Rnls, also known as renalase, is a bifunctional protein. Intracellularly, it is a FAD-dependent oxidoreductase (EC 1.6.3.5) that metabolizes intracellular nicotinamide adenine dinucleotide (NADH), modulates mitochondrial function, and protects energy metabolism. Extracellularly, lacking its N-terminal peptide and FAD cofactor, it functions as a signaling molecule mediating resistance to stressful stimuli and promoting cell and organ survival [3,5]. It is involved in multiple biological processes and diseases, and genetic models like KO mouse models are valuable for studying its functions.

In a mouse model for type 1 diabetes (T1D), genome-scale CRISPR-mediated deletion of RNLS made beta cells resistant to autoimmune killing, suggesting it is a modifier of beta cell vulnerability and a potential therapeutic target for T1D [1]. In cisplatin-induced chronic kidney disease (CKD) mouse models, genetic deletion of RNLS was associated with more severe CKD, indicating its protective role in the kidney [2]. In murine melanoma models, RNLS knockout led to tumour regression in a T-cell-dependent manner, and anti-RNLS antibody treatment enhanced T cell infiltration and activation, showing its role in the tumour microenvironment [4].

In conclusion, Rnls has diverse biological functions including protection of cells and organs from stress. Studies using KO mouse models have revealed its significance in diseases such as T1D, CKD, and melanoma, providing insights into potential therapeutic strategies targeting Rnls for these diseases.