The Journal Of Steroid Biochemistry And Molecular Biology[JOURNAL]
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200 papers
Vitamin D as a multisystem regulatory hormone: Molecular pathways, physiological integration, and implications for physical performance.
Nadh AG, Mohan A, Sajal H … +1 more , Raju R
J Steroid Biochem Mol Biol · 2026 Jun · PMID 41887370 · Publisher ↗
Vitamin D is a pleiotropic secosteroid hormone whose biological actions extend far beyond calcium- phosphate homeostasis. Emerging experimental evidence highlights the regulatory role of this vitamin across multiple orga...
Vitamin D is a pleiotropic secosteroid hormone whose biological actions extend far beyond calcium- phosphate homeostasis. Emerging experimental evidence highlights the regulatory role of this vitamin across multiple organ systems and signaling pathways involved in endocrine, musculoskeletal, immune, metabolic, and neurobiological functions. Concurrently, growing recognition of the high prevalence and multisystem implications of vitamin D deficiency has led to increasing incorporation of vitamin D screening into routine clinical and hospital practice. Despite the emerging evidence that excessive vitamin D exposure or supplementation can produce adverse physiological effects, clinical focus has largely centered on deficiency. Accordingly, this review synthesizes current evidence on vitamin D metabolism, its physiological roles across major organ systems, the molecular pathways and systemic effects associated with altered vitamin D status, both deficiency and excess, and the resulting risk factors and clinical consequences, with an emphasis on mechanistic integration rather than organ-specific compartmentalization. By positioning vitamin D as a regulator of interconnected molecular networks, this review provides a systems-level framework linking vitamin D signaling to metabolic efficiency, mitochondrial function, and musculoskeletal health. These mechanisms have direct implications for exercise performance, recovery, and injury risk, highlighting the importance of maintaining optimal vitamin D status in athletic and physically active populations.
Knowledge, attitudes and practices related to vitamin D in young adults in rural Sri Lankan settings.
Ranathunga T, Wickramasinghe H
J Steroid Biochem Mol Biol · 2026 Jun · PMID 41887369 · Publisher ↗
Vitamin D is a fat-soluble vitamin that can be synthesized in the skin upon sunlight exposure. Proper Knowledge, Attitudes, and Practices (KAP) related to vitamin D are essential to achieve optimum vitamin D status in th...
Vitamin D is a fat-soluble vitamin that can be synthesized in the skin upon sunlight exposure. Proper Knowledge, Attitudes, and Practices (KAP) related to vitamin D are essential to achieve optimum vitamin D status in the community. Therefore, this study aimed to identify the KAP related to vitamin D among young adults in a selected rural area in Sri Lanka. A total of 120 young male (n = 56) and female (n = 64) adults were recruited from a rural setting in Sri Lanka. Sociodemographic information and KAP related to vitamin D were gathered using questionnaires. A scoring system was used to analyze the KAP questionnaire. The collected data were analyzed using SPSS software. The mean KAP scores were 42.1 ± 13.3, 79.6 ± 8.9, and 65.6 ± 8.5, respectively, indicating poor knowledge, good attitudes and moderate level of practices related to vitamin D. Knowledge about vitamin D was significantly associated with the education level of the participants (p = 0.037). Attitudes were significantly associated with age (p < 0.0001), which older participants demonstrated more positive attitudes towards vitamin D. Practices were associated with gender (p = 0.001), indicating male participants had more sunlight exposure than female participants. In conclusion, this study revealed that many young adults in rural Sri Lankan settings exhibited poor knowledge, good attitudes, and moderate practices related to vitamin D. Nutrition education programs focused on behavior change are recommended to improve vitamin D-related knowledge in rural communities in Sri Lanka.
Vitamin D and its role in human milk oligosaccharide production.
Mead MJ, Woollen ST, Gregoski MJ … +10 more , Ebeling M, Shary JR, Furst A, Spann K, Chetta KE, Hollis BW, Baatz JE, Newton DA, Bode L, Wagner CL
J Steroid Biochem Mol Biol · 2026 Jun · PMID 41865803 · Publisher ↗
INTRODUCTION: Human milk oligosaccharides (HMOs) arise from tightly regulated glycosylation pathways and exert pleiotropic effects on infant immune, microbial, and neurodevelopmental trajectories. Vitamin D influences ge...
