Liver kinome reveals PS1145 as therapeutic agent for mitigating systemic inflammation in alcohol-related liver disease

Alcohol-related liver disease (ALD) lacks effective anti-inflammatory therapies, and since kinases orchestrate inflammation, kinome profiling offers a rational approach to identify and validate novel therapeutic targets. To analyse liver and monocyte kinome alterations in a chronic ethanol-fed pre-clinical rat model and identify therapeutic targets capable of mitigating inflammation. Pathway-specific inhibitors, including PS1145 (IKK-phosphorylation-inhibitor), PH797804 (MAPK14-inhibitor), resveratrol, and prednisolone were evaluated in ALD-rats, PBMCs from patients, and the NIAAA mouse model. Kinome profiling identified 497 hepatic and 345 monocyte kinases in ALD rats (FDR1.5, p < 0.05). By 24 weeks, 172-liver and 48-monocyte kinases were upregulated, primarily involving MyD88-TLR4, PI3K-Akt, TNF, TGFβ-TGFβR1, senescence and ROS-generating kinases and IL-1-driven MAPK14 and IKK phosphorylation(p < 0.05). Targeting this axis, PS1145 suppressed NFκB activation and inflammation in THP1, HepG2 cells, PBMCs from healthy and SAH-patients, outperforming PH797804, resveratrol, and prednisolone (FC>1.5,p < 0.05). PS1145 significantly reduced IL-6, TNFα, and NFκB, while increasing IL-10. In NIAAA-mouse model, PS1145 treatment reduced hepatic steatosis, cellular stress, and inflammation, IL36R disrupting TLR dimerization more effectively than standard therapies (p < 0.05). PS1145 blocks IKK phosphorylation and TLR dimerization, attenuating inflammation and improving liver pathology, highlighting its therapeutic potential in ALD. Kinome profiling identified IKK phosphorylation as a therapeutic target for controlling systemic inflammation in alcohol-associated liver disease (ALD). Pharmacological inhibition of IKK-phosphorylation using PS1145 effectively ameliorated alcohol-induced liver injury by preventing NF-κB activation through retention of the NF-κB complex in the cytoplasm. PS1145 treatment also downregulated IL-36 receptor expression, thereby attenuating TLR4-driven inflammatory signaling in the liver. Together, these findings demonstrate that targeted inhibition of IKK phosphorylation can suppress maladaptive NF-κB and IL-36R/TLR4 pathways, offering a promising strategy for mitigating systemic inflammation in ALD. • Kinome profiling of liver and monocytes identified targets for controlling systemic inflammation in ALD. • IKK, an NFκB activator, was identified as a potential therapeutic target. • Blocking IKK phosphorylation retains IKK in cytoplasm, limiting NFκB inflammation. • PS1145, an IKK inhibitor, reduced systemic inflammation via IKKp and IL36R reduction.