Background: Dihydroartemisinin (DHA), the principal active metabolite of the Chinese medicine Artemisia annua L., exhibits only modest efficacy against nonalcoholic fatty liver disease (NAFLD). Herein, we employed fluorination to enhance the therapeutic potency of DHA and systematically evaluated the capacity of its fluorinated derivatives to rectify lipid metabolic disturbances associated with NAFLD, thereby contributing to the modernization of Chinese medicine. Objectives: This study aimed to develop a monofluorinated derivative of DHA, systematically evaluate its lipid-lowering and hepatoprotective effects in NAFLD models, and elucidate the molecular mechanisms by which it regulates the cholesterol biosynthesis pathway. Ultimately, this research seeks to expand the clinical applications of DHA analogues and provide new avenues for the development of therapies for metabolic liver diseases. Methods: The target compound, F-DHA, was synthesized via chemical modification of the C-12 hydroxyl group of DHA. Its structure was unequivocally confirmed by comprehensive spectroscopic analyses, including 1 H-NMR, 13 C-NMR, 19 F-NMR, infrared spectroscopy, and high-resolution mass spectrometry. The therapeutic potential of F-DHA was subsequently evaluated using in vitro assays in HepG2, Huh7, LO2, and 3T3-L1 cell lines, as well as in an in vivo high-fat diet-induced NAFLD male C57BL/6J mouse model. To investigate the underlying pharmacological mechanisms, transcriptomic analysis was further conducted. Results: After successful synthesis via monofluorination of the C-12 hydroxyl group, the DHA derivative F-DHA was confirmed as a high-purity compound by comprehensive spectroscopic analyses. In vitro and in vivo evaluations in NAFLD models demonstrated that F-DHA significantly outperformed native DHA, markedly reducing lipid accumulation in hepatocytes and adipocytes and alleviating hepatic steatosis, dyslipidemia, and liver injury in high-fat diet-fed mice. Mechanistic transcriptomic profiling indicated that the protective effects of F-DHA were mediated through suppression of the cholesterol biosynthesis pathway. Conclusion: This study provides the first evidence that monofluorination of an artemisinin-based scaffold confers direct modulatory activity on cholesterol metabolism, thereby offering both a validated chemical entity and a mechanistic rationale for the development of innovative NAFLD therapeutics that concurrently regulate lipid homeostasis and protect liver function.
Wang et al. (Mon,) studied this question.