INTRODUCTION: Human milk oligosaccharides (HMOs) arise from tightly regulated glycosylation pathways and exert pleiotropic effects on infant immune, microbial, and neurodevelopmental trajectories. Vitamin D influences gene transcription and cellular metabolism, yet its potential role in mammary glycosylation remains unexplored. We examined whether maternal vitamin D status during lactation is associated with HMO composition and whether effects vary by maternal secretor phenotype. METHODS: We performed a post hoc analysis of two clinical studies: the NICHD vitamin D lactation randomized controlled trial (2005-2012) and the Lactation Immune Trial pilot (n = 88). Serum 25-hydroxyvitamin D [25(OH)D, vitamin D status] and 19 HMOs concentrations were measured at 1 and 4 months postpartum. Secretor status was defined by presence of 2'-fucosyllactose. Statistical analyses were conducted using SAS 9.4 with p < 0.05. RESULTS: The cohort comprised 41% White, 7% Black, and 52% Hispanic women. Black and Hispanic mothers exhibited lower 25(OH)D concentrations than White mothers (p < 0.001), and Hispanic mothers were more likely to be secretors (p = 0.006). In secretors, higher 25(OH)D was significantly associated with increased fucosylated and complex HMOs, including lacto-N-fucopentaose II, lacto-N-hexaose, and fucosyl-disialyl-lacto-N-hexaose I at 1 month, with sustained association for the latter at 4 months. In non-secretors, higher 25(OH)D was associated with lower 6'-sialyllactose at 4 months. Distinct HMO patterns were observed by secretor phenotype. CONCLUSION: Vitamin D status is associated with differential HMO profiles during early lactation, supporting a potential role for vitamin D-mediated regulation of mammary glycosylation that is modified by secretor status.
Hydration and interfacial behavior of 7-ketocholesterol monolayers: A comparative molecular dynamics study with cholesterol using the OPC water model.
Kobierski J, Wnętrzak A, Chachaj-Brekiesz A … +1 more , Dynarowicz-Latka P
J Steroid Biochem Mol Biol · 2026 Jun · PMID 41864549 · Publisher ↗
We investigate how oxidation of cholesterol at the C7 position alters sterol hydration and interfacial organization by combining Langmuir monolayer experiments with all-atom molecular dynamics simulations employing the O...
We investigate how oxidation of cholesterol at the C7 position alters sterol hydration and interfacial organization by combining Langmuir monolayer experiments with all-atom molecular dynamics simulations employing the OPC water model. While cholesterol forms tightly packed and weakly hydrated monolayers, 7-ketocholesterol exhibits increased molecular area, enhanced compressibility, and pronounced orientational disorder. These differences originate from altered hydration: the hydroxyl group of 7-ketocholesterol at C3 position retains cholesterol-like hydration, whereas the additional carbonyl group at C7 introduces a pressure-dependent hydration site that becomes increasingly exposed upon monolayer expansion. Consequently, 7-ketocholesterol monolayers accommodate more interfacial water, display deeper water penetration, and form an extensive network of water-mediated sterol-sterol bridges. Energetic analysis reveals that van der Waals cohesion remains comparable to cholesterol, whereas electrostatic interactions are significantly less unfavorable due to effective hydration and screening of polar groups. These hydration-driven effects, captured only with an accurate interfacial water description, provide a molecular basis for the altered mechanical properties and biological behavior of 7-ketocholesterol-rich membranes.
Vitamin D deficiency selectively exacerbates mitochondrial dysfunction in receptor-rich soleus muscle during disuse-induced atrophy.
Matsumoto M, Yanagisawa N, Iida K
J Steroid Biochem Mol Biol · 2026 Jun · PMID 41856333 · Publisher ↗
This study investigated the role of vitamin D (VD) in disuse skeletal muscle atrophy, with a particular focus on muscle type-specific differences. Male C57BL/6 J mice were fed either a standard or VD-deficient diet and s...
This study investigated the role of vitamin D (VD) in disuse skeletal muscle atrophy, with a particular focus on muscle type-specific differences. Male C57BL/6 J mice were fed either a standard or VD-deficient diet and subjected to hindlimb immobilization to induce disuse atrophy. The expression of vitamin D receptor (VDR) was analyzed across several skeletal muscles, and muscle fiber atrophy and mitochondrial function were evaluated. In addition, cultured C2C12 myotubes were used to assess the direct effects of VD on oxidative stress-induced mitochondrial dysfunction. VDR expression was markedly higher in the soleus (SOL) muscle than in other muscles at both mRNA and protein levels. VD deficiency selectively exacerbated immobilization-induced atrophy solely in the SOL muscle, characterized by a significant reduction in muscle fiber cross-sectional area and downregulation of mitochondria-related genes (Pgc1α, Cox1, Cox5b, Cytb, Sdha). Consistently, mitochondrial function, which was assessed based on succinate dehydrogenase activity, further decreased in the VD-deficient SOL muscle. In contrast, the gastrocnemius (GC) and tibialis anterior (TA) muscles showed no significant VD-dependent changes. In C2C12 myotubes, active VD [1,25(OH)₂VD₃] attenuated hydrogen peroxide-induced reductions in mitochondrial gene expression and mitochondrial DNA content, suggesting a direct protective role of VD in muscle cells. Taken together, these findings demonstrate that VD deficiency aggravates disuse muscle atrophy through impaired mitochondrial function, particularly in muscles with high VDR expression, such as the SOL. The study highlights muscle type-specific vulnerability to VD deficiency and suggests that VD supplementation can protect certain muscles from disuse-induced atrophy.
Sexual dimorphism in liver fibrotic metabolic dysfunction: Effects of testosterone and estrogen on CCl-induced liver injury in ovariectomy and orchiectomy models.
