Recently, the 75th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) was held in San Diego, USA. At the event, a team led by Dr. Hong Tang and Dr. Lang Bai from the Infectious Diseases Center of West China Hospital of Sichuan University, presented 11 research projects, with two of them receiving the prestigious "Poster of Distinction." Their work spanned critical areas, including hepatitis B (HBV), metabolic dysfunction-associated steatotic liver disease (MASLD), liver fibrosis, hepatocellular carcinoma (HCC), and acute-on-chronic liver failure (ACLF), showcasing significant advances from the Chinese infectious disease research community. This report highlights the key findings and breakthroughs.
Part 1: Hepatitis B
Imatinib Promotes HBV Reactivation via Oxidative Stress-Induced Incomplete Autophagy (Poster No. 1242)
Imatinib, a landmark drug in molecular targeted cancer therapy, carries a high risk of triggering HBV reactivation. In this study, Dr. Lingyao Du and Dr. Weixiu Li explored the underlying mechanisms by which imatinib induces HBV reactivation. HBV-infected hepatocyte lines (HepG2.2.15 and HepAD38) were treated with imatinib, and HBV expression levels were analyzed using Southern blot and ELISA. Oxidative stress and autophagy markers were evaluated through immunofluorescence and Western blot.
The results showed that imatinib treatment increased HBV DNA replication and viral protein expression while inducing oxidative stress, evidenced by elevated ROS and MDA levels. Imatinib also inhibited the downstream mTOR pathway, blocking autophagic flux and interfering with autophagosome maturation. This provided a replication niche for HBV and promoted its secretion. The antioxidant N-acetylcysteine mitigated imatinib-induced HBV reactivation and partially restored autophagic flux.
This study suggests that imatinib may trigger HBV reactivation through oxidative stress-induced incomplete autophagy and highlights antioxidant therapy as a potential strategy to prevent HBV reactivation.
Part 2: MASLD
CircPOLD1 Promotes MASLD Progression via Interaction with HuR (Poster of Distinction, No. 1009)
Circular RNA (circRNA) has emerged as a significant factor in diseases such as metabolic-associated steatotic liver disease (MASLD), yet its underlying mechanisms remain incompletely understood. The role of circRNA nuclear export and its interaction with RNA-binding proteins (RBPs) in MASLD pathogenesis is particularly unclear. Dr. Qingmin Zeng’s study aimed to elucidate the role of circPOLD1 in MASLD progression.
The research revealed that circPOLD1, derived from the POLD1 gene, is upregulated in liver tissues and cell models of MASLD patients. Silencing circPOLD1 promoted hepatic lipid transport and reduced lipid accumulation. Mechanistically, circPOLD1 interacts with the RNA-binding protein HuR, facilitating HuR’s translocation from the nucleus to the cytoplasm. This interaction activates the phosphorylation of Akt and FoxO1, leading to the suppression of microsomal triglyceride transfer protein expression.
Additionally, the SUMOylation of the RNA nuclear transport regulator DDX39A was found to regulate the nuclear retention of circPOLD1. These findings underscore the critical role of circPOLD1 in the pathogenesis of MASLD and provide insights into its regulatory mechanisms.
Part 3: Liver Fibrosis
HUC-MSC Exosome-Derived miR-100-5p Alleviates Liver Fibrosis by Inducing Autophagy in Hepatic Stellate Cells (Poster No. 3573)
Human umbilical cord-derived mesenchymal stem cell (hUC-MSC) exosomes have shown potential in treating liver fibrosis by delivering various factors. Dr. Yonghong Wang’s study investigated the therapeutic effects and mechanisms of hUC-MSC-derived exosomes in liver fibrosis.
The research demonstrated that hUC-MSC exosomes effectively inhibited liver fibrosis in both cell and animal models. High-throughput sequencing identified miR-100-5p as a highly expressed component within the exosomes. In vitro experiments revealed that miR-100-5p significantly suppressed the proliferation of LX-2 cells and the expression of fibrosis-related markers. Further analysis confirmed that the target gene of miR-100-5p is mTOR.
