Noncoding RNA regulates the expression of Krm1 and Dkk2 to synergistically affect aortic valve lesions.

Calcific aortic valve disease (CAVD) is becoming an increasingly important global medical problem, but effective pharmacological treatments are lacking. Noncoding RNAs play a pivotal role in the progression of cardiovascular diseases, but their relationship with CAVD remains unclear. Sequencing data revealed differential expression of many noncoding RNAs in normal and calcified aortic valves, with significant differences in circHIPK3 and miR-182-5p expression. Overexpression of circHIPK3 ameliorated aortic valve lesions in a CAVD mouse model. In vitro experiments demonstrated that circHIPK3 inhibits the osteogenic response of aortic valve interstitial cells. Mechanistically, DEAD-box helicase 5 (DDX5) recruits methyltransferase 3 (METTL3) to promote the N6-methyladenosine (m6A) modification of circHIPK3. Furthermore, m6A-modified circHIPK3 increases the stability of Kremen1 (Krm1) mRNA, and Krm1 is a negative regulator of the Wnt/ß-catenin pathway. Additionally, miR-182-5p suppresses the expression of Dickkopf2 (Dkk2), the ligand of Krm1, and attenuates the Krm1-mediated inhibition of Wnt signaling. Activation of the Wnt signaling pathway significantly contributes to the promotion of aortic valve calcification. Our study describes the role of the Krm1-Dkk2 axis in inhibiting Wnt signaling in aortic valves and suggests that noncoding RNAs are upstream regulators of this process.

Integrative clinical and preclinical studies identify FerroTerminator1 as a potent therapeutic drug for MASH.

The complex etiological factors associated with metabolic dysfunction-associated fatty liver disease (MAFLD), including perturbed iron homeostasis, and the unclear nature by which they contribute to disease progression have resulted in a limited number of effective therapeutic interventions. Here, we report that patients with metabolic dysfunction-associated steatohepatitis (MASH), a pathological subtype of MAFLD, exhibit excess hepatic iron and that it has a strong positive correlation with disease progression. FerroTerminator1 (FOT1) effectively reverses liver injury across multiple MASH models without notable toxic side effects compared with clinically approved iron chelators. Mechanistically, our multi-omics analyses reveal that FOT1 concurrently inhibits hepatic iron accumulation and c-Myc-Acsl4-triggered ferroptosis in various MASH models. Furthermore, MAFLD cohort studies suggest that serum ferritin levels might serve as a predictive biomarker for FOT1-based therapy in MASH. These findings provide compelling evidence to support FOT1 as a promising novel therapeutic option for all stages of MAFLD and for future clinical trials.

High CIB1 expression in colorectal cancer liver metastases correlates with worse survival and the replacement histopathological growth pattern.

To date, nearly one-quarter of colorectal cancer (CRC) patients develop liver metastases (CRCLM), and its aggressiveness can be correlated to defined histopathological growth patterns (HGP). From the three main HGPs within CRCLM, the replacement HGP emerges as particularly aggressive, characterized by heightened tumor cell motility and vessel co-option. Here, we investigated the correlation between the expression of calcium- and integrin-binding protein 1 (CIB1), a ubiquitously expressed gene involved in various cellular processes including migration and adhesion, and disease-free (DFS) and overall survival (OS) in primary CRC patients. Additionally, we explored the correlation between CIB1 expression and different HGPs of CRCLM. Proteomic analysis was used to evaluate CIB1 expression in a cohort of 697 primary CRC patients. Additionally, single-cell and spatial RNA-sequencing datasets, along with publicly available bulk sequencing data were used to evaluate CIB1 expression in CRCLM. In silico data were further validated by formalin-fixed paraffin-embedded immunohistochemical stainings. We observed that high CIB1 expression is independently associated with worse DFS and OS, regardless of Union Internationale Contre le Cancer stage, gender, or age. Furthermore, the aggressive replacement CRCLM HGP is significantly associated with high CIB1 expression. Our findings show a correlation between CIB1 levels and the clinical aggressiveness of CRC. Moreover, CIB1 may be a novel marker to stratify HGP CRCLM.