Background and Aims: Metabolic dysfunction-associated steatohepatitis (MASH), a progressive form of metabolic dysfunction-associated steatotic liver disease (MASLD), involves inflammation, fibrosis, steatosis, and oxidative stress. Previous research from our lab shows that cannabigerol (CBG) reduces inflammation and fibrosis in male MASH mice, but its effects in females remain unknown. Given immune cell population changes in MASLD patients, this study examines CBG’s impact on methionine-choline deficient (MCD) diet-induced MASH in female mice. Methods: MCD-fed female mice are supplemented with two different doses for three weeks. Liver fibrosis, steatosis, oxidative stress, ductular reaction, and inflammation are assessed via Sirius Red, Oil Red O, immunohistochemistry, and immunofluorescence staining. Immune cell changes in non-parenchymal cells (NPCs) are analyzed via flow cytometry. Results: CBG treatment improves liver health by reducing leukocyte infiltration. Both CBG doses significantly decrease fibrosis, oxidative stress, ductular proliferation, and inflammation in MCD-fed mice, including monocyte and T lymphocyte reductions. Additionally, CBG downregulates mast cell activation, inhibiting transforming growth factor (TGF)-β1 release, thereby suppressing hepatic stellate cell activation. This reduces collagen deposition, fibrosis, and ductular proliferation. Conclusions: Our findings provide insights for pre-clinical and clinical research, highlighting CBG’s potential therapeutic role and dosage considerations in mitigating liver fibrosis and inflammation in female patients.

Recently, GnRHa puberty blockers have been under scrutiny, with newly identified risks of heart and brain damage and recurrent concerns about fertility, cancer risk, and bone health. This study explores the effects of GnRHa on liver morphology, function, and injury response. Peripubertal male and female Sprague-Dawley rats received daily GnRHa triptorelin (100 μg) subcutaneously. Liver oxidative stress, inflammation, and fibrosis were evaluated via malondialdehyde and 8-OHdG (oxidative damage), immunohistochemistry for CK19 (cholangiocytes) and CD45 (leukocytes), and collagen staining as well as áSMA (liver fibrogenesis) and TIMP1 (extracellular matrix breakdown) expression, respectively. Following GnRHa treatment, only male rats exhibited increased ductular reaction and oxidative stress. In contrast, GnRHa-treated female rats showed increased leukocyte infiltration. In both sexes, GnRHa-treated rats showed increased fibrosis, with significantly increased collagen deposition and áSMA expression. Interestingly, GnRHa-treated female rats exhibited increased TIMP1 expression, whereas male rats showed decreased TIMP1 expression. Overall, GnRHa puberty blocking leads to significantly increased liver injury in both sexes. Specifically, biological females are at increased risk of hepatic inflammation, while biological males are at increased risk of oxidative stress. Human clinical trials are crucial for further exploring these findings.