Chen ZY, Panga MJ, Wang X … +2 more , Chen S, Zhao Y
J Steroid Biochem Mol Biol · 2026 Jun · PMID 41850443 · Publisher ↗
Liver fibrosis is closely linked to metabolic dysfunction and hormonal regulation, with sex differences influencing disease progression. This study combined untargeted liver metabolomic profiling with ovariectomy and orc...
Liver fibrosis is closely linked to metabolic dysfunction and hormonal regulation, with sex differences influencing disease progression. This study combined untargeted liver metabolomic profiling with ovariectomy and orchiectomy mouse models to investigate the roles of estrogen and testosterone in liver injury caused by carbon tetrachloride (CCl₄). Estrogen deficiency aggravated fibrotic injury and liver dysfunction in female mice, whereas testosterone deficiency exerted relatively modest effects in males. Estrogen supplementation significantly attenuated fibrosis in estrogen-deficient females, while testosterone supplementation produced limited and context-dependent responses. Metabolomic profiling revealed hormone-specific metabolic remodeling: estrogen predominantly influenced tryptophan, glycerophospholipid, and nicotinate metabolism, whereas testosterone was associated with alterations in purine, taurine/hypotaurine, and cysteine-methionine pathways. Notably, glycerophospholipid metabolism emerged as a shared but oppositely regulated pathway between estrogen and testosterone exposure. These findings support the established protective role of estrogen and highlight sex-dependent differences in hormone-associated metabolic remodeling during liver fibrosis.
Targeting 7-ketocholesterol-driven metabolic dysfunction in obesity: Therapeutic potential of Bifidobacterium and dietary antioxidants.
S AN
J Steroid Biochem Mol Biol · 2026 Jun · PMID 41850442 · Publisher ↗
7-Ketocholesterol (7-KC), a highly cytotoxic oxysterol generated during cholesterol oxidation, accumulates in obesity-associated dyslipidemia and plays a significant role in sustaining chronic low-grade inflammation, oxi...
7-Ketocholesterol (7-KC), a highly cytotoxic oxysterol generated during cholesterol oxidation, accumulates in obesity-associated dyslipidemia and plays a significant role in sustaining chronic low-grade inflammation, oxidative stress, and apoptosis. These pathogenic processes contribute to the development and progression of major obesity-related complications, including insulin resistance, cardiovascular disease, and non-alcoholic fatty liver disease. Existing pharmacological interventions offer limited efficacy in counteracting 7-KC induced cellular toxicity, highlighting the need for safe and sustainable nutrition-based strategies. This review examines emerging evidence supporting the role of Bifidobacterium species in modulating cholesterol metabolism, bile acid signaling, gut barrier integrity, and adipose tissue inflammation, all of which are central to oxysterol-mediated metabolic disruption. In addition, the synergistic effects of probiotics and dietary antioxidants in reducing oxidative stress, restoring gut microbial balance, and improving metabolic homeostasis are discussed. Finally, translational insights into functional foods, Synbiotic formulations, and precision nutrition approaches are presented as promising avenues to attenuate 7-KC toxicity and reduce the burden of obesity and its associated comorbidities.
Halogenated phenolic disinfectants suppress 11β-hydroxysteroid dehydrogenase 2 activity in human and rat models: Experimental and computational evidence.
Zhang Q, Lu B, Chi C … +5 more , Tang Y, Pan C, Ge RS, Ou R, Fei Q
J Steroid Biochem Mol Biol · 2026 Jun · PMID 41850441 · Publisher ↗
Halogenated phenolic disinfectants (HDs) are widely used in industrial and personal care products. However, whether these HDs inhibit human and rat 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) activity to interfere...
Halogenated phenolic disinfectants (HDs) are widely used in industrial and personal care products. However, whether these HDs inhibit human and rat 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) activity to interfere with glucocorticoid metabolism remains unclear. Michaelis-Menten kinetics showed high 11β-HSD2 activity (human placenta: Km, 46.0 nM, Vmax, 48.21pmol/mg/min; rat kidney: Km, 50.01 nM, Vmax, 70.6pmol/mg/min). Screening at 100 µM revealed significant inhibition by most HDs (residual activity <50%), except triclocarban and trichloroacetone. Dose-response assays identified hexachlorophene as the most potent inhibitor (human IC, 3.83 µM; rat IC, 1.48 µM). The binding affinities of hexachlorophene and dichlorophene were assessed using Surface Plasmon Resonance, showing KDs of 10.60 and 48.50 μM, respectively. Enzyme kinetics and Lineweaver-Burk plots demonstrated mixed inhibition by HDs, suggesting dual interference with substrate binding and NAD binding. In human BeWo trophoblast cells, HDs differentially suppressed cortisone formation, with dichlorophene, bromochlorophene, and fenticlor showing inhibition even at 1 µM. Molecular docking revealed HDs binding to NAD and cortisol binding sites in human 11β-HSD2, with hexachlorophene forming hydrogen bonds with catalytic residues (Ser219, Tyr232). Structure-activity relationship (SAR) and 3D-QSAR analyses highlighted inverse correlations between inhibitory potency and LogP/molecular volume (r = 0.9214 for pharmacophore). ADMET (absorption, distribution, metabolism, elimination, and toxicity) profiling indicated poor solubility, high plasma protein binding, and potential hepatotoxicity. Network toxicology analysis for hypertensive disorders of pregnancy (including gestational hypertension and preeclampsia), now supported by cellular bioassay data, implicates this dysregulated pathway in the potential pathogenesis of HD-induced disorders. These findings elucidate HDs as potent, species-conserved 11β-HSD2 inhibitors with mixed mechanisms, underscoring their endocrine-disrupting potential and structure-dependent bioactivity.
