Fig. 9

LANCL2 activation by BT-11 couples anti-inflammatory and detoxification mechanisms with relevance to Alzheimer’s disease (created with BioRender.com). (1) Inflammation Reduction: BT-11 or ABA activation of LANCL2 stimulates AC → cAMP → PKA → pCREB signaling leading to reduced inflammation (↑IL-10, ↓TNFα) as has been shown in human granulocytes, rat β-cells, and mouse T cells. ^4,27,74. LANCL2 may also regulate alternative pathways as shown in computational model of macrophage differentiation based in response to H. pylori, including MAPKs, Akt, NF-κB, and Fbxo7, which are engaged in metabolic, immune and oxidative-stress processes, as shown in mouse macrophages and T cells⁴⁹. (2) Detoxification: LANCL2’s glutathione S-transferase activity facilitates detoxification via glutathione conjugation in HEK293 and MEF cells ⁴⁴, and potentially MRP1-mediated removal of toxic cargo as shown in human cancer cell lines⁷⁵. LANCL2 localization to membrane, cytoplasm or nucleus, as shown in cancer cell lines⁴⁰, likely determines its anti-inflammatory and detoxification effects. Because chronic neuroinflammation and redox stress are key drivers of AD pathology, these LANCL2-modulated mechanisms provide a rationale for testing BT-11 in AD. AC, adenylyl cyclase; Akt, protein kinase B; Fbxo7, F-box only protein 7; HEK, human embryonic kidney; IL-10, interleukin 10; LANCL2, lanthionine synthetase C-like 2; MAPK, Mitogen-activated protein kinase; MEF, mouse embryonic fibroblasts; MRP1, multidrug resistance protein 1; NF-κB, Nuclear factor-kappa B; pCREB, phosphorylated cAMP response element-binding protein; PKA, protein kinase A; TNFα, tumor necrosis factor α.