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tamoxifen (tamoxifen, Douglas)

✓ Approved

Douglas Pharmaceuticals Limited · ESR1 · 小分子

什么是 tamoxifen？

tamoxifen 是一种小分子，由Douglas Pharmaceuticals Limited研发。该药已获批，用于治疗相关适应症，给药途径：Oral (PO)。

药物档案

商品名tamoxifen, Douglas
公司Douglas Pharmaceuticals Limited
药物类别小分子
分子靶点ESR1
给药途径Oral (PO)
状态Approved
来源： ClinicalTrials.gov, Douglas Pharmaceuticals Limited

作用机制

分子靶点

tamoxifen 作用于 1 个分子靶点：

ESR1estrogen receptor 1 (ER, ESR)
需要更深入的分析？Noah AI 可解释复杂机制并与同类药物比较。

治疗适应症

tamoxifen 针对 1 个适应症，涉及 1 个治疗领域。

治疗领域疾病/病症分期
Neoplasms benign, malignant and unspecified (incl cysts and polyps)Breast cancer✓ Approved

相关研究文献

PubMedBiochemical pharmacology2026-06-13

Targeting neuropilin-1 attenuates 4-hydroxytamoxifen-induced stemness and sensitizes ERα-re-expressing TNBC to tamoxifen.

Yu Qinglong Q, Tang Wei W, Xiao Yani Y, Kong Ying Y et al.

Reactivating functional estrogen receptor alpha (ERα) expression represents a promising strategy for tamoxifen (TAM)-based endocrine therapy in triple-negative breast cancer (TNBC). However, TAM and its metabolites may exert potential oncogenic effects, which could compromise TAM efficacy in TNBC. Here, we report that low-dose 4-hydroxytamoxifen (4-OHT), an active metabolite of TAM, enhances stemness in TNBC cells via the Neuropilin-1 (NRP-1)/Calpain-2 (CAPN2)/β-catenin axis. Mechanistically, 4-OHT stimulates CAPN2 activation by promoting its membrane localization, increasing substrate cleavage, and inducing degradation of its endogenous inhibitor calpastatin. Activated CAPN2 suppresses ubiquitin-mediated degradation of β-catenin, leading to elevated β-catenin stability and intracellular accumulation. This enhances β-catenin transcriptional activity and ultimately promotes stemness in TNBC cells. Kaplan-Meier survival analysis showed that high NRP1 expression correlates with poorer overall survival in breast cancer patients undergoing endocrine therapy. Moreover, 4-OHT triggers Ca2+ release and ERK phosphorylation in TNBC cells through the NRP-1/PLC-γ1 pathway, thereby activating CAPN2. Finally, we demonstrate that the NRP-1 inhibitor EG00229 sensitizes ERα-re-expressing TNBC cells to TAM treatment. Our study uncovers a molecular mechanism by which 4-OHT promotes TNBC stemness via the NRP-1/CAPN2/β-catenin signaling cascade. Targeting NRP-1 may serve as a valuable strategy to improve TAM efficacy in ERα-re-expressing TNBC.

PMID 42285368
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PubMedThe American journal of pathology2026-06-12

Plasticity of blood vessels and its role in bone homeostasis in the adult epiphysis.

Kise Hideki H, Ogata Toshiyuki T, Matsumoto Yuki Y, Shimizu Shota S et al.

Loss of vascular endothelial growth factor (VEGF) signaling profoundly impairs vascular growth during development. In contrast, once established in adulthood, blood vessels become largely quiescent and less dependent on VEGF signaling, providing the rationale for the clinical use of VEGF inhibitors to selectively target tumor angiogenesis. Here, we show that blood vessels in the epiphysis-the ends of long bones-retain an unexpected degree of plasticity in adult and even aged mice. Tamoxifen-inducible, endothelial-specific deletion of VEGF receptor 2 (Vegfr2), the principal mediator of VEGF signaling, induced marked vascular regression in the epiphysis and led to growth plate cartilage expansion following epiphyseal ischemia. Consistently, endothelial Vegfr2 deletion in adult mice significantly reduced local bone strength. Moreover, epiphyseal vascular regression exacerbated bone mineral density loss in an ovariectomy-induced mouse model of osteoporosis. Collectively, these findings advance our understanding of angiogenic-osteogenic coupling in adulthood and provide a mechanistic framework for the vulnerability of the femoral head and neck to fractures in the elderly.

PMID 42276412
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PubMedCell death & disease2026-06-12

VEGFR2 deletion increases susceptibility to photoreceptor degeneration through glial-neuronal interaction.

Bielmeier Christina B CB, Schmitt Sabrina I SI, Lehr Verena V, Grundl Anita A et al.

Intraocular anti-VEGFA injections are frequently used to counteract neovascularization in diseases such as the neovascular form of age-related macular degeneration (AMD). However, in the clinical context, patients with atrophic (dry) and neovascular (wet) AMD in the same eye will receive anti-VEGFA injections, but there are reports that this severely promotes the development of atrophic areas in dry AMD. To study this, we used mice with a tamoxifen-dependent deletion of Vegfr2 in the eye (Vegfr2Δeye) and the light damage model to mimic certain aspects of dry AMD. We examined retinal morphology and function, the degree of photoreceptor degeneration, and alterations of the retinal proteome. While steady-state retinal morphology and function were not altered due to VEGF signaling deficiency, light-induced photoreceptor degeneration was drastically exacerbated in Vegfr2Δeye retinae, concomitant with attenuated activation of the AKT kinase pathway. Furthermore, using single nuclei RNA sequencing data, we showed that in humans, Vegfr2 is predominantly expressed in macroglial cells of healthy, dry- and wet AMD retinae. This suggests a VEGF-dependent neuroprotective crosstalk from macroglial cells to photoreceptors and poses promising therapeutic options to attenuate photoreceptor degeneration in humans. Yet, our data also indicate that anti-VEGF therapy should be carefully considered in the presence of neurodegenerative comorbidities.

