The Journal Of Steroid Biochemistry And Molecular Biology[JOURNAL]
Sun
200 papers
Caveolin-1 regulates cellular cholesterol homeostasis and its potential as an atherosclerosis therapy target.
Peng Y, Chen S, Yu Y … +2 more , Tong W, Sun S
J Steroid Biochem Mol Biol · 2026 May · PMID 41771453 · Publisher ↗
Atherosclerosis is a chronic inflammatory disease characterized by lipid accumulation within the arterial wall, with disrupted cholesterol homeostasis serving as a central pathogenic driver. Caveolin-1 (Cav-1), the core...
Atherosclerosis is a chronic inflammatory disease characterized by lipid accumulation within the arterial wall, with disrupted cholesterol homeostasis serving as a central pathogenic driver. Caveolin-1 (Cav-1), the core structural component of caveolae, plays a multifaceted role in regulating cellular cholesterol metabolism. This review synthesizes recent advances in understanding Cav-1's diverse functions, including its domain-specific roles in cholesterol binding, transcriptional regulation of lipid synthesis, facilitation of triglyceride storage, and coordination of cholesterol efflux via interactions with ABCA1 and ABCG1. Cav-1 also governs lipoprotein endocytosis and transcytosis in endothelial cells, contributing to subendothelial lipid deposition. Beyond lipid trafficking, Cav-1 modulates autophagic pathways-either suppressing or enhancing autophagy depending on cellular context-and exerts dual effects on vascular inflammation and immune cell recruitment. Genetic models reveal that both Cav-1 overexpression in plaque-resident cells and endothelial Cav-1 deficiency can confer atheroprotection, highlighting its context-dependent roles. Importantly, recent studies have identified specific protein-protein interactions involving Cav-1 (e.g., with ABCA1 and ABCG1) as pharmacologically actionable nodes. Small molecules such as curcumin and probucol metabolites modulate Cav-1 expression or disrupt its interactions to enhance reverse cholesterol transport and stabilize plaques. This review integrates these findings to propose Cav-1 as a context-specific, precision therapeutic target in atherosclerosis.
Circadian rhythm disruption induces PCOS-like phenotypes by interfering with ovarian steroid hormone synthesis pathways.
Feng C, Guo L, Gao X … +7 more , Ji X, Liu Y, Liu J, Liu S, Liu Y, Ma L, He X
J Steroid Biochem Mol Biol · 2026 May · PMID 41771452 · Publisher ↗
Stressors are a critical contributor to reproductive dysfunction. This study investigated whether experimentally induced chronic stress leads to infertility and elucidated its disruptive mechanisms on the female reproduc...
Stressors are a critical contributor to reproductive dysfunction. This study investigated whether experimentally induced chronic stress leads to infertility and elucidated its disruptive mechanisms on the female reproductive endocrine system. Three chronic stress models were established in female ICR mice: chronic restraint stress (CRS), circadian rhythm disruption (CR), and chronic unpredictable mild stress (CUMS). Systemic evaluations revealed that the CR model most significantly activated the hypothalamic-pituitary-adrenal (HPA) axis, as indicated by elevated corticosterone and epinephrine levels. Macro- and micro-level quantitative analyses demonstrated that CR treatment significantly reduced body weight, ovarian and uterine coefficients, increased atretic follicles, disrupted estrous cycles, and decreased litter size. Hormonal assays showed decreased levels of luteinizing hormone (LH), progesterone, estradiol, and melatonin, while testosterone levels were elevated. This pattern of alterations closely resembled the endocrine profile of polycystic ovary syndrome (PCOS). Further ovarian transcriptome analysis identified 538 differentially expressed genes. Key estrogen synthesis genes (Star, Cyp19a1, Cyp17a1, 3β-Hsd, 17β-Hsd) and rate-limiting enzymes were significantly downregulated. Notably, expression of luteinizing hormone receptor (Lhr) showed compensatory upregulation, suggesting a feedback response to impaired steroidogenesis. Functional enrichment analysis highlighted significant alterations in steroid hormone synthesis, cAMP signaling, and metabolic pathways. Our findings suggest that circadian rhythm disruption impairs reproductive function primarily through downregulating key genes in the estrogen synthesis pathway. This work confirms the induction of a PCOS-like phenotype by artificial stress and reveals novel mechanistic insights, thereby identifying potential therapeutic targets for stress-associated PCOS.
