Rodent models of partial hepatectomy (PH) unveiled molecular drivers of successful Venetoclax LR, such as the priming cytokines tumor necrosis factor (TNF) and interleukin (IL)-6, that drive hepatocyte entry into cell cycle.1, 2 Shortly following hepatectomy, Kupffer cells release TNF, activating nuclear factor kappa B (NF-κB) in neighboring hepatocytes, thus increasing IL-6 secretion. In turn, IL-6 binds to

its receptor, activating the JAK/STAT3 (signal transducer and activator of transcription 3) pathway to promote hepatocyte proliferation.3 Accordingly, the superagonistic IL-6/soluble IL-6R fusion protein enhances LR.4 In contrast, mice with targeted disruption of IL-6 demonstrate impaired regeneration that could be reversed by overexpression or induction of STAT3.5-8 Levels of IL-6 after PH determine its hepatotrophic effect. Indeed, inappropriately high IL-6 levels rather inhibit LR by increasing expression of the cyclin dependent kinase inhibitor (CDKI), p21.9 IL-6 signaling in hepatocytes is finely regulated by a negative feedback loop provided

by IL-6/STAT3-mediated induction of suppressor of cytokine signal-3 (SOCS3).10 Accordingly, hepatocyte-specific SOCS3 knockout (hKO SOCS3) mice show improved LR following hepatectomy.11 In sum, the IL-6/STAT3/SOCS3 pathway is a promising target for proregenerative strategies. We previously demonstrated that A20/tnfaip3, a key element of the cellular U0126 purchase response to injury and inflammation,12, 13 exerts multiple hepatoprotective functions through combined anti-inflammatory, anti-apoptotic, and pro-proliferative effects in hepatocytes.14-16 A20 restrains inflammation by inhibiting Buspirone HCl NF-κB activation,17 blocks apoptosis by disrupting caspase-8 activation,18 limits ischemic damage by increasing peroxisome proliferator-activated receptor alpha (PPARα) expression,16 optimizes energy production through improved lipid/fatty acid metabolism, and promotes proliferation by decreasing

p21.15, 19 A20′s hepatoprotective functions improve LR and survival in mouse models of extreme liver injury, including extended (78%, EH) and radical/lethal (83%) hepatectomy, acute toxic hepatitis and lethal ischemia/reperfusion injury.14-16 A20 is an NF-κB-dependent gene14 that is part of the regenerative response of the liver, and accordingly, its expression levels increase in deceased and living donor liver grafts hours following reperfusion.20 A20 KO mice are born cachectic and die within 4-5 weeks of birth, mainly from unfettered liver inflammation, which shows A20′s high rank in the hierarchy of the liver physiologic anti-inflammatory armamentarium.21 Since transcription of key priming cytokine IL-6 is in part NF-κB-dependent,22 we questioned whether the NF-κB inhibitory protein A20 would decrease IL-6 levels, thereby attenuating its pro-proliferative advantage in hepatocytes. This work examines this question.