Moreover, exosomes overexpressing miR-100-5p markedly inhibited LX-2 cell proliferation and promoted apoptosis, effects that were influenced by autophagy inhibitors. This study uncovers a novel mechanism for stem cell exosome therapy in liver fibrosis, highlighting the therapeutic potential of miR-100-5p in regulating fibrosis through autophagy-related pathways.
Part 4: Hepatocellular Carcinoma (HCC)
- HBV Upregulates GRP78 to Promote Glucose Uptake and HCC Progression (Poster of Distinction, No. 1273)
Endoplasmic reticulum stress (ERS) is known to promote hepatocellular carcinoma (HCC) progression, and glucose-regulated protein 78 (GRP78) plays a critical role in ERS. However, the role of GRP78 in HBV-related HCC development remains unclear. In this study, Associate Professor Lingyao Du and Dr. Miao Liu investigated how HBV regulates glucose uptake in host cells via GRP78 to promote HCC progression.
The results showed that GRP78 overexpression increased glucose uptake and lactate production by upregulating GLUT1. In vitro experiments demonstrated that knocking down GLUT1 reduced glucose uptake, lactate production, and cell proliferation. Furthermore, HBV upregulated the GRP78-GLUT1 pathway, enhancing glucose uptake and lactate production in host cells.
In vivo experiments using PET/CT imaging revealed that GLUT1 knockdown reduced glucose uptake in subcutaneous tumors and inhibited tumor formation in nude mice. Compared to L02 cells, L02-pHBV4.1 xenografts exhibited increased glucose uptake, larger tumor volumes, and significantly higher expression levels of GRP78, GLUT1, and Ki67 in tumor tissues.
These findings indicate that HBV may enhance glucose uptake and glycolysis through the GRP78-GLUT1 pathway, promoting cell proliferation and contributing to HCC progression.
2. RNA-Binding Protein Trx Regulates Alternative Splicing to Promote HCC Metastasis (Poster No. 3390)
Epithelial-mesenchymal transition (EMT) plays a central role in hepatocellular carcinoma (HCC) metastasis, with RNA-binding proteins (RBPs) being key contributors. Dr. Xiangnan Teng and Dr. Jin Shang conducted a study to investigate the mechanisms by which RBPs promote HCC metastasis.
Using whole-transcriptome sequencing, the team identified differentially expressed RBPs. In vitro and in vivo experiments confirmed their impact on metastasis. RNA immunoprecipitation and pull-down assays were used to evaluate the interactions between RBPs and non-coding RNAs, while RNA-seq and alternative splicing analyses elucidated the post-transcriptional regulatory mechanisms.
The study revealed that Trx expression was upregulated in metastatic HCC patients and associated with poor prognosis. Overexpression of Trx promoted HCC cell migration, invasion, and lung metastasis. Mechanistically, Trx interacted with the non-coding RNA LINC00152, regulating alternative splicing programs targeting ANGPT1, which in turn activated the PI3K-Akt-mTOR pathway to drive cancer metastasis.
This research highlights the role of Trx in regulating alternative splicing and promoting HCC metastasis, suggesting that Trx could serve as a novel therapeutic target for HCC treatment.
- BMP9 Regulates Cell Cycle via CKS1B Lactylation in HCC (Poster No. 4234)
BMP9 plays a pivotal role in the progression of hepatocellular carcinoma (HCC). Lactylation, a post-translational modification occurring on lysine residues (K) of proteins, can significantly affect protein structure and function. However, the role of BMP9 in regulating protein lactylation in HCC remains unclear.
Dr. Han Chen’s study explored the effects of BMP9 and the BMP receptor inhibitor LDN-212854 on protein lactylation levels in HCC both in vitro and in vivo. The findings showed that BMP9 increased protein lactylation levels in HCC cell models in vitro, while LDN-212854 reduced lactylation levels. In a mouse xenograft model, LDN-212854 inhibited tumor growth and decreased the levels of lactylated proteins in tumor tissues.
