RARRES1 (retinoic acid receptor responder 1) is a podocyte-enriched transmembrane protein that functions as a regulator of cell death and mitochondrial homeostasis. Primary Function: RARRES1 acts as an inhibitor of the carboxypeptidase AGBL2 and regulates the alpha-tubulin tyrosination cycle 1. Additionally, RARRES1 controls mitochondrial biogenesis by facilitating TFAM degradation through interaction with LONP1 2. Mechanism: RARRES1 expression is upregulated by TNF-α and retinoic acid in podocytes 3. The protein undergoes proteolytic cleavage by matrix metalloproteinase 23 to generate soluble RARRES1 (sRARRES1), which is endocytosed and inhibits RIO kinase 1 (RIOK1), leading to p53 activation and podocyte apoptosis 45. Soluble RARRES1 also directly injures proximal tubular cells, causing vacuolation and lipid accumulation 5. Disease Relevance: RARRES1 expression positively correlates with renal function decline in focal segmental glomerulosclerosis and diabetic kidney disease 4. In renal cell carcinoma, membranous RARRES1 expression associates with favorable prognosis, while cytoplasmic/negative staining indicates elevated relapse risk 1. RARRES1 is downregulated in cutaneous squamous cell carcinoma and serves as a mitochondrial homeostasis regulator 2. RARRES1 is also expressed in sebaceous glands in inflammatory skin diseases 6. Clinical Significance: Podocyte-specific RARRES1 knockdown ameliorates experimentally-induced nephropathy, suggesting therapeutic potential 4. Targeting the RARRES1-LONP1/TFAM axis or MMP23-mediated cleavage may provide novel approaches for treating glomerular diseases and certain cancers.