Structure-activity relationships of steroid and sterol neuromodulators on inflammatory markers in a murine microglial cell line.
Shu HJ, Covey DF, Zorumski CF … +1 more , Mennerick S
J Steroid Biochem Mol Biol · 2026 May · PMID 41765147 · Full text
Neuroactive steroids are allosteric modulators of GABA receptors and are implicated in the etiology and treatment of neuropsychiatric disorders. Existing treatments are helpful but have drawbacks. Neuroactive steroids re...
Neuroactive steroids are allosteric modulators of GABA receptors and are implicated in the etiology and treatment of neuropsychiatric disorders. Existing treatments are helpful but have drawbacks. Neuroactive steroids recently gained attention as rapidly acting antidepressants in postpartum depression and other indications. Unlike other GABA receptor modulators, neurosteroids may possess anti-inflammatory actions, potentially contributing to therapeutic benefit. Here we seek to understand neuroactive steroid structure-activity relationships relevant to these anti-inflammatory effects. We used murine microglial BV2 cells challenged with lipopolysaccharide (LPS) as an inflammation model. We investigated structure-activity profile of neuroactive steroids and oxysterol-like compounds on cytokine transcription. LPS increased transcripts for cytokines IL-1β, IL-6 and TNF-α. Both allopregnanolone and its enantiomer significantly suppressed these LPS-induced increases, with no effect in the absence of LPS. CONCLUSIONS: Our results suggest that neuroactive steroids exhibit a distinct structure-activity profile compared with their GABA receptor modulation effects. Certain neuroactive steroids may selectively target neuroinflammation. The enantiomer of AlloP could be a tool compound to differentiate anti-inflammatory effects of neuroactive steroids from GABAergic and other enantioselective effects.
Bioprospection of Piliostigma thonningii ethanol extract for anti-fibroid activity via molecular docking and in vivo hormonal evaluation in female wistar rats.
Ogah CF, Olokun A, Ejiofor D … +2 more , Gyebi GA, Anyanwu GO
J Steroid Biochem Mol Biol · 2026 May · PMID 41763412 · Publisher ↗
This study investigated anti-fibroid potential of Piliostigma thonningii leaf extract using in vivo hormonal and histopathological evaluations of the ethanolic extract in female wistar rats complimented by in silico mole...
This study investigated anti-fibroid potential of Piliostigma thonningii leaf extract using in vivo hormonal and histopathological evaluations of the ethanolic extract in female wistar rats complimented by in silico molecular docking of phytochemical compounds. In vivo fibroid induction with diethylstilbestrol and progesterone significantly increased serum estradiol and progesterone levels (p < 0.05), accompanied by cystic degenerative changes in uterine and ovarian tissues. Treatment with P. thonningii crude extract (250 and 500 mg/kg) significantly reduced elevated hormone levels as well as showed observable improvements in uterine gross morphology and histopathological features. Molecular docking of thirty-one phytoconstituents identified via GCMS profiling of the plant's crude ethanol extract were docked at the ligand-binding domains of progesterone receptor (PR, PDB ID: 4OAR) and estrogen receptor (ER, PDB ID: 1QKU) using AutoDock Vina to explore possible mechanistic interactions. Among the top-ranked compounds, cyclopropaneoctanal-2-octyl exhibited favorable predicted binding interactions with key catalytic residue for PR (CYS and THR) and ER catalytic residue (HIS) comparable to the reference ligands ulipristal acetate and estrogen. Drug-likeness and ADMET prediction suggested that this compound possess acceptable pharmacokinetic properties and dynamic stability. These findings indicate that P. thonningii extract exerts anti-fibroid effects in vivo while in silico analysis provide mechanistic hypotheses regarding the potential contribution of the individual compounds to estrogen and progesterone receptor modulation.
