Cereblon (CRBN) was an E3 ubiquitin ligase complex substrate receptor that targeted ion channel proteins. L-type voltage-dependent calcium channels (LTCCs) density and dysfunction were essential in heart failure with reduced ejection fraction (HFrEF). However, the cellular mechanisms behind CRBN’s role in regulating Cav1.2α LTCC subtype during cardiac disease remain unknown. For a study, the researchers characterized the direct regulatory function of CRBN in Cav1.2α activity and how it might be used as a target to cure cardiac disease. HFrEF patients had higher CRBN concentrations in their cardiac tissues than did control patients. In vivo and ex vivo research showed that CRBN knockout (CRBN-/-/-+) and cardiac-specific knockout mice (Crbnfl/fl/Myh6Cre+) had enhanced cardiac contractility, which was influenced by the direct interaction of CRBN with Cav1.2α, according to in vitro and in vivo research. The Cav1.2α N-terminal was explicitly bound by the CRBN Lon domain, which was a Ca2+ sensor that has been shown previously to attach directly to the N-terminal of Cav1.2α.Cav1.2α ubiquitination and proteasomal degradation were increased by increasing CRBN levels, which coincided with a decrease in ICaL. In contrast, genetic or pharmacological CRBN depletion via TD-165, a novel PROTAC-based CRBN degrader, increased surface expression of Cav1.2α and improved ICaL. In vivo heart failure was prevented by maintaining low CRBN levels. Cereblon selectively damages Cav1.2α, allowing cardiac disease to develop. A targeted approach or fast lowering CRBN levels might have been helpful for HFrEF drugs.