Characterization of an NADPH-dependent 17β-hydroxysteroid dehydrogenase from a urinary tract bacterial isolate.
Binion B, Abdel-Hamid AM, Wang T … +7 more , Hurst JL, Ahmad S, Irudayaraj J, Daniel SL, Gaskins HR, Cann I, Ridlon JM
J Steroid Biochem Mol Biol · 2026 Jun · PMID 41845996 · Full text
Androgens are a class of steroid hormones that play essential roles in somatic development, reproductive physiology, and anabolic processes in both males and females. Beyond their physiological importance, androgens are...
Androgens are a class of steroid hormones that play essential roles in somatic development, reproductive physiology, and anabolic processes in both males and females. Beyond their physiological importance, androgens are implicated in the pathogenesis of several diseases and contribute to the progression of hormone-sensitive malignancies such as prostate, breast, lung, and ovarian cancers. The metabolic conversion of androgens is primarily catalyzed by two major enzyme classes: cytochrome P450 monooxygenases and NAD(P)H-dependent hydroxysteroid dehydrogenases (HSDHs). While endogenous androgen biosynthesis occurs predominantly in the testes, ovaries, adrenal glands, and placenta, emerging evidence suggests that host-associated microbial communities, including those residing in the urinary tract, may also contribute to local androgen metabolism. In our previous work, we identified the desG gene from the urinary tract isolate Propionimicrobium lymphophilum strain API-1, which encodes a novel NADPH-dependent 17β-HSDH. This enzyme catalyzes the bidirectional conversion between androstenedione (AD) and testosterone (T), suggesting a microbial route for androgen production within the urinary tract. In the present study, we expand on these findings by conducting detailed kinetic and substrate-specificity analyses of this enzyme, alongside bioconversion assays using a broad panel of steroid substrates. These results shed light on the steroid-transforming potential of urinary bacteria. IMPORTANCE: This work represents an important advance in the understanding of androgen metabolism by urinary tract bacteria through the characterization of an NADPH-dependent 17β-HSDH encoded by the desG gene. By elucidating kinetic properties, substrate specificity, and bioconversion capabilities of recombinant DesG, this research provides valuable insights into steroid hormone regulation.
Impact of cooking techniques on the formation of 7-ketocholesterol in food: A comprehensive review.
Mercatante D, Troisi C, Rodriguez-Estrada MT
J Steroid Biochem Mol Biol · 2026 Jun · PMID 41825720 · Publisher ↗
Thermal processing of foods promotes cholesterol oxidation, leading to the formation of 7-ketocholesterol (7-K), a major secondary oxysterol generated through radical- and photo-oxidative mechanisms. Cooking technologies...
Thermal processing of foods promotes cholesterol oxidation, leading to the formation of 7-ketocholesterol (7-K), a major secondary oxysterol generated through radical- and photo-oxidative mechanisms. Cooking technologies differently affect its accumulation, depending on temperature/time combinations, oxygen exposure, moisture loss, and matrix characteristics (lipid composition, endogenous antioxidants, pre-treatments). Dry-heat methods (such as grilling, roasting, pan-frying and deep-frying) generally intensify oxidation, while microwaving may further accelerate hydroperoxide degradation and interface-driven radical reactions. Conversely, vacuum-based low-temperature systems (such as sous-vide) may lead to lower 7-K formation. However, post-cooking conditions (including storage, reheating, and warm holding) can significantly enhance 7-K production, especially in PUFA-rich matrices and products previously subjected to oxidative stress. Considering that 7-K is absorbed to a limited extent but can reach systemic circulation, the evaluation of dietary exposure to 7-K present in commonly consumed cooked foods is relevant for assessing its potential contribution to diet-related oxidative burden. This review compiles current knowledge on formation mechanisms, technological drivers, and dietary occurrence of 7-K in thermally processed foods, highlighting key factors influencing its development across cooking methods.
Deletion of vitamin D receptor with calcium sensing receptor in keratinocytes promotes epidermal tumorigenesis by limiting dna repair and oxidative stress response genes.
Oda Y, Meyer MB, Yeh I … +4 more , Lin Z, Wong CT, Oh D, Bikle DD
J Steroid Biochem Mol Biol · 2026 Jun · PMID 41825719 · Publisher ↗
The vitamin D receptor (Vdr) and calcium-sensing receptor (Casr) regulate epidermal proliferation and differentiation. Deletion of both Vdr and Casr from Krt14 expressing epidermal keratinocytes (DKO) causes alopecia and...