A novel thiadiazole-steroid hybrid as a CYP19A1 inhibitor: Synthesis, molecular interaction analysis and assessment of steroid receptor signaling.
Volkova YA, Dzichenka YU, Sorokin DV … +11 more , Malakhova VR, Uvarov DY, Chursin AY, Sidunets YA, Chebotkova DV, Usanov SA, Bogdanov FB, Khamidullina AI, Salnikova DI, Scherbakov AM, Zavarzin IV
J Steroid Biochem Mol Biol · 2026 Jun · PMID 41763411 · Publisher ↗
The enzyme aromatase (CYP19A1) is an important target for the discovery of new therapeutic drugs against breast cancer. A series of novel heteroaryl steroidal derivatives, C-2- and C-16-thiadiazole-substituted estranes,...
The enzyme aromatase (CYP19A1) is an important target for the discovery of new therapeutic drugs against breast cancer. A series of novel heteroaryl steroidal derivatives, C-2- and C-16-thiadiazole-substituted estranes, were synthesized and biologically evaluated as potential aromatase inhibitors. These compounds exhibited cytotoxicity against breast cancer cells with IC values of 5.5 µM and higher. The lead compound, 2-(2'-P(O)(NHBu)-1',3',4'-thiadiazole)-Δ-estratrien-17-one, was shown to be selective against MCF7 cells with IC (MCF7) = 5.5 µM vs IC (MDA-MB-231) = 26.1 µM. It acts as both a potent selective agent blocking CYP19A1 and an effective apoptosis inducer, with no effects on the hormone receptors ERα and AR. The toxicity of the lead compound against normal epithelial cells has not been revealed. Molecular docking was used to more accurately define the binding mode of the lead compound to CYP19A1. In a word, here we describe a novel heteroaryl steroidal derivative promising as a CYP19A1 inhibitor for the treatment of hormone-dependent breast cancer.
Serendipity, steroids and science.
Sharifi N
J Steroid Biochem Mol Biol · 2026 Jun · PMID 41763410 · Full text
The androgen signaling pathway is probably the most important pathway in enabling prostate cancer progression but it also plays essential roles in numerous processes in normal physiology. Both testosterone and dihydrotes...
The androgen signaling pathway is probably the most important pathway in enabling prostate cancer progression but it also plays essential roles in numerous processes in normal physiology. Both testosterone and dihydrotestosterone are potent androgens that activate the androgen receptor (AR). The essentiality of the androgen pathway in prostate cancer is evidenced in part by the reactivation of AR in prostate cancer that becomes resistant to treatment by gonadal testosterone deprivation. Furthermore, steroid metabolic processes that allow the regeneration of potent androgens in prostate cancer tissues drive this treatment-resistant state, as is made clear by the survival benefit of blocking the synthesis of non-gonadal androgens, e.g., with abiraterone. Here, I narrate and review the process that led to a series of discoveries in androgen metabolism from our group. In this perspective and mechanistic narrative review, I give an honest description of the accidental nature of some of our initial findings, followed by data-driven hypothesis refinement and subsequent studies that illuminate elements of androgen metabolism, with a focus on metabolism of carbon 3, carbon 5 and carbon 17 of the steroid backbone.
Puerarin restores testicular steroidogenesis via VDR-cyclic AMP/PKA signaling in a chronic unpredictable stress (CUS) rat model.
Srivastava S, Agarwal V, Srivastava S … +6 more , Rehman M, Kaushik AS, Chaudhary R, Gosipatala SB, Kushwaha S, Mishra V
J Steroid Biochem Mol Biol · 2026 May · PMID 41759753 · Publisher ↗
Chronic psychological stress is a well-established factor contributing to male infertility by disrupting testicular function through oxidative stress, inflammation, and hormonal imbalance. This study aimed to investigate...
