Peli1, short for Pellino E3 Ubiquitin Protein Ligase 1, is an E3 ubiquitin ligase. It is a key regulator in multiple biological processes, participating in pathways such as NF-κB, AP-1, and Toll-like receptor signaling. Peli1 is involved in inflammation, autoimmunity, and is closely associated with various diseases, making it an important target for research, with genetic models like KO/CKO mouse models being valuable for studying its functions [1-10].

In cardiac fibrosis, CM-conditional deletion of Peli1 improved pressure overload-induced fibrosis. Exosomes from mechanical stretch-induced WT CMs promoted cardiac fibroblast activation, while Peli1-/-MS-Exos reversed this effect. Peli1 promoted miR-494-3p expression via NF-κB/AP-1 in cardiomyocytes, which then induced fibroblast activation [1].

In pancreatic cancer, Peli1 is overexpressed, interacting with RPS3 through the FHA structural domain, promoting its polyubiquitination, activating the PI3K/Akt/GSK3β signaling pathway, and facilitating cancer progression [2].

In breast cancer, EGFR activation leads to Peli1 phosphorylation, activating its E3 ubiquitin ligase, and Peli1, in turn, enhances EGFR stability via K63-linked polyubiquitination, promoting breast cancer metastasis [3].

Peli1-deficient mice showed alleviated peritonitis and increased resistance to LPS endotoxin shock, as Peli1 is required for NLRP3-induced caspase-1 activation and IL-1β maturation, mediating ASC ubiquitination [4].

Macrophage-specific Peli1 deletion in mice reduced M1 macrophage polarization, decreased myocardial infarct size, and improved cardiac function during myocardial ischemia/reperfusion injury [5].

In conclusion, Peli1 plays diverse and crucial roles in multiple biological processes and diseases. Through gene-knockout and conditional-knockout mouse models, its functions in cardiac fibrosis, pancreatic and breast cancers, inflammation, and myocardial ischemia/reperfusion injury have been revealed. These findings contribute to a better understanding of disease mechanisms and may provide potential therapeutic targets.