Peroxisome proliferator-activated receptor α (PPARα) is a key regulator to ameliorate liver injury in cases of acute liver failure (ALF). However, its regulatory mechanisms remain largely undetermined. Endoplasmic reticulum stress (ER stress) plays an important role in a number of liver diseases. This study aimed to investigate whether PPARα activation inhibit ER stress-induced hepatocyte apoptosis, thereby protecting against ALF. In a murine model of D-galactosamine (D-GalN) and lipopolysaccharide (LPS)-induced ALF, Wy-14643 was administered to activate PPARα, and 4-phenylbutyric acid (4-PBA) was administered to attenuate ER stress. PPARα activation ameliorated liver injury, because pre-administration of its specific inducer, Wy-14643, reduced the serum aminotransferase levels and preserved liver architecture compared with that of controls. The protective effect of PPARα activation resulted from the suppression of ER stress-induced hepatocyte apoptosis. Indeed, (1) PPARα activation decreased the expression of glucose-regulated protein 78 (Grp78), Grp94 and C/EBP-homologous protein (CHOP) in vivo; (2) the liver protection by 4-PBA was due to the induction of PPARα expression, because 4-PBA pretreatment promoted up-regulation of PPARα, and inhibition of PPARα by small interfering RNA (siRNA) treatment reversed liver protection and increased hepatocyte apoptosis; (3) in vitro PPARα activation by Wy-14643 decreased the hepatocyte apoptosis induced by severe ER stress, and PPARα inhibition by siRNA treatment decreased the hepatocyte survival induced by mild ER stress. Here, we demonstrated that PPARα activation contributes to liver protection and decreases hepatocyte apoptosis in ALF, particularly through regulating ER stress. Therefore, trageting PPARα could be a potential therapeutic strategy to ameliorate ALF.

Non-alcoholic fatty liver disease (NAFLD), characterized by excessive lipid accumulation in hepatocytes, is an increasing global healthcare burden. Sirtuin 2 (SIRT2) functions as a preventive molecule for NAFLD with incompletely clarified regulatory mechanisms. Metabolic changes and gut microbiota imbalance are critical to the pathogenesis of NAFLD. However, their association with SIRT2 in NAFLD progression is still unknown. Here, we report that SIRT2 knockout (KO) mice are susceptible to HFCS (high-fat/high-cholesterol/high-sucrose)-induced obesity and hepatic steatosis accompanied with an aggravated metabolic profile, which indicates SIRT2 deficiency promotes NAFLD-NASH (nonalcoholic steatohepatitis) progression. Under palmitic acid (PA), cholesterol (CHO), and high glucose (Glu) conditions, SIRT2 deficiency promotes lipid deposition and inflammation in cultured cells. Mechanically, SIRT2 deficiency induces serum metabolites alteration including upregulation of L-proline and downregulation of phosphatidylcholines (PC), lysophosphatidylcholine (LPC), and epinephrine. Furthermore, SIRT2 deficiency promotes gut microbiota dysbiosis. The microbiota composition clustered distinctly in SIRT2 KO mice with decreased Bacteroides and Eubacterium, and increased Acetatifactor. In clinical patients, SIRT2 is downregulated in the NALFD patients compared with healthy controls, and is associated with exacerbated progression of normal liver status to NAFLD to NASH in clinical patients. In conclusion, SIRT2 deficiency accelerates HFCS-induced NAFLD-NASH progression by inducing alteration of gut microbiota and changes of metabolites.

This report described a male patient presenting with recurrent fever, fatigue, persistent abdominal distension, and diarrhea, who was repeatedly misdiagnosed with decompensated cirrhosis at multiple hospitals. The diagnostic process was complex, ultimately leading to the diagnosis of TAFRO syndrome through lymph node and bone marrow biopsies, following ¹⁸F-FDG PET/CT imaging. The patient initially responded to treatment, while later succumbed to severe intra-abdominal infection and multiple organ failure. TAFRO syndrome, a rare subtype of Castleman disease, is frequently misdiagnosed due to limited clinical awareness, delaying appropriate treatment. This case highlighted the diagnostic challenges and therapeutic considerations associated with TAFRO syndrome, providing insights for clinical practice based on the existing research.

Intracellular iron homeostasis imbalance is linked to cellular ferroptosis and inflammatory injury diseases. NCOA4-mediated ferritin autophagy is vital for regulating intracellular iron homeostasis, but its impact on acute liver failure (ALF) pathogenesis and regulatory mechanisms remain unclear. This study explores the role and regulatory mechanisms of NCOA4 in hepatocyte ferroptosis and ALF progression. To investigate the relationship between NCOA4 expression and acute liver failure (ALF), we compared the protein expression levels in normal and pathological liver tissues. By establishing cell and mouse models, we determined the correlation among NCOA4 expression, ferroptosis, and inflammatory liver injury. Additionally, we explored the regulatory effect of NCOA4 on hepatocyte ferroptosis by interfering with gene expression and observing mitochondrial structure changes. Finally, we evaluated the regulation of NCOA4 expression and its protective effect against acute inflammatory injury in hepatocytes. Our results showed that NCOA4 expression was significantly higher in patients with hepatitis B virus - related acute - on - chronic liver failure (HBV - ACLF) compared to those with chronic hepatitis B. Similarly, NCOA4 was upregulated in ALF model mice and inflammatory hepatocytes. Silencing NCOA4 alleviated LPS - induced ferroptosis in inflammatory hepatocytes. Mechanistic research indicated that the transcription of hepatic nuclear factor 4 A (HNF4A) negatively regulated NCOA4. HNF4A transcriptionally inhibited NCOA4 expression, reducing hepatocyte ferroptosis through anti - ferritin autophagy. This study identified the HNF4A - NCOA4 axis and ferritinophagy as crucial factors in hepatocyte ferroptosis and the pathogenesis of acute liver failure (ALF). These findings suggest that the HNF4A - NCOA4 axis could be a potential therapeutic target for ALF.

Acute-on-chronic liver failure (ACLF) is a life-threatening syndrome characterized by systemic inflammation and immune dysregulation, in which macrophages play a key role in organ injury. This study aimed to investigate the role and mechanism of pyruvate dehydrogenase kinase 4 (PDK4) in ACLF to identify therapeutic targets that modulate macrophage function and mitigate ACLF progression.