Chronic psychological stress is a well-established factor contributing to male infertility by disrupting testicular function through oxidative stress, inflammation, and hormonal imbalance. This study aimed to investigate the protective effects of puerarin, a natural isoflavonoid, on chronic unpredictable stress (CUS)-induced testicular damage, with a specific focus on the vitamin D receptor (VDR)-mediated cyclic AMP/PKA signaling pathway. Adult male rats were divided into four groups (n = 6/group): Control, CUS, CUS + Puerarin (80 mg/kg; T1), and CUS + Puerarin (120 mg/kg; T2). CUS was given for 8 weeks, and puerarin was administered intraperitoneally during the final 4 weeks. Molecular docking was used to evaluate puerarin's binding affinity to VDR. Biochemical, molecular, histological, and ultrastructural analyses were performed to assess testicular function. CUS significantly reduced testicular VDR expression, cyclic AMP levels, PKA activity, and the expression of steroidogenic proteins (StAR and 17β-HSD3), while increasing IL-6, TNF-α, and oxidative stress markers. Puerarin treatment restored VDR expression, enhanced cyclic AMP levels, improved steroidogenic protein expression, and partially restored PKA activity. Sperm quality and testicular histoarchitecture were also markedly improved. This is the first study to demonstrate that puerarin alleviates stress-induced testicular dysfunction via the VDR-cyclic AMP/PKA signaling pathway. These findings position puerarin as a promising, multi-target, and affordable therapeutic option for managing stress-related male reproductive impairments.
40 years later: Why do immune cells have vitamin D receptors?
Froelich NE, Tang M, Cantorna MT
J Steroid Biochem Mol Biol · 2026 May · PMID 41759752 · Full text
Maternal vitamin D status is a critical factor that shapes the immune response of the offspring over the lifespan. Immune cells express vitamin D receptors and can produce local 1,25(OH)D. The ability of vitamin D to res...
Maternal vitamin D status is a critical factor that shapes the immune response of the offspring over the lifespan. Immune cells express vitamin D receptors and can produce local 1,25(OH)D. The ability of vitamin D to resolve inflammation and restrain pro-inflammatory T cells are central to the benefits of vitamin D both in autoimmunity and host resistance to infection. The functions of vitamin D to suppress T cells seems in conflict with the benefits of vitamin D in host immunity to some infections. Critical features by which vitamin D restores homeostasis following an immune challenge, include a delay in the production of 1,25(OH)D that coincides with the maximal expression of the VDR locally. In addition, vitamin D increases IL-10 and regulatory T cells. Controlling the magnitude of the immune response is a central feature for vitamin D as a regulator of the immune system. In the absence of vitamin D, inflammation accumulates and contributes to the pathogenesis of autoimmune and infectious diseases.
Morphological, histopathological, and transcriptomic analyses of gonads reveal reproductive impacts of levonorgestrel (LNG) exposure on Gambusia affinis.
Wang K, Lin S, Deng Z … +8 more , Cai G, Zhang M, Xie Z, Li S, Zhan L, Han C, Gong J, Li Q
J Steroid Biochem Mol Biol · 2026 May · PMID 41730512 · Publisher ↗
Levonorgestrel (LNG), a synthetic progestin, is extensively utilized in contraceptives and hormone replacement therapies in daily medical practice. To date, LNG has been frequently detected in various water bodies worldw...
Levonorgestrel (LNG), a synthetic progestin, is extensively utilized in contraceptives and hormone replacement therapies in daily medical practice. To date, LNG has been frequently detected in various water bodies worldwide, posing significant threats to aquatic organisms, particularly fish. Its presence disrupts the delicate hormonal balance and gonadal development pathways in fish, leading to adverse effects on their reproductive health and potentially altering population dynamics. In this study, adult female mosquitofish were chronically exposed to LNG at four distinct concentration levels (0 ng/L, 5 ng/L, 50 ng/L, and 500 ng/L) for a duration of 36 days. The masculinizing effects of LNG on female mosquitofish were evaluated through morphological, histological, and transcriptomic analyses. Results revealed that LNG exposure significantly reduces body weight and growth index while inducing masculinizing traits, including posterior orientation of the 14th, 15th, and 16th hemal spines and elongation of the third anal fin with an increased number of segments. Additionally, LNG suppresses ovarian development, particularly at concentrations of 50 ng/L and 500 ng/L, as evidenced by a reduction in the abundance of late vitellogenic oocytes. Transcriptomic analysis reveals substantial alterations in the expression of key genes associated with gonadal development, steroid metabolism, and reproductive function. Specifically, downregulation of genes such as cyp19a1 and cyp17a1, along with upregulation of dmrt1 and hsd17b3, highlights the disruptive impact of LNG on the hormonal balance and gonadal differentiation pathways in female mosquitofish. Within the context of this investigation, an excess of LNG might be directly transformed into testosterone, which suppressed the synthesis of both endogenous estrogens and androgens and induced masculinization.
