Succinate receptor 1 (SUCNR1) (SUCNR1)

Succinate receptor 1 (SUCNR1), also known as GPR91, is a G protein-coupled receptor that functions as a metabolic sensor for extracellular succinate, an intermediate of the tricarboxylic acid (TCA) cycle [1, 3, 5]. It is expressed in various tissues, including the kidney, liver, adipose tissue, and immune cells such as macrophages and neutrophils [4, 8, 30]. SUCNR1 signaling plays a pivotal role in linking metabolic stress and hypoxia to inflammatory and fibrotic responses, primarily through the activation of the succinate–SUCNR1–IL-1β pathway [2, 4, 12]. In this pathway, succinate accumulation leads to the stabilization of hypoxia-inducible factor 1-alpha (HIF-1α), which subsequently drives the production of the pro-inflammatory cytokine interleukin-1 beta (IL-1β) [2, 11, 14]. The receptor is implicated in the pathogenesis of several diseases, including renovascular hypertension, diabetic retinopathy, atherosclerosis, and chronic inflammatory conditions like rheumatoid arthritis and liver fibrosis [1, 8, 18, 28]. In the context of cancer, SUCNR1 activation in tumor-associated macrophages can promote an immunosuppressive microenvironment and therapy resistance [29, 31]. While no SUCNR1-targeted drugs are currently FDA-approved, several small-molecule antagonists and agonists are under investigation for their potential to treat metabolic and inflammatory disorders [19, 22, 24]. Therapeutic development faces challenges due to the receptor's context-dependent roles, where it may exert either pro- or anti-inflammatory effects depending on the tissue and metabolic state [4, 10, 30]. Monitoring succinate levels in plasma or tissue serves as a potential biomarker for disease progression and therapeutic efficacy [13, 14, 26].

Other names

GPR91G-protein coupled receptor 91P2Y purinoceptor 1-like

Antagonism of SUCNR1 to inhibit pro-inflammatory signaling and fibrosis, or agonism to modulate metabolic homeostasis and anti-inflammatory pathways.