Sensing succinate: SUCNR1 as a context-dependent metabolic and cellular signal integrator

Succinate (SUC), a central intermediate in the mitochondrial tricarboxylic acid (TCA) cycle, functions not only as a metabolic substrate but also acts as the endogenous ligand for succinate receptor 1 (SUCNR1), a G_i- and G_q protein-coupled receptor. SUC accumulates when energy demand exceeds oxygen supply or during metabolic rewiring, including hypoxia, endurance exercise, inflammation, and tumor progression. SUC can be released into the extracellular space, reaching levels sufficient to activate SUCNR1. SUCNR1 is expressed in various tissues, including the kidney, liver, and adipose tissue, as well as in immune cells and cancer subtypes. Rather than functioning as a simple pro- or anti-inflammatory receptor, SUCNR1 acts as a metabolic signal integrator whose output is determined by G protein preferences, receptor trafficking, and the balance between intra- and extracellular SUC pools. In immune cells, particularly macrophages, SUCNR1 signaling promotes either inflammatory activation or resolution depending on the metabolic state. In metabolic tissues and cancer, SUCNR1 coordinates adaptive responses to nutrient and oxygen stress while shaping the tissue microenvironment. Here, we review recent advances in SUC-SUCNR1 signaling across immune and metabolic systems, discuss unresolved controversies regarding signaling selectivity and spatial encoding, and evaluate the therapeutic opportunities and challenges of targeting this metabolic checkpoint.