Rnls, also known as renalase, is a bifunctional protein. Intracellularly, it metabolizes nicotinamide adenine dinucleotide (NADH), modulates mitochondrial function, and protects energy metabolism. Extracellularly, independent of its enzymatic properties, it functions as a signaling molecule mediating resistance to stressful stimuli and promoting cell and organ survival. It has been implicated in multiple biological processes related to various organs [4].

In a mouse model for type 1 diabetes (T1D), deleting RNLS made beta cells resistant to autoimmune killing, suggesting it as 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, while kidney-targeted delivery of a RNLS agonist peptide protected against CKD [2]. In melanoma models, RNLS knockout (KO) mice could reject tumours in a T-cell-dependent manner, and anti-RNLS antibody treatment enhanced T cell infiltration and activation [3].

In summary, Rnls plays essential roles in cell survival, organ protection, and immune-related processes. The gene knockout mouse models in T1D, CKD, and melanoma have revealed its significance in these disease areas, providing potential therapeutic directions by targeting Rnls in relevant diseases.