Polycystic ovarian syndrome - Exploring the therapeutic and biomedical insights into the role of silver nanoparticles.
Muthukumaran D, Anitha V, Baskar G … +1 more , Shanmugam R
J Steroid Biochem Mol Biol · 2026 May · PMID 41707839 · Publisher ↗
A prevalent endocrinopathy affecting reproductive-age women is polycystic ovarian syndrome (PCOS), which affects around 5-20 % of these individuals. PCOS is closely linked to the following causes: immunological, endocrin...
A prevalent endocrinopathy affecting reproductive-age women is polycystic ovarian syndrome (PCOS), which affects around 5-20 % of these individuals. PCOS is closely linked to the following causes: immunological, endocrine, and reactive oxygen species (ROS). Plant extracts are used in the synthesis of silver nanoparticles (AgNPs), which are employed for PCOS treatment. Ag NPs can regulate the hormonal imbalance, reducing pro-inflammatory cytokines and ovarian cysts in PCOS. Conventional medicines, such as metformin, clomiphene citrate, letrozole, flutamide, and rosiglitazone, can regulate menstrual irregularities, improve ovulation, reduce insulin resistance, and decrease androgen levels, but may also cause various side effects. As a result, AgNPs are more effective at optimized doses in the short term used in the treatment of PCOS. The present article provides an uncommon overview of the mechanism of action and safety of AgNPs that are biosynthesized to treat the PCOS condition. The review includes evidence from insulin, inflammation, oxidative processes, neuroendocrine factors and cystogenic pathways to combine and provide an overview. The review also discusses how to approach toxicity, especially dose-dependent, and the reproductive safety of AgNPs and their translational limitations to define the boundaries of AgNPs in the treatment of PCOS.
Estrobolome: Is there a missing link?
Benagiano G, Pluchino N, Archer DF … +1 more , Stanczyk FZ
J Steroid Biochem Mol Biol · 2026 May · PMID 41707838 · Publisher ↗
Estrogens play an important role throughout a woman's life; therefore, disrupting their physiological production will alter hormonal balance with consequences for estrogen-related conditions, such as endometriosis and ad...
Estrogens play an important role throughout a woman's life; therefore, disrupting their physiological production will alter hormonal balance with consequences for estrogen-related conditions, such as endometriosis and adenomyosis. The gut microbiome (GM) plays a critical role in regulating systemic estrogen concentrations, since a number of microorganisms present in the GM possess the enzyme β-glucuronidase (β-GLC), a key factor in regulating host estrogen metabolism. Although most studies have focused on the conversion of estrogen glucuronides to active estrogens by β-GLC in gut bacteria, it is known that the GM also contains steroid sulfatases (STS), which are able to convert inactive sulfated estrogens to active ones. This is especially important because estrone (E) sulfate (ES) is quantitatively the most important estrogen in the human and can be readily converted to E and estradiol (E). It has been shown that estrogen sulfates are present in bile and can therefore reach the intestines, raising the possibility of biologically active E and E formation in the intestine by bacterial enzyme transformation. Everything depends on the presence of sulfatases in the GM, and in this respect, STS have been found in a variety of microbial species. This means that sulfatases are poised to reactivate estrogens, which are then capable of undergoing enterohepatic recirculation and exerting systemic effects throughout the body. Given that estrogen sulfates represent the largest component of circulating estrogens that are secreted by the liver into the intestines via the bile, the role of gut microbial sulfatases may be superior to that of β-GLC.
