In this study, we established NAFLD‐ and UUO‐induced renal‐fibrosis models, used single‐cell transcriptomic sequencing and untargeted metabolomic sequencing, and identified the ANGPTL8/PIRB/ALOX5AP axis as a novel hub linking hepatic lipotoxic damage to renal immune‐metabolic dysregulation. Here, ALOX5AP is linked to metabolic dysfunction-associated steatotic liver disease.