferation and metastasis, the promotion of apoptosis and re-differentiation of tumor cells that drives exosome release to stimulate anti-tumor immunity in certain cancer types. The main challenge is to minimize the adverse effects of LXR induction on lipid metabolism via selective activation of LXRβ isoform. Several lead compounds were identified and tested in clinical trials for few pathologies discussed above. The discovery of a potent and selective LXR ligand involves a combination of multiple steps from lead discovery, optimization, preclinical and clinical testing before getting to marketing authorization. This review offers an overview of synthetic agonists for LXRs developed over the past three decades. Though multiple investigations have been in progress, no FDA-approved LXR-targeting drug is available so far.</p>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":" ","pages":"107137"},"PeriodicalIF":3.1,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149225364","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}

{"title":"Synthesis, molecular dynamics, and functional analysis of mitochondria-targeted estrogens through estrogen receptors.","authors":"Geovanni Alberto Ruiz-Romero, Magdiel Orozco-Valdivia, Javier I Wong-Romero, Ricardo Alberto González-Sánchez, Sergio Andrés Águila, Aldo Moreno-Ulloa, Rafael Vazquez-Duhalt, Kanchan Chauhan, Carolina Álvarez-Delgado","doi":"10.1016/j.jsbmb.2026.107138","DOIUrl":"https://doi.org/10.1016/j.jsbmb.2026.107138","url":null,"abstract":"<p><p>Estrogens play an important role in regulating mitochondrial function and cellular metabolism. Most of the effects of estrogens are mediated by estrogen receptors α and β (ERα and ERβ), located in various cellular compartments, including the mitochondria. The aim of this study was to validate the mitochondrial accumulation of mitochondria-targeted estrogens and determine whether their biological effects are mediated by ERs. Two mitochondria-targeted estrogen derivatives, mitoE2 and mitoEE2, were synthesized by covalently coupling a triphenylphosphonium (TPP) moiety to 17β-estradiol (E2) and 17α-ethynylestradiol (EE2), respectively, and were structurally characterized. Mitochondrial and cytosolic accumulation in MCF-7 cells was quantified by high resolution mass spectrometry. Cell viability assays were performed to assess the cytocompatibility of TPP. To investigate the binding of mitochondria-targeted estrogens to ERs molecular dynamics simulations were performed. Functional assays were assessed in vitro in the MCF-7 cell line through Manganese-dependent Superoxide Dismutase (MnSOD) activity assays using selective ER antagonists, and by gene expression analyses of mitochondrial-encoded cytochrome c oxidase COX1 and nuclear-encoded COX4. Both mitoE2 and mitoEE2 preferentially accumulated in mitochondria compared with the cytosol. The molecular dynamic simulations showed a thermodynamically stable binding to the ligand-binding domain of ERα and ERβ. In vitro analyses revealed that ERβ selectively mediates the inhibition of MnSOD activity induced by mitoE2 and that mitochondria-targeted estrogens differentially modulate COX1 and COX4 expression in a time-dependent manner. In conclusion, this work contributes to understanding the molecular mechanisms underlying the effects of mitochondria-targeted estrogens on mitochondrial function. Our findings support the need for further investigation to determine their role as modulators of mitochondrial processes and provide a mechanistic basis for future studies in additional cellular and disease-specific models.</p>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":" ","pages":"107138"},"PeriodicalIF":3.1,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149225375","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}