Review on 11-oxygenated steroids in hormone-related diseases: Polycystic ovary syndrome, endometrial cancer, prostate cancer.
Jin X, Werner HMJ, Romano A
J Steroid Biochem Mol Biol · 2026 May · PMID 41702503 · Publisher ↗
11-oxygenated androgens and oestrogens are biologically active molecules and have increasingly recognised roles in hormone dependent diseases. However, a comprehensive synthesis of existing evidence across major sex horm...
11-oxygenated androgens and oestrogens are biologically active molecules and have increasingly recognised roles in hormone dependent diseases. However, a comprehensive synthesis of existing evidence across major sex hormone-related conditions is still lacking. This review summarises current literature investigating the associations between 11-oxygenated sex steroids and three hormone dependent disorders - polycystic ovary syndrome (PCOS), endometrial cancer (EC), and prostate cancer (PC). Limitations and potential biases in current literature are discussed. This review highlights the emerging relevance of 11-oxygenated androgens in both men and women and emphasises the need for mechanistic and prospective studies to clarify their role in disease initiation, progression, and therapeutic resistance. The potential role of 11-oxygenated oestrogens in hormone dependent diseases remains unexplored.
Corrigendum to "Synergistic effects of sericin and mulberry leaf alkaloid combination therapy on type 2 diabetes via gut microbiota modulation" [J. Steroid Biochem. Mol. Biol. 255 (2026) 106883].
Yufan Z, Aihua X, Yulong H … +5 more , Wei F, Xue Y, Changhao L, Shengran W, Jisheng L
J Steroid Biochem Mol Biol · 2026 Apr · PMID 41690860 · Publisher ↗
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Integrative metabolomics and network pharmacology reveal the therapeutic mechanisms of Inonotus hispidus (Bull.) P. Karst. extract against primary dysmenorrhea.
Wang Q, Bao H, Zhao J … +1 more , Liang H
J Steroid Biochem Mol Biol · 2026 May · PMID 41679349 · Publisher ↗
Primary dysmenorrhea (PD) is a common gynecological disorder characterized by uterine hypercontraction and inflammation. This study employed an integrated strategy combining serum metabolomics, network pharmacology, and...
Primary dysmenorrhea (PD) is a common gynecological disorder characterized by uterine hypercontraction and inflammation. This study employed an integrated strategy combining serum metabolomics, network pharmacology, and experimental validation to investigate the therapeutic potential of different extracts of Inonotus hispidus. In a rat PD model induced by estradiol benzoate and oxytocin, petroleum ether extracts of I. hispidus (MP) significantly alleviated writhing responses, attenuated uterine tissue injury, and corrected key biochemical imbalances, including the pivotal PGFα/PGE ratio and levels of inflammatory cytokines (TNF-α, IL-6, IL-1β). Serum metabolomics analysis revealed that the therapeutic effect of MP was fundamentally linked to the systemic rectification of dysregulated arachidonic acid (AA) metabolism. Network pharmacology and subsequent experimental validation identified that MP concurrently modulates several interconnected signaling pathways. Crucially, MP activated PPARγ by promoting its dephosphorylation, which in turn potently suppressed the NLRP3 inflammasome. Concurrently, it regulated the PI3K/Akt/NF-κB survival-inflammatory axis and inhibited the RhoA/ROCK-mediated contractile pathway, reducing phosphorylation of downstream effectors MYPT1 and MLC. In vitro, the medicated serum (MP-S), containing systemically absorbed bioactive compounds, demonstrated superior and more comprehensive cytoprotection against oxytocin-induced oxidative stress, mitochondrial dysfunction, and apoptosis in rat uterine smooth muscle cells (RUSMCs) than the single compound ergosterone, underscoring the principle of multi-component synergy. Collectively, this work delineates a multi-target mechanism for MP against PD, involving the correction of AA metabolic dysregulation, activation of the PPARγ-NLRP3 axis to suppress inflammation, and inhibition of pathways driving smooth muscle hypercontraction, providing a solid scientific foundation for its development as a modern, multi-targeted therapeutic agent.