Proteomic and metabolomic analyses of lactylation-modified proteins in LDN-212854-treated Hep3B cells identified significant reductions in lactylation levels of cell cycle-related proteins, including CKS1B-K4, CKS2-K4, DCAF1-K284, RBL1-K1015, and CDC37-K126. Among these, CKS1B-K4 showed the greatest reduction. Mutation of the lysine (K) residue at CKS1B-K4 to arginine (R) to mimic delactylation significantly inhibited HCC cell proliferation and cell cycle progression.
This study highlights the critical role of BMP9 in regulating protein lactylation in HCC. It identifies CKS1B-K4 as a key regulator of the cell cycle in HCC cells and a potential target for interventions targeting the BMP signaling pathway in liver cancer treatment.
Part 5: Acute-on-Chronic Liver Failure (ACLF)
- Artificial Liver Support Systems Improve Short-Term Outcomes in HBV-ACLF (Poster No. 4024)
HBV-ACLF and the Role of Artificial Liver Support Systems (ALSS)
Hepatitis B-related acute-on-chronic liver failure (HBV-ACLF) is a rapidly progressing and life-threatening clinical syndrome. Artificial liver support systems (ALSS) are commonly used to eliminate toxins and metabolites from the body, aiding in the recovery of liver function in patients with liver failure. However, the efficacy of ALSS has required further validation.
Dr. Kunping Cui’s retrospective cohort study included 940 HBV-ACLF patients diagnosed using the COSSH-ACLF criteria between 2015 and 2021. The study found that the 28-day mortality rate in the ALSS group was significantly lower compared to the non-ALSS group. However, no significant differences were observed at 60 and 90 days. Multivariate COX regression analysis further demonstrated that ALSS reduced mortality at 28, 60, and 90 days. Additional model analyses yielded consistent results.
This study provides evidence that ALSS effectively reduces short-term mortality in HBV-ACLF patients, making it a valuable therapeutic option.
Impact of Plasma Adsorption (PA) and Low-Volume Plasma Exchange (LVPE) on Intracranial Pressure (ICP) in ACLF Patients
Research is ongoing to explore how therapies such as PA and LVPE influence intracranial pressure in patients with acute-on-chronic liver failure (ACLF). Let me know if you’d like the details of this section expanded further!
Impact of Plasma Adsorption and Low-Volume Plasma Exchange on Intracranial Pressure in ACLF (Poster No. 4026)
Effects of Plasma Adsorption (PA) and Low-Volume Plasma Exchange (LVPE) on Intracranial Pressure (ICP) in ACLF Patients
Patients with acute-on-chronic liver failure (ACLF) may experience complications such as cerebral edema and elevated intracranial pressure (ICP). However, the impact of plasma adsorption (PA) and low-volume plasma exchange (LVPE) on ICP remains unclear.
In a prospective observational cohort study led by Dr. Lang Bai and Dr. Yuanji Ma, ICP, mean arterial pressure (MAP), and cerebral perfusion pressure (CPP) were repeatedly measured using transcranial Doppler (TCD) and flash visual evoked potential (FVEP). The study enrolled 31 HBV-ACLF patients with a median MELD 3.0 score of 27.8. Differences were assessed using generalized estimating equations.
Key findings include:
- No significant changes in average ICP were observed after PA, LVPE, or 2 hours post-treatment compared to pre-treatment values, as measured by FVEP.
- MAP increased significantly after LVPE (P < 0.001) and 2 hours post-treatment (P = 0.015) compared to levels before LVPE (after PA).
- CPP also improved significantly after LVPE (P = 0.008) compared to pre-treatment levels (after PA).
- TCD measurements corroborated these findings, showing similar results to FVEP.
The study concludes that while PA and LVPE may not significantly affect ICP, LVPE could improve MAP and CPP, suggesting potential benefits for maintaining cerebral perfusion in ACLF patients.
