Lanthionine synthetase C-like protein (LANCL)

Lanthionine synthetase C-like (LANCL) proteins, comprising LANCL1, LANCL2, and LANCL3, are eukaryotic homologs of bacterial enzymes involved in lanthipeptide biosynthesis. In humans, these proteins have evolved to serve as critical regulators of immunometabolism and cellular redox balance. LANCL2 is a prominent therapeutic target for autoimmune and metabolic diseases; it acts as a receptor for the natural hormone abscisic acid and synthetic agonists like omilancor. Activation of LANCL2 restores immune tolerance in the gastrointestinal tract by promoting regulatory T cell (Treg) function and suppressing inflammatory cytokines, which has led to its clinical investigation for ulcerative colitis and Crohn's disease. Beyond immunology, LANCL2 plays a role in glycemic control by enhancing insulin sensitivity and mitochondrial respiration. LANCL1 is highly expressed in the central nervous system, where it functions as a glutathione-binding antioxidant that protects neurons from oxidative damage and neurodegeneration. While LANCL proteins are generally associated with protective anti-inflammatory roles, LANCL2 has also been identified as a potential driver in certain cancers, such as lung adenocarcinoma, suggesting a complex role in oncology. Therapeutic development currently focuses on gut-restricted or systemic small-molecule agonists to treat chronic inflammation and metabolic syndrome with minimal systemic toxicity.

Other names

LanC-like proteinLanthionine synthetase C-like protein 1Lanthionine synthetase C-like protein 2Lanthionine synthetase C-like protein 3LANCL1LANCL2LANCL3GPR69AGPR69Bp40Testis-specific adriamycin sensitivity protein

LANCL2 agonists activate an immunometabolic pathway that enhances the stability and suppressive function of regulatory T cells (Tregs) by increasing STAT5 signaling and pyruvate dehydrogenase (PDH) activity, while simultaneously downregulating pro-inflammatory Th17 and Th1 effector responses. In metabolic contexts, LANCL2 activation promotes glucose uptake via AMPK activation and GLUT4 translocation. LANCL1 functions primarily as a glutathione-binding protein that mitigates oxidative stress and prevents neuronal apoptosis.