TRIL (TLR4 interactor with leucine-rich repeats) is a transmembrane component of the TLR4 signaling complex that mediates innate immune responses to bacterial lipopolysaccharide (LPS) 1. The protein consists of a signal sequence, 13 leucine-rich repeats, a fibronectin domain, and a single transmembrane region 1. TRIL is highly expressed in brain tissue but also present in spinal cord, lung, kidney, and ovary 1. Mechanistically, TRIL directly interacts with TLR4 and LPS, with this interaction enhanced following LPS stimulation 1. TRIL promotes LPS-induced cytokine production through the TLR4-mediated NF-κB/IL-1β signaling pathway 2. Beyond innate immunity, TRIL functions in developmental signaling by dampening Nodal signaling through Pellino2- and Traf6-mediated activation of the ubiquitin ligase Nedd4l, which targets Nodal receptors for degradation 3. Disease relevance includes spinal cord ischemia-reperfusion injury, where TRIL suppression reduces inflammatory damage and improves neurological outcomes 2. Additionally, TRIL has been identified as part of the MLLT11-TRIL complex in endometrial cancer, where it promotes tumor progression through PI3K/AKT/mTOR pathway activation 4. Knockdown of TRIL attenuates LPS signaling in immune cells and primary glial cells 1, suggesting therapeutic potential in inflammatory conditions.