The vitamin D receptor (Vdr) and calcium-sensing receptor (Casr) regulate epidermal proliferation and differentiation. Deletion of both Vdr and Casr from Krt14 expressing epidermal keratinocytes (DKO) causes alopecia and delays wound re-epithelialization. Here, we demonstrate that DKO mice spontaneously develop squamous cell carcinoma with aging. We investigated the molecular mechanisms by which loss of Vdr/Casr leads to epidermal tumorigenesis. Ingenuity Pathway Analysis (IPA) predicted oxidative stress as a major pathway driving the biological processes resulting from Vdr/Casr deficiency. DKO keratinocytes showed reduced expression of genes involved in oxidative stress responses in neonatal epidermis, occurring prior to tumor formation. Spatial transcriptomic (Xenium) analysis demonstrated that reactive oxygen-metabolizing enzymes were markedly decreased in the supra-basal epidermal layers at the skin surface, consistent with differentiation defects caused by Vdr/Casr loss. These reductions were also evident in cells from the lower portion of the hair follicle, the infundibulum, which may arise from epidermal fate transformation toward sebaceous cells. Expression of DNA repair genes, including Xpc and Gadd45a, both implicated in epidermal tumorigenesis, was also decreased following Vdr/Casr deletion. Consistently, DKO keratinocytes exhibited impaired oxidative stress responses and reduced DNA repair capacity. Vdr/Casr deficiency prolonged UVB-induced reactive oxygen species and delayed clearance of UV-induced pyrimidine (6-4) pyrimidone photoproducts. Together, these findings suggest that DKO predisposes supra-basal epidermal cells and infundibulum-derived hair follicle stem cells to malignant transformation by impairing their ability to mitigate oxidative stress and DNA repair process.
Molecular characterization and differential regulation of sex steroids on the gonadotropin ligand-receptor system in mandarin fish (Siniperca chuatsi).
Liu S, Huang W, Ma Z … +10 more , Guo J, Zhou X, Shi H, Gong J, Lin H, Chen S, Han C, Li S, Sun C, Zhang Y
J Steroid Biochem Mol Biol · 2026 Jun · PMID 41825718 · Publisher ↗
The gonadotropin system plays a fundamental role in regulating teleost reproduction. This study characterizes the molecular properties and physiological functions of the Gth system in the mandarin fish (Siniperca chuatsi...
The gonadotropin system plays a fundamental role in regulating teleost reproduction. This study characterizes the molecular properties and physiological functions of the Gth system in the mandarin fish (Siniperca chuatsi). Sequence analysis reveals that both fshb and lhb subunits possess a single N-glycosylation site. Phylogenetic evidence indicates that the lhcgr duplication occurred prior to the teleost specific whole genome duplication event. Tissue distribution analysis demonstrates that lhcgr2 is strictly gonad-specific, while lhcgr1 exhibits a broad distribution across multiple organs, including the brain and liver. Furthermore, the spatiotemporal expression profiles delineate a clear regulatory sequence during gonadal development. At the molecular differentiation stage (15 days post hatching, dph), the significant upregulation of fshr and lhcgrs in males precedes histological gonadal differentiation at 30 dph. During the initiation of gametogenesis at 60 dph a distinct sexual dimorphism emerges. Female development is characterized by a significant increase in pituitary fshb to drive follicle recruitment. In contrast, male development relies on a receptor sensitization mechanism, where early endogenous androgens upregulate gonadal fshr and lhcgrs to sustain spermatogenesis through to sexual maturity at 360 dph. Additionally, experimental hormonal treatments confirm that androgens induce a male-biased receptor expression pattern, whereas estrogens suppress it. Pharmacological assays further identify a biased preference of Fshr for the MAPK pathway and prominent constitutive activity of Lhcgr2. Collectively, these findings provide a comprehensive model for the endocrine regulation of the male developmental trajectory in the mandarin fish.
Alpha-ketoglutarate enhances the proliferation and steroidogenic capacities of Tan sheep granulosa cells through autophagy pathway regulation.
Wang J, Wang L, Zhao M … +6 more , Min S, Yan Y, He J, Song H, Liu X, Chen Q
J Steroid Biochem Mol Biol · 2026 Jun · PMID 41819734 · Publisher ↗
Alpha-ketoglutarate（AKG）, a crucial intermediate in the tricarboxylic acid cycle, may affect ovarian function, oocyte maturation, and embryonic development in mammals. However, its specific impact on hormone secretion...
