The inhibition of Il1β synthesis mediated by a novel pyridine-sulfonamide compound protects against the progression of metabolic dysfunction-associated steatotic liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is currently the leading cause of chronic liver disease worldwide. The increasing MASLD burden and the lack of effective therapies underscore the urgent need for new therapeutic approaches. Interleukin 1 beta (IL1β) has been identified as a key mediator of MASLD progression, and is considered a promising therapeutic target. This study evaluated the efficacy of AIK3a305, a novel allosteric inhibitor of cJun N-terminal kinase (JNK), in preventing MASLD progression through a selective inhibition of IL1β synthesis. Macrophages were treated with LPS and palmitate to assess IL1β modulation, and hepatocytes with palmitic acid (PA) to explore lipid accumulation, lipoapoptosis, and inflammatory signaling, in the presence or absence of this compound. Mice fed a high-fat diet (HFD) or a choline-deficient, L-amino acid-defined (CDAA) diet were orally treated with AIK3a305 or vehicle, and livers were collected for histopathological and molecular analysis. AIK3a305 selectively inhibited LPS- and palmitate-induced IL1β expression in macrophages, while protecting hepatocytes from intracellular lipid accumulation and lipoapoptosis. These hepatic effects were associated with a suppression of JNK signaling, which triggered a decrease in IL1β expression, and a transient inhibition of the transcription factor NFκB and p38 pathways, and, thus, tumor necrosis factor α (TNFα) synthesis. In preclinical models of MASLD, treatment with AIK3a305 attenuated disease progression in animals fed either a HFD or a CDAA diet, as evidenced by improved liver histopathology, including reduced steatosis and inflammation. These findings position AIK3a305 as a promising therapeutic candidate for MASLD treatment.