{"title":"Evaluation of Murrayanine's Anticancer Potential in Breast Cancer: Integrative Computational, In Vitro, and Nanoparticle Delivery Approaches.","authors":"Yue Di, Xincheng Hu, Jindong Dai, Kanagaraj Rajalakshmi, Stalin Arulsamy, Natarajan Kiruthiga, Panneerselvam Theivendren, Selvaraj Muthusamy, Dongwei Zhu","doi":"10.1016/j.jsbmb.2026.107136","DOIUrl":"https://doi.org/10.1016/j.jsbmb.2026.107136","url":null,"abstract":"<p><p>Breast cancer continues to be a major threat to women's health on a global scale. Innovative treatments that are effective and well-tolerated are greatly needed. Nature-derived compounds, such as phytochemicals, have gained widespread interest owing to their diverse anti-tumor actions on cancer cells. Murrayanine, found in Murraya koenigii, has shown efficacy as an anticancer agent by promoting apoptosis, inducing reactive oxygen species, and regulating pivotal pathways like PI3K/Akt and NF-κB. This investigation evaluated the anti-breast cancer efficacy of Murrayanine by combining cytotoxicity assays, molecular docking and the production of solid lipid nanoparticles for improved delivery. Machine learning models, such as Random Forest, identified Murrayanine as a possible PARP10 inhibitor, suggesting molecules known as PARP inhibitors can pass through the cell barrier. Both network pharmacology and protein interaction analyses identified the proteins PARP, PTEN and TP53 as potential targets for breast cancer therapy. Molecular simulations revealed stable protein-drug interactions, suggesting its potential to produce a favorable effect on the molecular level. Murrayanine SLNs exhibited excellent biochemical features, controlled drug release and stability in in vivo settings. Dose-dependent cytotoxic effects were observed against MCF7 breast cancer cells, with an IC₅₀ of 37.35µg/mL determined. The experimental data suggest that Murrayanine delivered as SLNs is a promising preclinical candidate for breast cancer treatment. The PARP10-inhibitory mechanism and the PARP/PTEN/TP53 network targets proposed here are derived from machine learning classification and molecular modelling and therefore represent computational predictions rather than biochemically or in vivo confirmed outcomes. Conclusively, it is necessary to carry out biochemical validation, pharmacokinetic, and clinical evaluations to ascertain the anticancer efficacy of Murrayanine delivered by SLNs. An integrated use of computational and experimental approaches highlights the ability of natural product drug discovery to address breast cancer. Quantitatively, the Random Forest classifier achieved 91.23% accuracy (Kappa 0.8684, MCC 0.869, weighted F1 0.912) on the class-balanced training partition but only 80.0% accuracy (Kappa 0.2793, MCC 0.287) on an independent, natively imbalanced test partition, indicating overfitting; Murrayanine docked into the PARP10 catalytic domain (PDB 5LX6) with a binding affinity of -8.2kcal/mol in a protocol validated by redocking veliparib (RMSD 0.86Å), and the complex remained stable over 100ns (Rg 16.84 ± 0.21Å, ALA921 hydrogen-bond occupancy 78.4%, MM-GBSA ΔG -52.00kcal/mol). The SLNs showed an encapsulation efficiency of 82.64 ± 1.37%, a particle size of 179.0 ± 5.3nm, a zeta potential of -27.4 ± 1.6mV and 88.17% cumulative release at 72h, and were stable for 90 days at 4 °C.</p>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":" ","pages":"107136"},"PeriodicalIF":3.1,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149185727","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}

{"title":"Bis(monoacylglycero)phosphate protects murine RAW 264.7 macrophages against 7-Ketocholesterol-induced apoptosis and impaired autophagy","authors":"Remi Lambert ,&nbsp;Sherine Montillet ,&nbsp;Clara Hennot ,&nbsp;Agathe Diaz-Gonzalez ,&nbsp;Marion Guichard ,&nbsp;Emeline Cros-Perrial ,&nbsp;Lars Petter Jordheim ,&nbsp;Karen Gaget ,&nbsp;Federica Calevro ,&nbsp;Celine Luquain-Costaz ,&nbsp;Isabelle Delton","doi":"10.1016/j.jsbmb.2026.106955","DOIUrl":"10.1016/j.jsbmb.2026.106955","url":null,"abstract":"<div><div>Atherosclerosis, a leading cause of cardiovascular disease, is driven by the accumulation of oxidized low-density lipoproteins (oxLDL) in arterial walls. 