Ursolic Acid Modulates Estrogen Conversion to Relieve Inflammation in Metabolic Dysfunction-associated Steatotic Liver Disease via HSD17B14

Background and Aims: The incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) has been escalating annually, positioning it as the leading cause of chronic liver disease worldwide. Ursolic acid has demonstrated promising therapeutic efficacy in managing MASLD, thereby justifying the need for an in-depth exploration of its pharmacological mechanisms. This study aimed to investigate elucidate the therapeutic mechanisms by which ursolic acid modulates estrogen conversion in the treatment of MASLD. Methods: Building upon prior studies that have highlighted the potent anti-inflammatory effects of ursolic acid and its specific targeting of 1713-hydroxysteroid dehydrogenase 14 (HSD17B14), this investigation employed a western diet to induce MASLD in murine models with varying severities over different time intervals. Results: The protein expression of HSD17B14 initially increased, followed by a subsequent decrease. This trend was accompanied by corresponding changes in 1713-estradiol (E2) and estrone (E1) levels. Intervention with ursolic acid resulted in a reduction in HSD17B14 and E1 levels during the phase of high HSD17B14 expression, while simultaneously elevating E2 levels. In steatotic hepatocytes, E1 promoted cellular inflammation, whereas E2 exhibited anti-inflammatory effects. However, the alleviated effects of E2 were antagonized by HSD17B14. As expected, ursolic acid modulated HSD17B14, thereby mitigating the inflammatory response in steatotic hepatocytes. Conclusions: HSD17B14, a crucial enzyme regulating the balance between E1 and E2, catalyzes the conversion of estrogen E2 into E1, thereby exacerbating tissue inflammation induced by metabolic stress. Ursolic acid, by modulating HSD17B14-mediated estrogen conversion, appears to ameliorate immune-related inflammation in MASLD.