Targeting RIPK1 for the treatment of depression: From neuroinflammation to synaptic plasticity.

Abstract

Depression, a prevalent mental health disorder, has attracted increasing attention owing to its association with neuroinflammation. Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) plays a crucial role in maintaining cellular and tissue homeostasis by regulating inflammatory responses and cell death signalling pathways, both of which are closely linked to various physiological and pathological processes. Accordingly, RIPK1 functions as an upstream kinase that modulates inflammation and cell death. Tumour necrosis factor-α (TNF-α), a key pro-inflammatory cytokine implicated in the pathogenesis of various human diseases, acts as a principal upstream activator of RIPK1. Accumulating evidence further indicates that RIPK1 may contribute to a detrimental neuroinflammatory environment in mental disorders such as depression. However, its specific regulatory role and underlying mechanisms in depression remain incompletely understood. This review first summarises current advances in understanding the molecular structure and biological functions of RIPK1, with particular emphasis on multiple cellular pathways associated with depression. Subsequently, it discusses the mechanisms by which RIPK1 participates in the pathological process of depression, including its role in neuroinflammation and synaptic plasticity. Finally, we outline the effects of RIPK1 inhibitors in animal models, which have been shown to prevent neuronal cell death and reduce neuroinflammation. Collectively, these findings suggest that targeting RIPK1 may represent a promising therapeutic strategy with potential for clinical translation, highlighting its value as a potential therapeutic target in depression. However, further work is still needed to bridge the gap between preclinical mechanisms related to the RIPK1 inflammatory pathway and their actual clinical efficacy.