Toll/interleukin-1 receptor domain-containing adaptor protein (TIRAP) in Hepatic Stellate Cells: Beyond Membrane and Cytoplasmic Presence

The Toll/interleukin-1 receptor domain-containing adaptor protein (TIRAP) is a key adaptor in Toll-like receptor signaling, classically functioning as a cytoplasmic bridging adaptor for Myeloid differentiation primary response 88 (MyD88) recruitment. While its role in inflammatory signaling is well established, its contribution to alcohol-induced liver fibrosis remains unclear. Using lipopolysaccharide (LPS) and ethanol-stimulated hepatic stellate cells (LX-2), we demonstrate, for the first time, nuclear translocation of TIRAP under alcoholic conditions. Confocal microscopy and nuclear–cytoplasmic fractionation confirmed TIRAP enrichment in the nucleus. Importantly, silencing of TIRAP in LX-2 significantly reduced the nuclear translocation and expression of fibrotic markers (such as α-SMA and collagen) in HSCs, suggesting a key role of nuclear TIRAP in driving fibrogenesis. Overall, these findings reveal a novel role for TIRAP beyond cytoplasmic signaling, suggesting potential nuclear functions that may regulate transcriptional programs driving inflammation and fibrosis.