β‐elemene ameliorates metabolic dysfunction‐associated steatohepatitis by targeting PPARα in experimental diet‐induced models

Background and Purpose Metabolic dysfunction‐associated steatohepatitis (MASH) is an escalating global health concern with few effective pharmacological treatment options available. β‐elemene (ELE) is a natural product derived from Curcuma Rhizoma , which has anti‐tumour and anti‐inflammatory effects. However, its efficacy and molecular mechanism in MASH have not been elucidated. Experimental Approach Two diet‐induced MASH models were used to evaluate the therapeutic potential of ELE in vivo . Additionally, RNA sequencing, network pharmacological analysis, and target validation were performed to elucidate the underlying mechanisms. Key Results ELE markedly ameliorated lipid dysfunction and the inflammatory response in MASH mice and fatty acids‐stimulated hepatocytes. RNA‐sequencing analysis indicated that ELE exerted its therapeutic effects through activating the PPARα signalling pathway. Particularly, we found that ELE directly binds to PPARα protein, preventing its degradation via K48‐linked polyubiquitination. Notably, the protective effects of ELE on MASH were abolished in the absence of PPARα. Conclusion and Implications Our studies reveal that ELE is a novel stabiliser of PPARα, effectively inhibiting its ubiquitin‐mediated degradation in MASH. By preserving the PPARα signalling pathway, ELE enhances lipid homeostasis and relieves the inflammation. Therefore, ELE holds significant potential as a therapeutic candidate for the treatment of MASH.