Alpha-ketoglutarate（AKG）, a crucial intermediate in the tricarboxylic acid cycle, may affect ovarian function, oocyte maturation, and embryonic development in mammals. However, its specific impact on hormone secretion by granulosa cells remains undefined.In this study, we employed EdU, CCK-8, qRT-PCR, Western blot, and immunofluorescence analyses to observe that AKG can modulate the function and steroid metabolism of ovarian granulosa cells in Tan sheep. Our findings indicate that treatment with 5 mM AKG significantly stimulated granulosa cell proliferation, with up-regulated expression of Proliferating Cell Nuclear Antigen(PCNA) protein and mRNA, and an increased proportion of EdU positive cells. Concurrently, AKG enhanced cell survival by reducing the expression of the pro-apoptotic protein BAX, increasing the expression of the anti-apoptotic protein BCL2, and inhibiting pro-caspase3 activation. Additionally, AKG significantly increased the expression of key steroidogenic enzymes (CYP11A1, CYP19A1) and the secretion of estradiol and progesterone.Further investigation revealed that AKG attenuated autophagy by regulating the expression of autophagy related proteins (LC3II/I, ATG7, Beclin1, P62), reducing MDC fluorescence signals, and enhancing mitochondrial membrane potential.Experiments using rapamycin, an mechanistic target of rapamycin pathway inhibitor, confirmed that AKG regulates autophagy via activation of the mechanistic target of rapamycin signaling pathway, thereby influencing steroid hormone synthesis.In conclusion,this study is the first to reveal the molecular mechanisms by which AKG regulates ovarian function, AKG optimizes granulosa cell function by promoting proliferation, inhibiting apoptosis and autophagy, and enhancing steroid hormone synthesis, thereby providing a theoretical framework for improving follicle development and female animal fertility.
A metabolic-immune subtype of breast cancer defined by G6PD and SHMT2: From single‑cell dissection to dual-targeted therapy.
Wang Y, Li J, Yan Y … +1 more , Sun L
J Steroid Biochem Mol Biol · 2026 Jun · PMID 41819344 · Publisher ↗
Breast cancer heterogeneity limits the precision of current prognostic and therapeutic strategies, underscoring the need for molecular frameworks that capture underlying metabolic drivers. Here, we systematically dissect...
Breast cancer heterogeneity limits the precision of current prognostic and therapeutic strategies, underscoring the need for molecular frameworks that capture underlying metabolic drivers. Here, we systematically dissected the landscape of amino acid metabolism (AAM) in breast cancer through integrated bulk and single‑cell transcriptomics, machine learning, in silico knockout, and computational drug screening. From 379 AAM-related genes, we identified 48 survival‑associated AAM genes, which were genomically altered in 53% of patients. Unsupervised consensus clustering defined three stable subtypes with distinct metabolic-immune phenotypes. Among these, the aggressive CL2 subtype exhibited a hyper‑anabolic state tightly coupled with an immunosuppressive microenvironment characterized by M2 macrophage enrichment and CD8⁺ T cell exclusion. An 11‑gene prognostic signature was developed and validated across independent cohorts, quantitatively capturing the CL2 phenotype with 77.8% concordance in anabolic pathways and 93.8% in catabolic pathways. Single‑cell dissection revealed that this metabolic program is epithelial‑intrinsic and actively orchestrates immune exclusion: high‑risk epithelial cells preferentially engage macrophages via APP signaling while exhibiting minimal crosstalk with cytotoxic lymphocytes. Within this circuitry, G6PD and SHMT2 emerged as dual‑functional hubs linking anabolic output to immune evasion, with their overexpression confirmed by qPCR and immunohistochemistry. Finally, molecular docking and dynamics simulations identified piceid as a putative dual inhibitor of G6PD and SHMT2, with favorable binding free energies (-35.53 and -56.49 kcal/mol, respectively). Our study establishes a previously unrecognized AAM‑driven subtype, provides a robust prognostic tool, and proposes a first‑in‑class dual‑targeting strategy, highlighting the therapeutic potential of targeting metabolic vulnerabilities in aggressive breast cancer.
Characterization of an NADPH-dependent 17ɑ-hydroxysteroid dehydrogenase encoded by the desF gene from the gut bacterium Clostridium scindens VPI 12708.
Wang T, Binion B, Alves JMP … +1 more , Ridlon JM
J Steroid Biochem Mol Biol · 2026 Jun · PMID 41794297 · Publisher ↗
Epitestosterone (epiT) is the isomer of the androgen testosterone. Historically, the role of epiT has remained unclear. Recently, it has been reported that epiT promotes nuclear androgen receptor (AR)-dependent prostate...
Epitestosterone (epiT) is the isomer of the androgen testosterone. Historically, the role of epiT has remained unclear. Recently, it has been reported that epiT promotes nuclear androgen receptor (AR)-dependent prostate cancer cell proliferation. The gut bacterium Clostridium scindens VPI 12708 was shown to convert androstenedione (AD) to epiT over three decades ago. The bacterial enzymatic pathways involved in epiT formation have only recently been reported. The desF gene encodes 17α-hydroxysteroid dehydrogenase which converts AD to epiT using NADPH as a cofactor. In this study, we quantitatively characterized DesF kinetic parameters and substrate specificity. The results revealed that the optimal pH for the reductive reaction is 7.0, and for the oxidative reaction it is 7.5 and 8.0. The kinetic analysis showed that for the reductive reaction, the K was 8.1 ± 1.8 µM and the V was 6.4 ± 0.3 µmol·min·mg; for the oxidative direction, the K was 27.3 ± 3.3 µM and the V was 7.2 ± 0.3 µmol·min·mg. Moreover, the substrate specificity analysis revealed that 11-keto-AD is the most favourable substrate for DesF, and the 17-keto group of 11-keto-AD can be converted to the 17α-hydroxy group. The phylogenetic relation between DesF and other characterized hydroxysteroid dehydrogenases reveals common ancestry with human HSD17B10 and Eggerthella lenta 3β-HSDH. These results are a significant advance in understanding epiT formation by the gut microbiome.
