RBCK1, also known as ring-B-box-coiled-coil protein interacting with protein kinase C-1, is an E3 ubiquitin ligase. It is involved in multiple cellular processes and signaling pathways. As a component of the linear ubiquitin chain assembly complex, it influences NF-κB signaling in the immune response [6]. It is also associated with ubiquitination-mediated protein degradation processes, which are crucial for maintaining cellular homeostasis [2,3,5].

In pancreatic cancer, genetic depletion of RBCK1 in a mouse xenograft model increased the killing effects of ferroptosis inducer, indicating that RBCK1 confers ferroptosis resistance by facilitating MFN2 degradation [2]. In heart failure with preserved ejection fraction (HFpEF), lovastatin-induced improvement in diastolic function in male mice was abolished by loss of function of endothelial AP-2α or circRNA-RBCK1, suggesting that statins upregulate the AP-2α/circRNA-RBCK1 signaling to prevent diastolic dysfunction [1]. In clear cell renal cell carcinoma (ccRCC), in vitro and in vivo studies demonstrated that RBCK1 contributed to decreasing the sensitivity of ccRCC to sunitinib, and its inhibition inactivated the AKT and MAPK signaling pathways [4].

In conclusion, RBCK1 plays essential roles in various biological processes and disease conditions. Studies using gene knockout or conditional knockout mouse models have revealed its significance in cancer-related processes like ferroptosis resistance, metastasis, and chemoresistance, as well as in heart-related conditions such as HFpEF. These model-based research findings contribute to understanding the underlying mechanisms of these diseases and potentially developing new therapeutic strategies.