High Systemic Immune Inflammation Index (SII) Positively Correlates With Poor Short-Term Prognosis in ACLF Patients
- Systemic Immune Inflammation Index (SII) Predicts Poor Prognosis in ACLF (Poster No. 4027)
The Systemic Immune Inflammation Index (SII) is an independent prognostic factor in various diseases, but its role in predicting outcomes in acute-on-chronic liver failure (ACLF) patients has been less studied. In a retrospective study conducted by Professor Lang Bai and Dr. Yuanji Ma, 258 ACLF patients treated with artificial liver support systems (ALSS) were analyzed. The study revealed the following findings:
- The 90-day transplant-free survival rate was 58.5%, and the overall survival rate was 66.3%.
- The median SII was 465.5.
- Adjusted restricted cubic spline (RCS) modeling demonstrated a linear exposure-response relationship between SII levels and 90-day transplant-free and overall survival rates.
- Cox regression analysis confirmed a positive correlation between high SII and poor survival outcomes.
Patients with SII ≥ 480 were found to have more severe conditions, lower 90-day transplant-free survival rates, and lower overall survival rates compared to those with SII < 480.
This study highlights that higher SII levels are significantly associated with poor short-term prognosis in ACLF patients, suggesting that SII could serve as a useful prognostic marker in this population.
Correlation Between Platelet Levels (PLT) and Bleeding Events in ACLF Patients
- Platelet Levels and Bleeding Risk in ACLF Patients Undergoing ALSS (Poster No. 4028)
Patients with chronic liver disease often experience reduced platelet (PLT) levels, which increases the risk of bleeding. However, the relationship between PLT levels and bleeding events in acute-on-chronic liver failure (ACLF) patients undergoing artificial liver support systems (ALSS) treatment remains unclear.
In this retrospective study led by Dr. Lang Bai and Dr. Yuanji Ma, 262 ACLF patients were analyzed, of whom 56 experienced bleeding events during hospitalization. The study evaluated the association between baseline PLT levels, the frequency of ALSS treatment, and bleeding events, as well as the relationship between PLT reduction rates and bleeding risks.
Key findings include:
- Patients who experienced bleeding events had significantly lower baseline PLT levels compared to those who did not.
- Baseline PLT levels were negatively correlated with bleeding events, while the PLT reduction rate and the most recent PLT levels showed no significant association with bleeding events.
- Compared to patients with baseline PLT grade 0, those with grades 1, 2, and 2-3 had an increased risk of bleeding.
- The frequency of ALSS treatment was not correlated with the rate of PLT reduction.
This study indicates that lower baseline PLT levels are associated with a higher risk of bleeding events in ACLF patients during hospitalization, emphasizing the need to monitor and manage PLT levels to reduce bleeding complications.
- Optimal Plasma Volume for DPMAS Treatment in Severe Liver Disease (Poster No. 4029)
The appropriate plasma volume processed (VPP) during dual plasma molecular adsorption system (DPMAS) therapy for severe liver disease remains uncertain. In this prospective observational study, led by Dr. Lang Bai and Dr. Yuanji Ma, the relationship between VPP and changes in total bilirubin levels was investigated.
A total of 29 patients with severe liver disease undergoing DPMAS therapy were included. Total bilirubin levels were repeatedly measured at four different time points corresponding to increasing plasma volumes:
· 0.0 hours (0 mL)
· 2.0 hours (3000 mL)
· 2.5 hours (3750 mL)
· 3.0 hours (4500 mL)
The results revealed:
· Total bilirubin levels decreased progressively across all four VPP time points (P < 0.001).
· The reduction in total bilirubin levels was similar in patients with baseline bilirubin ≥ 425 μmol/L and those with < 425 μmol/L (adjusted odds ratio: 1.001).
· Among patients with greater height or lower albumin levels, the positive correlation between VPP and bilirubin reduction was not significant.
The study concludes that the optimal VPP for DPMAS therapy can reach 4500 mL, especially for patients with greater height or lower albumin levels. These findings provide valuable clinical guidance for the application of DPMAS in the treatment of severe liver disease.