Heterologous expression of 20α-hydroxysteroid dehydrogenase in Escherichia coli for the production of 20α-hydroxyprogesterone.
Du S, Yan S, Aisan M … +5 more , Xu H, Xue H, Zhong C, Gao X, Chen C
J Steroid Biochem Mol Biol · 2026 Jun · PMID 41794296 · Publisher ↗
20α-Hydroxyprogesterone (20α-DHP) is an endogenous progestogenic metabolite of progesterone, biosynthesized primarily through the catalytic action of 20α-hydroxysteroid dehydrogenase (20α-HSD). To screen for highly activ...
20α-Hydroxyprogesterone (20α-DHP) is an endogenous progestogenic metabolite of progesterone, biosynthesized primarily through the catalytic action of 20α-hydroxysteroid dehydrogenase (20α-HSD). To screen for highly active 20α-HSDs, five enzymes derived from phylogenetically diverse species-human, orangutan, mouse, bovine, and porcine-were systematically evaluated using multiple sequence alignment, molecular docking, and molecular dynamics simulations. The corresponding genes were subsequently expressed heterologously in E. coli BL21(DE3), and activity screening identified the human-derived 20α-HSD as the superior candidate. Enzymatic characterization revealed maximal activity at pH 8.0 and 35°C, negligible sensitivity to metal ions, and high substrate affinity and catalytic efficiency. Expression conditions were further optimized, with 0.2 mM IPTG at 20°C for 20 h established as the optimal induction parameters. Systematic optimization of reaction parameters-including organic solvent types and optimal concentration of the organic solvent, catalytic time, NADPH concentration, and recombinase concentration -achieved a progesterone conversion rate of 66.75%. To minimize cofactor consumption and enhance process economics, a glucose dehydrogenase-mediated NADPH in situ regeneration system was constructed, sustaining a conversion rate of 64.62%. Scale-up to a 100 mL preparative reaction yielded a conversion rate of 60.83%. Following column chromatography purification, 20α-DHP was isolated in 45.36% yield with 95% purity, as confirmed by HPLC and ¹H NMR analyses. In summary, this study achieved the successful heterologous expression of 20α-HSD in E. coli and established an efficient, green, and highly selective biosynthetic route for 20α-DHP, providing a viable technical foundation for its potential industrial-scale production.
Emerging role of 7-Ketocholesterol and hydroxylated 7-Ketocholesterol in the pathophysiology of disease.
Dias IH, Petler N, Harihararajah K … +3 more , Kremenska Y, Anderson AM, O'Connor MS
J Steroid Biochem Mol Biol · 2026 Jun · PMID 41794295 · Publisher ↗
Cholesterol oxidation at the C7 position is a hallmark of non-enzymatic lipid peroxidation. Reactive oxygen species initiate hydrogen abstraction at the allylic C7 position of cholesterol, leading to the formation of 7-h...
Cholesterol oxidation at the C7 position is a hallmark of non-enzymatic lipid peroxidation. Reactive oxygen species initiate hydrogen abstraction at the allylic C7 position of cholesterol, leading to the formation of 7-hydroperoxides, which subsequently decompose to yield 7-hydroxycholesterols and 7-ketocholesterol (7KC). Due to the relative chemical stability, 7KC accumulates preferentially and is commonly detected in biological samples, compared to more labile hydroperoxide intermediates. 7KC is known to induce oxidative stress, mitochondrial dysfunction, and endoplasmic reticulum stress, leading to apoptosis, autophagy, or necrotic cell death depending on cell type and exposure conditions. In addition, 7KC promotes inflammatory pathways and membrane dysfunction, contributing to tissue damage in diseases associated with chronic oxidative stress. These mechanisms open opportunities for the development of targeted intervention strategies. Accumulation of 7KC also acts as a substrate that may undergo further metabolic or oxidative transformations. Importantly, cells possess enzymatic systems capable of introducing hydroxyl groups at the cholesterol side chain that 7KC can be further modified into double-substituted oxysterols (7-keto-25-hydroxycholesterol and 7-keto-27-hydroxycholesterol) combining a 7-keto moiety with side-chain hydroxylation. These metabolites of 7KC represent the dynamic interplay between oxidative damage and cellular sterol metabolic pathways. Elucidating their biological functions will be essential for a more comprehensive understanding of oxysterol biology in health and disease.
A larval ceRNA network centered on the lnc1778-miR-381-y-HSD17B8 axis regulates sex steroid hormone metabolism in Eriocheir sinensis.
Zhao F, Shi Y, Kong X … +4 more , Zhang K, Zhang C, Yin S, Ning X
J Steroid Biochem Mol Biol · 2026 May · PMID 41775289 · Publisher ↗
The Chinese mitten crab (Eriocheir sinensis) displays significant sexual dimorphism, a trait with considerable economic impact. However, the molecular mechanisms underlying its sex determination remain largely unknown. E...
