The role of HECT-type E3 ubiquitin ligases in inflammation.

Homologous to the E6-AP Carboxyl Terminus (HECT)-type E3 ubiquitin ligases are key components of the ubiquitin-proteasome system (UPS) and play an important role in the regulation of inflammatory responses. Inflammation serves as a core defense mechanism of the host against infection and tissue damage, while its dysregulated and unresolved activation drives the pathogenesis of diverse chronic inflammatory diseases. In recent years, the functions of HECT-type E3 ubiquitin ligases in inflammatory signaling pathways have gradually been revealed, particularly the differential roles of members of the HECT and RCC1-Like Domain Containing E3 Ubiquitin Protein Ligase (HERC) and Neural Precursor Cell Expressed Developmentally Downregulated 4 (NEDD4) subfamilies in immune cell activation, cytokine expression, and ubiquitination modifications. Although some molecular mechanisms of certain HECT-type E3 ubiquitin ligases have been reported, the complex regulatory networks and mechanisms of action of these ligases remain largely unelucidated, with conflicting research conclusions, unclarified cell type-specific functional heterogeneity, and notable limitations in current research systems remaining unresolved. This article systematically reviews the research progress of HECT-type E3 ubiquitin ligases in inflammation, focusing on the functional characteristics of different subfamilies and their molecular mechanisms in regulating inflammatory processes, and further conducts a critical analysis of conflicting findings in existing studies, the limitations of current research, and the context-dependent functions of specific ligases in different cell types. It aims to provide theoretical support and research directions for a deeper understanding of the biological functions of HECT-type E3 ubiquitin ligases and their application as potential therapeutic targets in inflammation-related diseases.