Decoding chemerin proteolytic processing and isoform signaling across disease contexts

Chemerin (RARRES2) is a multifunctional adipokine widely implicated in metabolic, inflammatory, cardiovascular, and neoplastic diseases, yet its clinical interpretation remains confounded by reliance on "total chemerin" measurements that obscure its proteoform-specific signaling. This single value is mechanistically misleading because chemerin is secreted as an inactive precursor and undergoes extracellular proteolytic processing into C-terminal isoforms with graded receptor potency and compartment-specific distribution. This review decodes chemerin's functional duality through three integrated layers: (1) protease-encoded isoform "barcodes" that dictate bioactivity, (2) compartment-specific isoform landscapes in human biofluids and disease microenvironments, and (3) receptor context across CMKLR1, GPR1, and CCRL2 that shapes signaling output. We provide a conceptual roadmap for translating chemerin biology, emphasizing isoform-resolved quantification via targeted /MRM-MS and a compartment-aware framework for interpreting clinical associations. This framework helps interpret heterogeneous disease associations and highlights testable entry points for context-specific targeting.