What can we learn from the history of steroid metabolites and the ongoing identification of novel biologically active steroid metabolites?
Odermatt A, Morris DJ
J Steroid Biochem Mol Biol · 2026 May · PMID 41679348 · Publisher ↗
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, follo...
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.
Bis(monoacylglycero)phosphate protects murine RAW 264.7 macrophages against 7-Ketocholesterol-induced apoptosis and impaired autophagy.
Lambert R, Montillet S, Hennot C … +8 more , Diaz-Gonzalez A, Guichard M, Cros-Perrial E, Jordheim LP, Gaget K, Calevro F, Luquain-Costaz C, Delton I
J Steroid Biochem Mol Biol · 2026 May · PMID 41679347 · Publisher ↗
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 athe...
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 Sqstm1, Becn1, and Pink1. 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.
Current mass spectrometry methods for the analysis of 7-ketocholesterol and related sterols.
Griffiths WJ, Asgari MA, Wang Y
J Steroid Biochem Mol Biol · 2026 May · PMID 41679346 · Publisher ↗
In this article we summarise the current mass spectrometry methods used for analysis of 7-ketocholesterol and related sterols, focusing on the advantages of the different methods with emphasis on pre-analytical and analy...
In this article we summarise the current mass spectrometry methods used for analysis of 7-ketocholesterol and related sterols, focusing on the advantages of the different methods with emphasis on pre-analytical and analytical precautions to avoid artefactual ex vivo formation of these oxysterols.
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.
Zheng J, Wang Q, Zhang H … +5 more , Xu Y, Wang F, Wang Y, Li X, Ge RS
J Steroid Biochem Mol Biol · 2026 May · PMID 41662993 · Publisher ↗
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 underlyin...
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 Il2rg 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 [H] 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.
Fenchone alleviates 7-ketocholesterol-induced oxiapoptophagy through activation of KLF4-PPARγ-Arg1-mediated M2 macrophage signalling.
Ravi S, Martin LC, Kumaresan M … +3 more , Mani JS, Manikandan B, Ramar M
J Steroid Biochem Mol Biol · 2026 May · PMID 41651434 · Publisher ↗
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 pr...
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.
Targeting cholinesterases with steroid hormone derivatives: Insights from In Vitro assays and molecular modeling.
Ajduković JJ, Matošević A, Bosak A … +5 more , Kovačević S, Banjac MK, Kuzminac IZ, Nikolić AR, Savić MP
J Steroid Biochem Mol Biol · 2026 Apr · PMID 41628836 · Publisher ↗
Steroids represent a large family of organic compounds that, as signaling molecules, play important role in variety of physiological processes as control of metabolic pathways, inflammation processes, immune response, an...
Steroids represent a large family of organic compounds that, as signaling molecules, play important role in variety of physiological processes as control of metabolic pathways, inflammation processes, immune response, and growth, development and reproduction. Modifying the steroid core has allowed the creation of novel synthetic derivatives, which can offer significant benefits in medicine for treating a wide range of pathological conditions. Quite a number of natural steroids have been identified as effective inhibitors of cholinesterases, pointing them out as potential therapeutic alternatives in the application in Alzheimer's disease (AD). Nevertheless, only a limited number of synthetic steroids have so far been studied as cholinesterase inhibitors, highlighting an opportunity for the development of new therapeutic agents derived from natural steroidal frameworks. In this study, we selected a set of structurally diverse steroid hormone derivatives and evaluated in vitro their inhibitory activity against human AChE and BChE. IC values were estimated for several of the most active compounds, with pyridine-containing hydroxy derivative 8 exhibiting affinity toward BChE (IC 2.76 µM), similar to that for clinically used cholinesterase inhibitors. In silico analyses suggest that hydrophobic interactions with key amino-acid residues predominantly govern the binding of these compounds within the enzyme's active site.
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