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

Abstract

RATIONALE: 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. OBJECTIVE: 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. FINDINGS: Kinome profiling identified 497 hepatic and 345 monocyte kinases in ALD rats (FDR<0.01), with a time-dependent increase in MAPK14-associated kinases in both tissues (FC>1.5, p&#x202f;<&#x202f;0.05). By 24 weeks, 172-liver and 48-monocyte kinases were upregulated, primarily involving MyD88-TLR4, PI3K-Akt, TNF, TGF&#x3b2;-TGF&#x3b2;R1, senescence and ROS-generating kinases and IL-1-driven MAPK14 and IKK phosphorylation(p&#x202f;<&#x202f;0.05). Targeting this axis, PS1145 suppressed NF&#x3ba;B activation and inflammation in THP1, HepG2 cells, PBMCs from healthy and SAH-patients, outperforming PH797804, resveratrol, and prednisolone (FC>1.5,p&#x202f;<&#x202f;0.05). PS1145 significantly reduced IL-6, TNF&#x3b1;, and NF&#x3ba;B, 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&#x202f;<&#x202f;0.05). CONCLUSION: PS1145 blocks IKK phosphorylation and TLR dimerization, attenuating inflammation and improving liver pathology, highlighting its therapeutic potential in ALD.