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Targeting PKLR and lipogenic enzymes through JNK inhibition to develop a therapeutic strategy for MASLD and MASH
Woonghee Kim1, Mengzhen Li1, Xinmeng Liao1
1Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden.
Background:
Pyruvate kinase liver and red blood cells (PKLR) is linked to metabolic dysfunction-associated steatotic liver disease (MASLD). Previous study, we identified JNK-IN-5A, a c-Jun N-terminal kinase (JNK) inhibitor that suppresses PKL expression in HepG2 cells using computational drug repurposing and screened out four hit JNK-IN-5A derivatives (SET-151, SET-152, SET-162, SET-130).
Materials And Methods:
We validated therapeutic efficacy of JNK-IN-5A and four derivative (SET-151, SET-152, SET-162, SET-130). HepG2 de novo lipogenesis (DNL) steatosis model was used in vitro validation. RNA sequencing data were analysed using systems biology approaches, including transcriptomic profiling and COMPASS analysis. GLP-like toxicity assessment in rat model shows in vivo safety and MASLD rat model revealed in vivo therapeutic effect to MASLD and MASH.
Results:
In a HepG2 DNL steatosis model, all compounds reduced intracellular triacylglycerol (TAG) and inhibited key DNL proteins (PKL, FASN, ACACA, SCD1, SREBP1-c, ChREBP). Transcriptomic profiling revealed stronger anti-steatotic effects with SET-151, SET-152, and SET-162, which uniquely downregulated genes in pyruvate metabolism, bile acid synthesis, fatty acid metabolism, and glycolysis. Compass analysis showed these derivatives significantly altered lipid-related metabolic reactions, unlike JNK-IN-5A. In a high-sucrose, high-fat diet-induced MASLD rat model, JNK-IN-5A and SET-152 reduced hepatic lipid accumulation, liver stiffness, and MASLD biomarkers.
Conclusion:
Our findings identify PKLR as a promising therapeutic target for MASLD and MASH. SET-152 suppressing PKLR through JNK inhibition highlights its potential as a new drug for MASLD and MASH therapy.
Insights
Pyruvate kinase liver and red blood cells (PKLR) inhibition shows promise for treating metabolic dysfunction-associated steatotic liver disease (MASLD) and its inflammatory form (MASH). SET-152, a JNK inhibitor, effectively reduced liver fat and improved biomarkers in preclinical models.
Area of Science:
- Biochemistry
- Pharmacology
- Hepatology
Background:
- Pyruvate kinase liver and red blood cells (PKLR) is implicated in metabolic dysfunction-associated steatotic liver disease (MASLD).
- Previous research identified JNK-IN-5A, a c-Jun N-terminal kinase (JNK) inhibitor, that suppresses PKLR expression.
- Four JNK-IN-5A derivatives (SET-151, SET-152, SET-162, SET-130) were identified for further investigation.
Purpose of the Study:
- To validate the therapeutic efficacy of JNK-IN-5A and its derivatives in preclinical models of MASLD.
- To investigate the molecular mechanisms underlying the anti-steatotic effects of these compounds.
- To assess the in vivo safety and efficacy of JNK-IN-5A and SET-152 in a MASLD rat model.
Main Methods:
- In vitro validation using a HepG2 de novo lipogenesis (DNL) steatosis model.
- RNA sequencing and systems biology approaches (transcriptomic profiling, COMPASS analysis).
- In vivo assessment including GLP-like toxicity in rats and efficacy in a diet-induced MASLD rat model.
Main Results:
- All tested compounds reduced intracellular triacylglycerol (TAG) and inhibited key DNL proteins in HepG2 cells.
- SET-151, SET-152, and SET-162 demonstrated potent anti-steatotic effects, downregulating genes in pyruvate metabolism, bile acid synthesis, fatty acid metabolism, and glycolysis.
- In vivo, JNK-IN-5A and SET-152 reduced hepatic lipid accumulation, liver stiffness, and MASLD biomarkers in rats.
Conclusions:
- PKLR is identified as a significant therapeutic target for MASLD and MASH.
- SET-152, by inhibiting PKLR via JNK, presents potential as a novel therapeutic agent for MASLD and MASH.
- The study highlights the therapeutic potential of targeting PKLR through JNK inhibition for liver disease treatment.
