Rnf31, also known as Ring Finger Protein 31, is an E3 ubiquitin ligase and a core component of the linear ubiquitin chain assembly complex (LUBAC). It is involved in ubiquitination, a post-translational modification of proteins, and participates in regulating multiple signaling pathways, such as the NF-κB pathway [7,6]. It has significant importance in various biological processes and diseases.

Genetic ablation of Rnf31 in cancer cells strongly sensitizes them to killing by innate natural killer (NK) cells and adaptive CD8+ T cells in a TNF-dependent manner, suggesting Rnf31 inhibition could be a clinical opportunity for immunotherapy-refractory cancers [1]. In hepatocytes, Rnf31 alleviates liver steatosis by promoting p53/BNIP3-related mitophagy. Reducing Rnf31 expression leads to mitochondrial dysfunction, disturbed mitophagy, and increased steatosis [2].

In triple-negative breast cancer (TNBC), Rnf31 depletion increases cell proliferation and migration, while Rnf31 represses cell progression and immune evasion via YAP/PD-L1 suppression, indicating its tumor-suppressive function in TNBC [3]. In B16 melanoma cells, lacking Rnf31 impairs tumor growth by increasing intratumoral CD8+ T cells infiltration, as Rnf31 promotes tumorigenesis by inhibiting RIPK1 kinase-dependent apoptosis [4].

In neonatal necrotizing enterocolitis (NEC), Rnf31-mediated IKKα ubiquitination aggravates inflammation and intestinal injury through regulating NF-κB activation, and suppressing Rnf31-mediated IKKα degradation may be a therapeutic strategy for NEC [5]. In hepatocellular carcinoma (HCC), high Rnf31 expression is related to worse survival rates, and Rnf31 promotes tumor aggressiveness via NF-κB activation [6].

In ulcerative colitis (UC), Rnf31 expression is elevated. Rnf31 knockdown reduces NLRP3 inflammasome activation, and in vivo Rnf31 knockdown mice show reduced NLRP3 expression and alleviated DSS-induced tissue inflammation. Also, Rnf31 promotes NRF2 degradation, and depleting Rnf31 relieves DSS-induced colitis in mice [8,9]. In acute liver injury, Rnf31 degrades A20 by ubiquitination and activates the TLR4/MyD88/NF-κB signaling pathway to aggravate the injury [10].

In conclusion, Rnf31 plays diverse roles in multiple biological processes and diseases. Gene-knockout studies have revealed its importance in tumorigenesis, immune-cell-mediated tumor killing, liver steatosis, and inflammatory diseases such as NEC, UC, and acute liver injury. These findings provide insights into potential therapeutic strategies targeting Rnf31 for treating related diseases.