Ybx3, also known as DNA-binding protein-A (DbpA), is a DNA/RNA binding protein belonging to the cold-shock protein family. It is involved in crucial cellular processes such as gene transcription, DNA repair, protein synthesis, and cell growth and proliferation. It has been associated with multiple signaling pathways including PI3K/AKT, cAMP, calcium, focal adhesion, Ras, Rap1, NF-κB, and Chemokine signaling pathways [1].

In nasopharyngeal carcinoma (NPC), knockdown of Ybx3 by lentivirus shRNA suppressed NPC cell migration in vitro and metastasis in vivo, and was found to regulate NPC metastasis through the PI3K/AKT signaling pathway [1]. In clear cell renal cell carcinoma (ccRCC), high Ybx3 expression correlated with tumor stage and histological grade, and its silencing in A498 cells affected cell proliferation, migration, and invasion [6]. In bladder cancer, lncRNA BLACAT3 recruits Ybx3 to shuttle into the nucleus, enhancing NCF2 transcription and promoting angiogenesis and hematogenous metastasis [3]. In mesenchymal stem cells, circSERPINE2 interacts with Ybx3, affecting its association with the PCNA promoter and ultimately MSC senescence [4]. In SARS-CoV-2 infected cells, disrupting the interaction between viral RNA and host mRNA or knocking down Ybx3 decreased host mRNA stability and viral replication [5]. In brown adipocytes, Ybx3 is essential for differentiation and thermogenesis, and BAT-specific loss of Ybx3 in mice dampened thermogenesis and exacerbated diet-induced obesity [2]. In skeletal muscle cells, Ybx3 post-transcriptionally controls SLC1A5 mRNA, and its reduction impairs cell proliferation and differentiation [7].

In conclusion, Ybx3 is a multi-functional protein involved in various biological processes and disease conditions. Through gene knockout or knockdown models in different cell types and animal models, its role in cancer metastasis, cell differentiation, thermogenesis, cell senescence, and viral replication has been revealed. These findings suggest Ybx3 could be a potential therapeutic target for multiple diseases, including cancers, obesity, and viral-induced immunopathogenesis.