Targeting the heterodimer MDM2/MDM4 is a novel and effective route for the reactivation of wild‐type p53 in human tumors with reduced toxicity in nontransformed cells. To improve the therapeutic potential of peptides that interfere with MDM4 binding to MDM2, we demonstrated the tumor‐suppressive activity of a short peptide (Pep3S), which is composed of the last five amino acids of the MDM4 protein. Compared to longer peptides (previously identified), Pep3S binds MDM2 with high affinity, increases p53‐dependent cell death in 2D and 3D colorectal cancer models, and is more efficacious in suppressing xenograft tumor growth. Furthermore, its encapsulation in poly (lactic‐co‐glycolic acid) (PLGA) nanoparticles potentiated and prolonged its activity. A p53‐specific target gene array revealed an uncommon p53 signature, with Pep3S leading to p53‐mediated repression of a subset of p53 targets. Comparative analysis indicated that this repression is driven by p53‐mediated activation of miR‐34a, which is functional in Pep3S‐induced cell death. Of note, unlike other p53‐reactivating molecules, Pep3S led to significant downregulation of the cell cycle inhibitor CDKN1A/p21, one of the best‐characterized p53‐targets. Genetic manipulation of MDM4 demonstrated the requirement of the dissociated protein for p21 downregulation, whereas the miR‐34a signature was not altered. At odds with Nutlin‐3a, the proliferation status of nontumor muscle and lymphoblastoid cells was not altered by Pep3S. These data indicate that targeting the MDM2/MDM4 interaction region provides a different route for wild‐type p53 reactivation in human tumors, potentially reducing toxicity to proliferating nontumor tissue. The development of a PLGA/Pep3S formulation represents a promising approach for therapeutic purposes.

Facioscapulohumeral dystrophy (FSHD) is an autosomal dominant muscular dystrophy and one of the most frequent hereditary myopathies. The pathology shows a wide range of clinical signs, with modifying factors contributing to this variability, especially in patients with mild disease. Among these factors, the beneficial activity of estrogen hormones is controversial. We investigated the effect of 17β-estradiol (E₂) and the 5α-dihydrotestosterone-derived 3β-androstenediol (3β-diol) on muscle regeneration. To recapitulate human hormone sensitivity, we developed a humanized heterokaryon FSHD mouse model by engrafting human immortalized myoblasts or human primary muscle mesenchymal stromal cells into surgically treated murine muscle. Inducible lentiviral expression of the pathogenic FSHD gene, DUX4, in human cells impaired the structural and functional recovery of murine muscle, providing a humanized mouse model of DUX4-mediated pathogenicity and proving that the biological effect of DUX4 spreads across the neighbouring murine nuclei. Both hormones counteracted DUX4 transcriptional activity and rescued structural and functional muscle performance impaired by DUX4 expression, while being inefficient in control grafts. The beneficial activity of estrogen in this heterokaryon model supports the hypothesis that these hormones contribute as a modifying factor in FSHD.

Ovarian cancer (OC) remains one of the most lethal gynecologic malignancies, with nearly 80% of patients diagnosed at advanced stages due to the absence of early symptoms and the nonspecific nature of later clinical manifestations. This highlights the urgent need for robust molecular biomarkers that can refine patient stratification and guide personalized therapeutic approaches. A major determinant of OC aggressiveness is the epithelial-to-mesenchymal transition (EMT), a transcriptionally driven program that represses epithelial identity while promoting mesenchymal traits, thereby enhancing invasion, dissemination, recurrence, and resistance to therapy. EMT dysregulation is widespread in OC and fuels tumor heterogeneity, metastatic spread, and chemoresistance. To investigate the contribution of EMT-related genes in OC biology, we analyzed whole-genome sequencing and RNA-seq data from 419 patients in The Cancer Genome Atlas (TCGA) Pan-Cancer Atlas, assessing their genomic and transcriptomic alterations. We integrated these findings with transcriptomic and drug-sensitivity data from the CTRPv2 portal, performing Pearson correlation analyses to identify therapeutic vulnerabilities associated with EMT gene expression. Our analysis identifies recurrent genomic and transcriptomic alterations across several EMT-associated genes. Notably, we identified a four-EMT gene signature (EFNA1, OVOL2, GATA3, and DSG2) whose expression correlates with differential sensitivity to VEGFR and EGFR inhibitors in OC cell lines. Overall, these results suggest that EMT-driven molecular changes contribute to the onset and progression of OC and highlight a subset of EMT genes as promising predictive biomarkers for targeted therapy responses.