PAQR4 is a seven-transmembrane orphan receptor that primarily functions in regulating cellular ceramide homeostasis and adipose tissue metabolism. Mechanistically, PAQR4 mediates the stability and activity of ceramide synthases CERS2 and CERS5, controlling de novo ceramide biosynthesis 1. In metabolic contexts, PAQR4 overexpression in adipocytes causes ceramide accumulation, impairing adipogenesis and triggering adipocyte de-differentiation, leading to lipodystrophy, hyperglycemia, and hyperinsulinemia; conversely, adipocyte-specific PAQR4 deletion improves glucose homeostasis during diet-induced obesity 1. Beyond metabolism, PAQR4 is significantly upregulated across multiple cancer types and functions as an oncogene. High PAQR4 expression correlates with poor prognosis, advanced tumor stage, and altered immune microenvironments in bladder, renal, and hepatocellular carcinomas 2. In breast cancer, PAQR4 promotes proliferation by reducing CDK4 protein degradation through decreased polyubiquitination 3. PAQR4 also participates in chemotherapy resistance through multiple signaling pathways and influences cellular senescence and immune evasion 4. Clinically, PAQR4 represents a promising therapeutic target for both metabolic disorders and malignancies, with potential as a prognostic biomarker across cancer types 5.