TNIP1 (TNFAIP3-interacting protein 1) is a polyubiquitin-binding protein that functions as a critical negative regulator of inflammatory signaling. Primary function: TNIP1 inhibits NF-κB activation by facilitating A20/TNFAIP3-mediated deubiquitination of IKBKG and regulating TAX1BP1 1. It also suppresses ERK1/2 signaling by blocking MAPK nuclear translocation [UniProt annotation]. Recent studies reveal TNIP1 negatively regulates selective autophagy, including mitophagy, through bipartite interactions with LC3/GABARAP and TAX1BP1 via conserved LIR and AHD3 domains 2. Disease relevance: TNIP1 dysfunction is implicated in multiple autoimmune and inflammatory conditions. Loss-of-function variants associate with systemic lupus erythematosus and lupus nephritis 3, while the Q333P gain-of-function variant causes systemic autoimmune disease with elevated IgG4 through impaired mitophagy and increased TLR7 signaling 4. Polymorphisms associate with psoriasis susceptibility 5. TNIP1 is also identified as a novel risk factor for frontotemporal lobar degeneration with TDP-43 pathology 6, and elevated TNIP1 expression associates with antidepressant response in major depressive disorder 7. Clinical significance: TNIP1's role as an anti-inflammatory regulator positions it as a candidate therapeutic target for inflammatory and autoimmune diseases, with emerging evidence supporting TLR7-targeted therapeutics for TNIP1-mediated autoimmunity 48.