7-Ketocholesterol (7KC), a major oxysterol found in oxLDL and atherosclerotic plaques, triggers multiple cell injuries including loss of lysosomal integrity, oxidative stress, apoptosis, and impaired autophagy in vascular cells. Bis(monoacylglycero)phosphate (BMP), also known as lysobisphosphatidic acid, is a unique phospholipid concentrated in the endolysosomal compartment, known to regulate vesicle dynamics, lysosomal enzyme activities, intracellular cholesterol trafficking and its oxidative metabolism. Using a validated model of BMP enrichment in murine RAW 264.7 macrophages, we investigated whether BMP could exert protective activity against 7KC-induced damage. Our findings revealed that BMP enrichment provides comprehensive protection against 7KC at the cellular level by preserving cell viability, morphology, and neutral lipid balance. Mechanistically, BMP enrichment prevented apoptosis by maintaining mitochondrial integrity and blocking caspase activation. This was demonstrated by normalized BAX/BCL2 ratios, preserved pro-Caspase-3 levels, and reduced PARP cleavage. Remarkably, BMP enrichment also restored autophagic flux, thereby preventing the pathological accumulation of LC3-II and p62 that characterizes autophagy dysfunction. Enhanced colocalization between LC3 and BMP suggests direct functional interactions in the stress response. Gene expression analysis confirmed that BMP enrichment normalized the transcriptional dysregulation of key autophagy regulators, including <em>Sqstm1</em>, <em>Becn1</em>, and <em>Pink1</em>. Taken together, these results suggest that BMP is an endogenous protective factor that counteracts 7KC-induced cellular damage at multiple steps by regulating cell death and autophagy pathways in a coordinated manner.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"259 ","pages":"Article 106955"},"PeriodicalIF":2.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146182883","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}

{"title":"Fenchone alleviates 7-ketocholesterol-induced oxiapoptophagy through activation of KLF4-PPARγ-Arg1-mediated M2 macrophage signalling","authors":"Sangeetha Ravi ,&nbsp;Livya Catherene Martin ,&nbsp;Manikandan Kumaresan ,&nbsp;Jaya Suriya Mani ,&nbsp;Beulaja Manikandan ,&nbsp;Manikandan Ramar","doi":"10.1016/j.jsbmb.2026.106951","DOIUrl":"10.1016/j.jsbmb.2026.106951","url":null,"abstract":"<div><div>7-ketocholesterol (7KCh), a cytotoxic oxysterol enriched in atherosclerotic plaques, provokes macrophage dysfunction through oxiapoptophagy, a linked process of oxidative stress, apoptosis and autophagy culminating in pro-inflammatory M1 polarization. Targeting this process could mitigate oxysterol-driven vascular inflammation. In this study, murine IC-21 macrophages were induced with 7KCh and co-exposed to fenchone, a bicyclic monoterpene with known anti-inflammatory properties. Cellular oxidative stress, apoptosis and autophagy were assessed by spectrofluorometric and cytometric assays. Expression of key mediators (iNOS, COX2, HO1, Casp3, Bcl2, LC3B, PARP1, Arg1, KLF4 and PPARγ) was quantified by RT-qPCR and western blotting. Molecular docking was used to identify interactions of fenchone with KLF4 and PPARγ. The results showed that 7KCh significantly increased ROS and NO production, disrupted mitochondrial membrane potential and induced apoptosis and autophagy in macrophages. Fenchone co-treatment counteracted these effects, restoring redox balance and membrane integrity. Molecular analyses revealed downregulation of iNOS, COX2, Casp3 and PARP1, alongside upregulation of HO1, Arg1, KLF4 and PPARγ. Docking analysis confirmed strong binding of fenchone to KLF4 and PPARγ, suggesting transcriptional regulation of macrophage polarization via the KLF4-PPARγ-Arg1 axis. These findings suggest that fenchone mitigates 7KCh-induced oxiapoptophagy and reprograms macrophages toward an anti-inflammatory M2 phenotype through modulation of KLF4/PPARγ signalling, positioning fenchone as a potential immunomodulatory candidate for combating oxysterol-mediated vascular inflammation.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"259 ","pages":"Article 106951"},"PeriodicalIF":2.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146133531","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}