PMID 42276988
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PubMedNeuroscience research2026-06-12

ALS-associated protein TDP-43 disturbs axonal projections in the somatosensory cortex.

Abzhanova Elvira E, Kawae Yuzuki Y, Mizuno Hiromi H, Umemoto Terumasa T et al.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by loss of upper and lower motor neurons that gradually causes muscle weakness and paralysis, eventually resulting in death. While ALS was once believed to specifically target motor neurons, recent clinical studies have revealed sensory involvement. The pathological hallmark of ALS is TAR DNA-binding protein 43 (TDP-43) aggregation in cytoplasm, with increasing evidence of its presence in both motor　and sensory neurons. However, sensory abnormalities remain poorly characterized. To address this research gap, we analyzed the effects of TDP-43 expression on layer 2/3 (L2/3) pyramidal neurons of the primary somatosensory cortex in mice projecting through corpus callosum. In utero electroporation (IUE) was performed to express GFP alone (control) or in combination with TDP-43. Compared with the control, mice co-expressing GFP and TDP-43 showed disturbed callosal axonal projections of L2/3 neurons. Mutant TDP-43 variants displayed a more pronounced phenotype, indicating pathogenic role during fetal cortical development. To distinguish developmental from maintenance effects, tamoxifen-inducible TDP-43 expression was used to initiate postnatal TDP-43 expression. Postnatal induction resulted in shorter axonal length and reduced branching rather than gross projections disturbance. Taken together, these results demonstrate that TDP-43 expression can disturb the integrity of axonal projections, such as callosal projections of L2/3 neurons in the somatosensory cortex.

PMID 42276329
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PubMedInternational journal of molecular sciences2026-06-12

Peripartum-Associated Heart Failure Develops Independently of RHOT Proteins.

Froese Natali N, Sina Eluiesa E, Galuppo Paolo P, Werlein Christopher C et al.

Pregnancy-associated hemodynamic overload and hormonal changes induce hypertrophy and metabolic remodeling of the maternal heart. Mitochondrial motility, mediated by ras homolog family member T (RHOT) 1 and RHOT2, is essential for cardiac adaptation to increased workload, cardiomyocyte hypertrophy, and sarcomere maturation. To test the hypothesis that Rhot1/2 expression is required for pregnancy- and postpartum-associated adaptations of the maternal heart, female mice with tamoxifen-inducible, cardiomyocyte-selective deletion of Rhot1 and Rhot2 (iRhot1/2-KO) were mated. Following gene deletion in adult mice, cardiac tissue and function were analyzed after three to five successive pregnancies and postpartum nursing periods. Age-matched nulliparous iRhot1/2-KO mice and age-matched mice expressing Rhot1 and Rhot2 served as controls. Motility of mitochondria isolated from iRhot1/2-KO hearts was impaired, as determined by the number of mobile mitochondria in an in vitro motor protein-driven single mitochondrion motility assay performed on surface-immobilized microtubules. Despite loss of Rhot1/2 expression, contractile function assessed by transthoracic echocardiography, mRNA expression of peripartum-associated heart failure markers, cardiac structure, mitochondrial morphology, mitochondrial enzymatic activity, and mitochondrial DNA content were all comparable to controls expressing Rhot1/2 at the investigated time points. RNA sequencing-based gene profiling identified a transcriptional program through which RHOT proteins preserve cardiac energetic and contraction gene expression during pregnancy and postpartum. Together, cardiomyocyte-selective loss of Rhot1/2 expression in the adult heart does not cause peripartum-associated heart failure, despite reduced cardiac energetic and contraction gene expression.

PMID 42278517
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PubMedAndrology2026-06-12

ClpP Ensures Mitochondrial Integrity and Spermatocyte Meiotic Progression in Mice.

Feng Hai-Wei HW, Gao Yan-Lin YL, Jiang Bin-Jie BJ, Zubair Muhammad M et al.

Caseinolytic peptidase P (ClpP) plays a key role in maintaining cellular homeostasis for mitochondrial quality control. However, the specific function of ClpP during meiosis and its subcellular localization in spermatocytes remain poorly understood. To investigate the function of ClpP in spermatocyte meiosis. ClpP expression was examined in mouse spermatocytes, and tamoxifen was utilized to achieve spatiotemporal-specific deletion of Clpp mediated by Ddx4-CreERT2 in spermatocytes. We analyzed the meiotic progression of Clpp conditional KO (ClppcKO) using spermatocyte chromosome spreading, combined with immunofluorescence and transmission electron microscopy, to determine the morphology and number of spermatocyte mitochondria in ClppcKO mice. A progressive increase in ClpP expression levels was evident from the leptotene stage to the pachytene stage in mouse spermatocytes, and a decrease in ClpP expression was observed from the diplotene stage to the metaphase I (MI) stage. Compared with wild-type male mice, adult ClppcKO male mice had reduced testis size and no mature spermatozoa in their epididymides. A large proportion of pachytene and diplotene spermatocytes, as well as round or elongated spermatids, were eliminated from the seminiferous tubules of the ClppcKO mice. The mitochondria of ClppcKO spermatocytes appeared as "giant mitochondria." However, ClppcKO spermatocytes exhibited normal meiotic synapsis and impaired recombination, with reduced RAD51 foci and abnormal MLH1 localization. ClpP is critical for spermatocyte survival and mitochondrial integrity during meiosis. As a consequence of its deficiency, meiotic progression and spermatogenesis are disrupted, highlighting its essential role in the meiosis of spermatocytes.

PMID 42281331
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