BACKGROUND: Ubiquitin-specific protease 38 (USP38), belonging to the USP family, is recognized for its role in controlling protein degradation and diverse biological processes. Ventricular arrhythmias (VAs) following heart failure (HF) are closely linked to ventricular electrical remodeling, yet the specific mechanisms underlying VAs in HF remain inadequately explored. In this study, we examined the impact of USP38 on VAs in pressure overload-induced HF.
METHODS: Cardiac-specific USP38 knockout mice, cardiac-specific USP38 transgenic mice and their matched control littermates developed HF induced by aortic banding (AB) surgery. After subjecting the mice to AB surgery for a duration of four weeks, comprehensive investigations were conducted, including pathological analysis and electrophysiological assessments, along with molecular analyses.
RESULTS: We observed increased USP38 expression in the left ventricle of mice with HF. Electrocardiogram showed that the USP38 knockout shortened the QRS interval and QTc, while USP38 overexpression prolonged these parameters. USP38 knockout decreased the susceptibility of VAs by shortening action potential duration (APD) and prolonging effective refractory period (ERP). In addition, USP38 knockout increased ion channel and Cx43 expression in ventricle. On the contrary, the increased susceptibility of VAs and the decreased expression of ventricular ion channels and Cx43 were observed with USP38 overexpression. In both in vivo and in vitro experiments, USP38 knockout inhibited TBK1/AKT/CAMKII signaling, whereas USP38 overexpression activated this pathway.
CONCLUSIONS: Our data indicates that USP38 increases susceptibility to VAs after HF through TBK1/AKT/CAMKII signaling pathway, Consequently, USP38 may emerge as a promising therapeutic target for managing VAs following HF.

OBJECTIVE: Atrial structural and electrical remodelling is a major reason for the initiation and perpetuation of atrial fibrillation (AF). Ubiquitin-specific protease 38 (USP38) is a deubiquitinating enzyme, but its function in the heart remains unknown. The aim of this study was to investigate the effect of USP38 in pressure overload-induced AF.
RESULTS: Cardiac-specific knockout USP38 and cardiac-specific transgenic USP38 mice and their corresponding control mice were used in this study. After 4 weeks with or without aortic banding (AB) surgery, atrial echocardiography, atrial histology, electrophysiological study, and molecular analysis were assessed. Ubiquitin-specific protease 38 knockout mice showed a remarkable improvement in vulnerability to AF, atrial weight and diameter, atrial fibrosis, and calcium-handling protein expression after AB surgery. Conversely, USP38 overexpression further increased susceptibility to AF by exacerbating atrial structural and electrical remodelling. Mechanistically, USP38 interacted with and deubiquitinated nuclear factor-kappa B (NF-κB), and USP38 overexpression increased the level of p-NF-κB in vivo and in vitro, accompanied by the upregulation of NOD-like receptor protein 3 (NLRP3) and inflammatory cytokines, suggesting that USP38 contributes to adverse effects by driving NF-κB/NLRP3-mediated inflammatory responses.
CONCLUSIONS: Overall, our study indicates that USP38 promotes pressure overload-induced AF through targeting NF-κB/NLRP3-mediated inflammatory responses.

Accumulating evidence has shown that H6 Family Homeobox 3 (HMX3) plays a crucial role in nervous system regulation. However, the regulatory mechanism of HMX3 in colorectal cancer (CRC) has seldom been studied. Herein, HMX3 was significantly downregulated in CRC, as demonstrated by qRT-PCR and WB analysis on clinical samples and a panel of cell lines. Besides, it was found that the expression of HMX3 was negatively correlated with survival of CRC patients. The functional analyses (EdU staining, CCK-8, colony formation, Transwell, and wound scratch assays) showed that CRC cell proliferation, migration, and invasion were significantly suppressed by HMX3 overexpression, while enhanced by HMX3 knockdown. Moreover, in vivo experiment revealed HMX3 overexpression could also suppress tumor growth. Combining bioinformatics and WB analysis, we preliminarily uncovered that HMX3 was involved in apoptosis and KRAS signaling pathways. Mechanistically, Ubiquitin-specific protease 38 (USP38) was identified as a novel post-translational regulator of HMX3, which could directly interact with HMX3 to stabilize its protein expression via deubiquitination. Furthermore, the role of USP38 silencing in promoting cell proliferation, migration, and invasion of CRC cells was blocked by HMX3 overexpression. In conclusion, our findings suggested that USP38/HMX3 axis is a novel promising therapeutic candidate for CRC.