Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · 2026
Liver kinome reveals PS1145 as therapeutic agent for mitigating systemic inflammation in alcohol-related liver disease.
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Yadav Manisha, Gupta Abhishak, Yadav Sanju, Sharma Vipul, Magar Yash, Deepanshu Deepanshu, Khan Tahseen, Sharma Neha, Yadav Kavita, Sharma Nupur, Bindal Vasundhra, Pandey Sushmita, Tripathi Gaurav, Saif Rimsha, Mathew Babu, Tripathi Dinesh Mani, Kumari Anupama, Sharma Shvetank, Sarin Shiv Kumar, Maras Jaswinder Singh
Аннотация
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 < 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).
CONCLUSION: PS1145 blocks IKK phosphorylation and TLR dimerization, attenuating inflammation and improving liver pathology, highlighting its therapeutic potential in ALD.
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 < 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).
CONCLUSION: PS1145 blocks IKK phosphorylation and TLR dimerization, attenuating inflammation and improving liver pathology, highlighting its therapeutic potential in ALD.