{"title":"What can we learn from the history of steroid metabolites and the ongoing identification of novel biologically active steroid metabolites?","authors":"Alex Odermatt ,&nbsp;David J. Morris","doi":"10.1016/j.jsbmb.2026.106954","DOIUrl":"10.1016/j.jsbmb.2026.106954","url":null,"abstract":"<div><div>Historically, it was thought that primary steroids released from endocrine glands exert their hormonal effects through corresponding receptors in peripheral tissues, and that their metabolism then inactivates them, followed by excretion. However, the metabolism of primary steroids is not just a way of inactivating and excreting them, but generates a variety of metabolites with different biological properties. In this review, we outline how various active steroid metabolites were discovered, describe some of the ways they are generated, and how they can in a non-classical way act on receptors or alter the activity of steroid metabolizing enzymes, thereby indirectly affecting receptor activities. Examples include the 5α-reduced ring-A metabolites of 11-deoxycorticosterone (DOC) and progesterone that are formed in the brain, act as neurosteroids and exert effects through the GABA-A membrane receptor. Another example is 11-ketoprogesterone that potently activates mineralocorticoid receptors (MR), but not glucocorticoid receptors (GR), and is more potent than its 11β-hydroxylated form, in contrast to glucocorticoids. Moreover, we discuss the microbiome as important source of bioactive metabolites, exemplified by the 11β-hydroxylated 5α-reduced ring-A corticosteroid and progesterone metabolites that were shown as potent 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2) inhibitors. 11β-HSD2 inhibition results in cortisol-induced MR activation, sodium retention and hypertension. Furthermore, microbial 17,20-desmolase activity can convert glucocorticoids to androgens, potentially influencing diseases and therapeutic outcomes. There are still many knowledge gaps regarding bioactive steroid metabolites. Identifying additional bioactive steroid metabolites and characterizing their genomic and non-genomic effects should help uncovering their cell-specific functions and contributions to the maintenance of homeostatic regulation.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"259 ","pages":"Article 106954"},"PeriodicalIF":2.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146182826","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}

{"title":"Interleukin-2 receptor γ blocks the development of Leydig cells from stem/progenitor cells in male rats via JAK1-STAT3 pathway and GSDMD-mediated pyroptosis","authors":"Jingyi Zheng ,&nbsp;Qingyuan Wang ,&nbsp;Huiqian Zhang ,&nbsp;Yubin Xu ,&nbsp;Feilu Wang ,&nbsp;Yiyan Wang ,&nbsp;Xiaoheng Li ,&nbsp;Ren-Shan Ge","doi":"10.1016/j.jsbmb.2026.106953","DOIUrl":"10.1016/j.jsbmb.2026.106953","url":null,"abstract":"<div><div>Interleukin-2 (IL-2) receptor γ (IL2RG) is present in the Leydig cell lineage, but its functional role remains elusive. To investigate how IL2RG impacts Leydig cell development from stem cells and elucidate the underlying mechanisms, we used a rat model of ethane dimethanesulfonate (EDS)-induced cell depletion in Wild-type (WT) and <em>Il2rg</em> knockout (KO) mice. WT and KO male rats received intratesticular IL-2 injections (1 and 10 ng/testis) from day 7 to day 21 post-EDS. Stem Leydig cells around tubules and isolated progenitor Leydig cells were cultured with IL-2 (1 and 10 ng/mL) with/without STAT3 inhibitor. Hormone levels, cell counts, gene/protein expression, and signaling pathways were analyzed. The results revealed that IL-2 significantly reduced serum testosterone levels in WT rats but had no effects in KO rats, without altering luteinizing hormone and follicle-stimulating hormone levels. Furthermore, IL-2 lowered Leydig cell numbers and the labeling index of PCNA in CYP11A1⁺ Leydig cells at 10 ng/testis, and downregulated the expression of SCARB1, HSD3B1, CYP17A1, SRD5A1, and NR5A1, as well as their corresponding mRNA levels in WT rats with no effect observed in KO rats. IL-2 also inhibited the incorporation of 5-ethynyl-2′-deoxyuridine (EdU) into stem Leydig cells in WT rats and [³H] thymidine incorporation into progenitor Leydig cells, as well as their differentiation. Importantly, the effects of IL-2 were reversed by the STAT3 inhibitor. Signaling pathway analysis showed that IL-2 exerted effects via increasing JAK1, STAT5, and STAT3 phosphorylation. This study provides insights into the inhibitory effects of IL2RG on Leydig cell development and highlights the involvement of the JAK-STAT pathway, offering potential targets for further exploration in the context of Leydig cell biology and male reproductive health.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"259 ","pages":"Article 106953"},"PeriodicalIF":2.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146151290","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}