Abstract: High-dose acetaminophen (AAP) has demonstrated promising anti-cancer activity in early-stage clinical trials. Our reverse translational studies have demonstrated that high-dose AAP has anti-cancer activity via modulation of JAK-STAT signaling in a free radical independent fashion, suggesting that AAP can be administered concurrently with rescue cocktails to prevent liver toxicity. High-dose AAP inhibits STAT3 within the tumor, a key transcription factor regulating cancer stem cell proliferation and function. AAP inhibits STAT6-mediated M2 polarization of tumor-associated macrophages in the tumor immune microenvironment, leading to enhanced anti-tumor immunity. Fomepizole-based rescue strategies offer optimal liver protection from AAP toxicity in pre-clinical mouse models, allowing dose escalation to 100-fold higher than standard AAP dosing without hepatotoxicity.

Abstract: Compensated advanced chronic liver disease (cACLD) represents asymptomatic patients who face the risk of developing clinically significant portal hypertension (CSPH). CSPH, marked by a hepatic venous pressure gradient (HVPG) ≥ 10 mmHg, heralds complications like oesophageal varices, affecting approximately 50% of cirrhosis patients. These varices pose a grave threat due to potential bleeding, which can be fatal. Endoscopic screening, the gold standard for detecting varices, is costly and invasive, highlighting the need for non-invasive tools (NITs). This study focuses on validating and comparing the effectiveness of various NITs, including the Baveno VI criteria (B6C), in an Australian cohort. These NITs offer a promising alternative, potentially alleviating the pressure on endoscopic services by accurately identifying high-risk varices, ensuring timely and effective intervention.

Abstract: Cell-death-inducing DNA fragmentation factor-alpha (DFFA)-like effector b (CIDEB) was first identified as an apoptosis-inducing protein. Further research revealed a pivotal role in lipid metabolism, regulating very-low-density lipoprotein (VLDL), lipid droplets (LDs), sterol response element-binding protein (SREBP), and chylomicrons. Recent studies have uncovered that rare germline variants in CIDEB protect against liver diseases, including MAFLD, cirrhosis, and viral hepatitis. Furthermore, CIDEB influences steps of the hepatitis C virus (HCV) replication cycle. This review summarizes the current knowledge about CIDEB’s roles in apoptosis, lipid metabolism, and viral hepatitis, and highlights its critical role in liver diseases.

Abstract: Sex hormones deeply influence cardiometabolic health. Interestingly, the relationship between testosterone and metabolic derangements is sex-dimorphic, such that low testosterone levels are associated with an adverse cardiometabolic phenotype in men, while high androgen levels are associated with a similar adverse phenotype in women. In addition, oestrogen deficiency in women is also associated with metabolic diseases. The mechanisms through which the alteration of testosterone levels negatively influences metabolism and hepatic steatosis are complex, and include the dysregulation of the expression of the genes involved in de novo lipogenesis, reduced fatty acid oxidation and hepatic lipid export, insulin resistance, oxidative stress, and inflammation. The aim of our paper is to explore this complex sex-dimorphic relationship.