Rnf128, a RING finger protein, functions as an E3 ubiquitin ligase. It is involved in multiple biological processes by regulating ubiquitination, thus influencing various signaling pathways such as Wnt/β -catenin, EGFR/MEK/ERK, and TLR4-NF-κB pathways. Its dysregulation is associated with several diseases, highlighting its biological importance. Genetic models, like KO/CKO mouse models, have been crucial in studying its functions [1-10].

In melanoma, Rnf128 downregulation activates Wnt/β -catenin signaling via CD44 and CTTN ubiquitination, promoting cell EMT and stemness, and patients with low Rnf128 and high CD44/CTTN have a poor prognosis [1]. In atherosclerosis, Rnf128 in macrophages promotes Lys63-linked polyubiquitination on SRB1, preventing its degradation, and aggravating the disease [2]. In acute lung injury, Rnf128-deficient mice show severe lung damage and increased immune cell infiltration as Rnf128 inhibits neutrophil activation and regulates alveolar macrophage activation [3]. In hepatocellular carcinoma, Rnf128 overexpression promotes malignant behaviors through the EGFR/MEK/ERK pathway [4]. In colitis and colorectal cancer, Rnf128-deficient mice are hypersusceptible, as Rnf128 attenuates these conditions by triggering the degradation of IL-6 receptors [5]. In macrophages during colitis, Rnf128 deficiency promotes inflammation by suppressing the autophagic degradation of S100A8 [6]. In colorectal cancer cells, Rnf128 overexpression suppresses cell proliferation and metastasis via inhibition of Wnt/β -catenin signaling [7]. In innate antiviral immunity, Rnf128 deficiency attenuates immune responses as Rnf128 promotes K63-linked ubiquitination of TBK1 [8]. In esophageal squamous cell carcinoma, Rnf128 promotes invasion and metastasis via the EGFR/MAPK/MMP-2 pathway [9].

In conclusion, Rnf128, as an E3 ubiquitin ligase, plays diverse roles in multiple biological processes and diseases. The use of KO/CKO mouse models has significantly contributed to understanding its functions in diseases such as melanoma, atherosclerosis, acute lung injury, various cancers, and inflammatory bowel diseases, providing insights into potential therapeutic targets.