MED12 (Mediator Complex Subunit 12)

Notably, we find that vitamin D3 (VD3), a modifiable risk factor in UF development, suppresses pathogenic R-loop accrual and ameliorates replication stress-driven chromosomal instability, contributing to growth inhibition of patient-derived MED12-mutant UF xenografts in vivo. Altogether these findings uncover a molecular basis by which the predominant UF driver converges with a known risk factor at the interface of genomic instability, with significant translational implications for personalized UF prevention and treatment.

Botanical names have been validated, and data were assessed using the Four Pillars of Best Practice in Ethnopharmacology, the ConPhyMP framework, and the GA checklist for reproducibility and quality assurance. By bridging traditional knowledge with current scientific evidence, this review supports the potential role of culturally rooted botanical drugs in integrative fibroid management and highlights directions for future pharmacological and clinical research.

This study revealed uterine leiomyoma subtypes to have distinct chromosomal aberration landscapes. Our large sample collection, detailed subclassification and extensive expression data integration enabled the identification of rare aberrations and subtype-specificity not previously feasible. Further research is implicated in studying the recurrently aberrant regions to identify the specific targets. This study shows, once again, the benefits for accurate subtype information in leiomyoma research and provides a new framework for further studies - towards comprehensive knowledge on the tumorigenesis and potential subtype-specific diagnostic and therapeutic strategies.

Treatment of primary cultured MED12 wild-type cells with CDK8 inhibitors significantly inhibited cell growth and increased apoptosis. MED12 wild-type leiomyoma cells without GnRH agonist treatment showed high CDK8 activity, and inhibition of CDK8 activity suppressed cell growth in vitro.

Overall, our findings highlight recurrent somatic ACTB mutations in more than half of sporadic TABs. CS-associated TABs but not sporadic TABs showed loss of PTEN expression. The presence of bilateral and/or multiple TABs should prompt PTEN IHC to rule out the possibility of CS.

Other metabolic regulators, such as hypoxia-inducible factor 1-alpha (HIF-1α), mammalian target of rapamycin (mTOR), and phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), may also sustain the fibrotic phenotype through coupling signaling that drives ECM production to metabolic programming. Overall, the proposed metabolic perspective of uterine fibroid pathogenesis invites further exploration of mechanistic investigation in uterine-specific models and therapeutic targeting through larger cohort studies.

Gene ontology and pathway analyses of the differentially expressed genes of the xenograft tumors suggested that regression occurred by different mechanisms in the two subtypes. Our results also suggested, for the first time, that UPA caused SMC death by a mechanism other than progesterone receptor inhibition.

UL evolves through chromosomal instability, whereas FA evolves through a mutator phenotype, with important implications for understanding tumor biology and molecular-based risk stratification. These findings support a paradigm of tissue-specific oncogenic evolution and underscore the potential clinical utility of genomic profiling in distinguishing benign tumors with atypical molecular features.

ChIP-PCR, luciferase assay and siRNA knock down assay indicate that MED12 binds to the promoter region of STAT1 to suppress its transcription, while the transcription factor STAT1 promotes the transcription of TAP2, thus inhibiting the antigen processing and presentation. Collectively, MED12 mutation is an independent and valuable biomarker for predicting the response to immune checkpoint inhibitor (ICI)therapy in NSCLC by modulating CD8 + T cell cytotoxicity via the STAT1/TAP2 axis.

Race/ethnicity, MED12 mutations, and ovarian steroids influence the expression of ncRNA expression, further implicating their relevance to fibroid pathogenesis. Therapeutic targeting of these dysregulated ncRNAs in fibroids could enable more precise and individualized non-hormonal-based treatment for this common gynecologic tumor.

These findings suggest that targeting the MEK/ERK signaling pathway, such as with trametinib, may provide a viable strategy to overcome RTKi resistance in MED12-mutant NSCLC. Furthermore, MED12 is identified as a crucial biomarker and potential therapeutic target for overcoming RTKi resistance.

These findings indicate that lncRNA expression in fibroids is modulated by menopausal status, likely reflecting hormonal influence. Hormone-responsive lncRNAs may play key roles in fibroid pathogenesis and represent potential targets for therapeutic intervention.