TRAF6, short for TNF receptor associated factor 6, is a non-conventional E3 ubiquitin ligase. It plays a pivotal role in multiple pathways such as NF-κB activation, autophagy, and immune-related signaling, being of great biological importance in innate and acquired immunity [1,2,3,4,5,6,8,10]. It can catalyze the synthesis and linkage of lysine-63 (K63) ubiquitin, which is related to the stabilization of substrate proteins [2].

In various disease-related studies, knockdown or inhibition of TRAF6 has shown distinct effects. In THP-1 cells with PRDX1-knockdown (where PRDX1 normally inhibits TRAF6 ubiquitin-ligase activity), NF-κB activation, pro-inflammatory cytokine production, and resistance against Salmonella typhimurium infection increased, indicating TRAF6's role in negatively regulating TLR4 signaling for NF-κB activation and autophagy functions [1]. In melanoma cells, suppression of TRAF6 expression down-regulated PD-L1 expression, and inhibition of TRAF6 by Bortezomib enhanced cytolytic activity of CD8+ T cells, suggesting its role in regulating PD-L1 expression and anti-tumor immunity [2]. In a chronic inflammatory pain model, huc-MSCs-derived exosomes attenuated pain via the miR-146a-5p/TRAF6 axis, which increased autophagy and inhibited pyroptosis [3]. In colorectal cancer, TRAF6 inhibited epithelial-mesenchymal transition (EMT) and metastasis through driving selective autophagic CTNNB1 degradation, but was phosphorylated and degraded by GSK3β in most clinical cases, and pharmacological inhibition of GSK3β stabilized TRAF6 and suppressed EMT and metastasis [5]. In breast cancer, inhibition of TRAF6 reduced cell migration, invasion, growth, tumour burden, and metastasis, and high expression of TRAF6 was associated with poor survival rate [7]. In leukemia, loss of TRAF6 in AML cells impaired leukemic function and induced metabolic alterations, highlighting its oncogenic function [8]. In osteoarthritis, miR-146b-5p in fucoidan-pretreated MSC-derived exosomes inhibited TRAF6 activation, suppressing inflammation and extracellular matrix degradation while promoting chondrocyte autophagy [9].

In conclusion, TRAF6 is crucial in regulating multiple biological processes including immune responses, autophagy, and cell-growth-related events. Through gene-knockdown or inhibition models in different disease conditions such as cancer, inflammation-related diseases, and leukemia, its role in disease-associated biological pathways has been revealed. These findings provide potential therapeutic targets for treating various diseases where TRAF6-related pathways are dysregulated.