Frontiers in pharmacology · 2026
Targeting PKLR and lipogenic enzymes through JNK inhibition to develop a therapeutic strategy for MASLD and MASH.
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Kim Woonghee, Li Mengzhen, Liao Xinmeng, Özmen Sevilay, Yıldız Edanur, Saraçoğlu Melik, Baba Cem, Celikezen Fatih Caglar, Atalay Said Ali, Akkuş Ahmet Tuğrul, Alper Fatih, Jin Han, Yang Hong, Iqbal Shazia, Sebhaoui Jihad, Ashraf Sajda, Belmen Burcu, Boren Jan, Uhlen Mathias, Zhang Cheng, Turkez Hasan, Mardinoglu Adil
Аннотация
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.
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.