TNIP3 (TNFAIP3 interacting protein 3) is a multi-functional negative regulator of inflammatory and stress-response pathways with tissue-specific protective roles. Canonically, TNIP3 inhibits NF-κB activation downstream of TNF, TLR4, and IL-1 signaling, though this inhibition is independent of TNFAIP3 binding 1. Beyond this classical function, TNIP3 demonstrates distinct mechanisms in different pathophysiological contexts. In hepatocytes, TNIP3 directly interacts with TAK1 to inhibit its ubiquitination and activation, suppressing nonalcoholic steatohepatitis progression 1. During hepatic ischemia-reperfusion injury, TNIP3 activates Hippo-YAP signaling by promoting LATS2 ubiquitination and degradation, protecting against liver damage 2. In cardiomyocytes, TNIP3 stabilizes STAT1 by suppressing K48-type ubiquitination, thereby protecting against pathological cardiac hypertrophy 3. TNIP3 is also upregulated in Kupffer cells following hepatic reperfusion, suggesting a protective role in liver transplantation 4. Clinically, TNIP3 dysregulation associates with major depressive disorder, where elevated TNIP3 mRNA in TNF-α-secreting cells correlates with disease severity 5. Loss-of-function TNIP3 mutations in NF-κB regulators contribute to coeliac disease-associated lymphomagenesis 6. These findings position TNIP3 as a promising therapeutic target for hepatic, cardiac, and immune-related diseases.