{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T15:52:21Z","timestamp":1782921141128,"version":"3.54.5"},"reference-count":75,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and Methods<\/jats:title>\n                    <jats:p>\n                      We validated therapeutic efficacy of JNK-IN-5A and four derivative (SET-151, SET-152, SET-162, SET-130). HepG2\n                      <jats:italic>de novo<\/jats:italic>\n                      lipogenesis (DNL) steatosis model was used\n                      <jats:italic>in vitro<\/jats:italic>\n                      validation. RNA sequencing data were analysed using systems biology approaches, including transcriptomic profiling and COMPASS analysis. GLP-like toxicity assessment in rat model shows\n                      <jats:italic>in vivo<\/jats:italic>\n                      safety and MASLD rat model revealed\n                      <jats:italic>in vivo<\/jats:italic>\n                      therapeutic effect to MASLD and MASH.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1823203","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T15:29:28Z","timestamp":1782919768000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting PKLR and lipogenic enzymes through JNK inhibition to develop a therapeutic strategy for MASLD and MASH"],"prefix":"10.3389","volume":"17","author":[{"given":"Woonghee","family":"Kim","sequence":"first","affiliation":[{"name":"Science for Life Laboratory, KTH \u2013 Royal Institute of Technology","place":["Stockholm, Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengzhen","family":"Li","sequence":"additional","affiliation":[{"name":"Science for Life Laboratory, KTH \u2013 Royal Institute of 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