Spexin

Spexin (SPX), also designated neuropeptide Q (NPQ), is a 14-amino-acid peptide hormone encoded by the C12orf39 gene on human chromosome 12 and processed from a 116-amino-acid prepropeptide by dibasic cleavage and C-terminal alpha-amidation [1, 2]. The mature human sequence (NWTPQAMLYLKGAQ-NH2) is perfectly conserved across all mammalian species examined and differs by only one to two residues from teleost orthologs, placing spexin among the most evolutionarily conserved vertebrate peptide hormones [3]. First identified in 2007 by Mirabeau and colleagues through a hidden Markov model algorithm designed to detect novel secreted peptide hormones in the human genome, and first confirmed biochemically in murine esophageal and gastric tissue [1], spexin was subsequently shown to activate galanin receptor type 2 (GALR2) and galanin receptor type 3 (GALR3) with nanomolar potency (EC50 values of approximately 45.7 and 112.2 nM respectively) while showing no measurable activity at galanin receptor type 1 (GALR1) [4, 5]. This receptor selectivity profile distinguishes spexin from galanin itself, which activates all three galanin receptor subtypes, and establishes spexin as a naturally occurring GALR2/GALR3-selective agonist. The peptide is expressed broadly across central and peripheral tissues including the hypothalamus, hippocampus, amygdala, adipose tissue, liver, gastrointestinal tract, pancreas, kidney, heart, ovary, and testis [6, 7]. Functionally, spexin has been characterized as a satiety factor that suppresses food intake in goldfish, zebrafish, and mice through hypothalamic regulation of orexigenic (neuropeptide Y, agouti-related protein) and anorexigenic (proopiomelanocortin, cocaine- and amphetamine-regulated transcript) neuropeptides [8, 9, 10]. In adipose tissue, spexin inhibits long-chain fatty acid uptake into adipocytes and promotes weight loss in diet-induced obese rodents [11]. Circulating spexin concentrations are significantly reduced in human obesity, type 1 diabetes, type 2 diabetes, metabolic syndrome, and polycystic ovary syndrome, establishing the peptide as a candidate biomarker for metabolic dysregulation [12, 13, 14]. Beyond metabolic regulation, spexin-based GALR2-selective agonists produce anxiolytic effects in murine behavioral models [5], and the metabolically stabilized analog LIT-01-144 produces potent non-opioid peripheral antinociception in persistent inflammatory pain through GALR2 activation [15]. In reproductive physiology, spexin inhibits gonadotropin (LH and FSH) synthesis and secretion in multiple vertebrate species and negatively regulates ovarian steroidogenesis [16, 17]. No human clinical trials of exogenous spexin administration have been reported; the compound remains in the preclinical and biomarker research phase. This monograph reviews the chemistry, gene structure, and peptide processing of spexin; the receptor pharmacology and signal transduction through GALR2 and GALR3; the preclinical pharmacology across metabolic, appetite, nociceptive, anxiolytic, reproductive, and cardiovascular domains; the human biomarker and associative clinical evidence; sourcing and handling considerations for research-grade material; analog development for metabolic stability; and a comparative assessment against five related peptide or receptor-targeted candidates on five competency standards.