The Chinese mitten crab (Eriocheir sinensis) displays significant sexual dimorphism, a trait with considerable economic impact. However, the molecular mechanisms underlying its sex determination remain largely unknown. Early larval development, encompassing profound physiological transformation, is hypothesized to be a critical window for sexual fate decision. Here, we conducted whole-transcriptome sequencing of three early larval stages (megalopa before and after desalination, and the first juvenile crab stage), and integrated the data with previously published adult gonad transcriptomes. This enabled the construction of a sex steroid hormone-related ceRNA network active throughout development. Within this network, we identified a central regulatory axis consisting of lnc1778, miR-381-y, and Estradiol 17-beta-dehydrogenase 8 (HSD17B8). Their ceRNA interaction was experimentally validated using dual-luciferase reporter assays and expression correlation analyses. Expression profiling across larval stages and adult tissues revealed dynamic and sexually dimorphic patterns in adult tissues. HSD17B8 and lnc1778 were positively co-expressed in both sexes, significant negative correlations between HSD17B8/lnc1778 and miR-381-y were observed only in females. Furthermore, in vitro functional assays demonstrated that HSD17B8 catalyzes the conversion of estradiol-17β (E2) to estrone (E1) and testosterone (T) to androstenedione (A4), using NAD as a coenzyme. Our findings reveal a novel lncRNA-mediated ceRNA regulatory mechanism that regulates sex steroid hormone metabolism during early development and plays a key role in gonadal differentiation in E. sinensis. This study provides fundamental insights into crab gonadal development and offering potential molecular targets for sex-controlled aquaculture.
Interplay between 7-ketocholesterol and tamoxifen shapes stress responses in breast cancer cells.
Seborova K, Koucka K, Tesarova T … +6 more , Kurucova M, Ehrlichova M, Holy P, Hlavac V, Soucek P, Spalenkova A
J Steroid Biochem Mol Biol · 2026 Jun · PMID 41775288 · Publisher ↗
7-ketocholesterol (7-KC) is a highly abundant and biologically active lipid oxidation product that perturbs membrane integrity, sterol homeostasis, mitochondrial function, and redox balance. In parallel, tamoxifen, a cor...
7-ketocholesterol (7-KC) is a highly abundant and biologically active lipid oxidation product that perturbs membrane integrity, sterol homeostasis, mitochondrial function, and redox balance. In parallel, tamoxifen, a cornerstone therapy for estrogen receptor-positive breast cancer, induces not only estrogen receptor antagonism but also pronounced metabolic and organelle-associated stress. Here, we investigated transcriptional responses of breast cancer cell line models to tamoxifen, 7-KC, and their combination. Tamoxifen elicited a shared antiproliferative response in MCF-7 and BT-20 cells, characterized by suppression of cell cycle progression, DNA replication, and mitosis. However, the downstream stress responses diverged markedly between the two models. MCF-7 cells activated adaptive programs, including unfolded protein response, autophagy, and metabolic reprogramming toward glycolysis, consistent with cytostatic survival. In contrast, BT-20 cells exhibited suppression of metabolic and redox pathways accompanied by inflammatory and apoptotic signaling, indicating impaired stress adaptation. Combined tamoxifen and 7-KC treatment further amplified these divergent stress-response phenotypes. Analysis of the correlation of 16 oppositely regulated genes with clinical data of breast cancer patients validated ST8SIA6 as the main candidate associated with adaptive stress tolerance. Overall, our findings indicate that the capacity to integrate metabolic and redox stress determines tumor cell type-specific responses to combined endocrine and oxysterol-induced stress in breast cancer.
Steroid-induced modulation of the tumor immune microenvironment: Implications for cancer progression and immunotherapy outcomes.
Kaliyamoorthi K
J Steroid Biochem Mol Biol · 2026 May · PMID 41775287 · Publisher ↗
Glucocorticoids (GCs) remain indispensable in oncology due to their strong anti-inflammatory, anti-oedema, and immunosuppressive effects, which are crucial for controlling cancer symptoms and treatment-related toxicities...
Glucocorticoids (GCs) remain indispensable in oncology due to their strong anti-inflammatory, anti-oedema, and immunosuppressive effects, which are crucial for controlling cancer symptoms and treatment-related toxicities. However, the expanding use of immunotherapies, particularly immune checkpoint blockade and CAR-T cell approaches, has highlighted the paradoxical influence of steroids on anti-tumor immunity. GCs profoundly reshape the tumor immune microenvironment (TIME) by suppressing cytotoxic T-cell activity, enhancing regulatory T cells, polarizing macrophages toward tumor-promoting states, inhibiting NK and dendritic cell function, and expanding myeloid-derived suppressor cells. Together, these alterations weaken immune surveillance and may promote tumor progression, metastasis, and therapeutic resistance. Both systemic and tumor-derived GC signaling further interact with niches that sustain cancer stemness. Clinical data indicate that the timing, dose, and duration of steroid exposure are decisive, with early or high-dose administration frequently associated with poorer immunotherapy outcomes. Therefore, clarifying GC-driven immune modulation is critical to balance toxicity control while preserving anti-tumor efficacy in precision immunotherapy.
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