During liver injury, intrahepatic macrophage compartment is augmented by circulating monocytes that infiltrate the liver driven by C-C motif chemokine ligand/C-C motif chemokine receptor (CCL/CCR) axis including CCL1‒CCR8 axis, thereby contributing to liver inflammation. Numerous small molecular receptor antagonists, including R243, have been developed for targeting CCR8; however, these agents face challenges in clinical translation, potentially attributed to their poor pharmacokinetic profiles, lack of target specificity, and potential adverse effects. In this study, we designed four CCR8 antagonizing peptides (AP8i-AP8iv) and performed molecular characterization in silico and therapeutic investigation in vitro and in vivo. Based on in silico docking, molecular dynamic simulation using homology build model and in-vitro (competitive) binding studies, AP8ii (YEWRFYHG) evidenced highly favorable and selective interactions at the CCR8-active site. AP8ii inhibited CCL1-driven chemotaxis and LPS/IFNγ-induced pro-inflammatory activation of monocytes-macrophages in vitro. In a CCl₄-induced acute liver injury mouse model, AP8ii treatment decreased intrahepatic infiltration of circulating monocytes. Moreover, AP8ii reduced liver inflammation, as indicated by decreased F4/80, IL6 and iNOS expression, diminished ALT levels, and attenuated fibrosis, as indicated by reduced collagen-I expression. In conclusion, we report a novel CCR8-antagonizing peptide that inhibited CCL1-driven intrahepatic monocytes infiltration and differentiation into pro-inflammatory phenotype, consequently ameliorating liver inflammation and fibrogenesis in an acute liver injury mouse model.

In the context of ARVC, a systematic review of the validation of the ARVC risk score can provide insights into the accuracy and reliability of this score in identifying patients at high risk of ARVC. Digital databases were searched to identify the relevant studies using Medical Subject Headings (MeSH). A total of 8 studies were included in this systematic review. A total of 8 studies were included in this review. The review found that the sensitivity of the ARVC risk scores ranged from 80 to 95%, and the specificity ranged from 31 to 79%. The PPV was 55%, and the NPV was 88%. The ARVC score provided a C-index for a 5-year VA risk prediction of 0.84 [95% CI (0.74–0.93)] and a Harrell C-index of 0.70 (95% CI 0.65–0.75). The calibration slope was 1.01 (95% CI 0.99–1.03). ARVC score demonstrated a significant event 5-year threshold between 15 and 20% and the classical ARVC 5-years/freedom-from-VA rate was 0.76(0.66–0.89) and the non-classical form 5-years/freedom-from-VA rate was 0.58 (0.43–0.78). In conclusion, the validation of ARVC risk scores is an essential step toward improving the accuracy of ARVC diagnosis and risk stratification. Further studies are needed to establish the accuracy and reliability of ARVC risk scores and to address the limitations of the current evidence.