Aims: Antiplatelet therapy has been reported to reduce liver fibrosis and hepatocellular carcinoma (HCC), and has exhibited antitumor properties in other cancers. However, the effects of antiplatelet therapy after diagnosis of HCC are unknown. We investigated the effects of antiplatelet therapy on prognosis, tumor progression, liver function and safety in HCC patients. Methods: We retrospectively analyzed 772 HCC patients. Antiplatelet therapy was defined as the regular intake of aspirin or clopidogrel from HCC diagnosis through to an endpoint of either overall survival (OS) or liver-related death. Overall survival, liver-related death, tumor progression, Child–Pugh deterioration and hemorrhage were analyzed for patients who either had or had not undertaken antiplatelet therapy. Results: The numbers of patients who did and did not undertake antiplatelet therapy were 111 and 661, respectively. Patients who undertook antiplatelet therapy were older and had better liver function at diagnosis. Antiplatelet therapy resulted in significant improvements in OS (p < 0.01) and lower risk of liver-related death (p < 0.01). Multivariate Cox regression analysis revealed that antiplatelet therapy had a significant negative association with liver-related death (hazard ratio (HR): 0.64, 95% confidence interval (CI): 0.44–0.93, p = 0.02). In patients who underwent transcatheter arterial chemoembolization (TACE) as the first treatment, antiplatelet therapy prevented tumor progression (p < 0.01) and Child–Pugh deterioration (p < 0.01). Antiplatelet therapy did not increase the risk of hemorrhagic events. Conclusions: Antiplatelet therapy reduced liver-related death and improved OS safely in HCC patients.

Zinc is an essential trace element and plays critical roles in cellular integrity and biological functions. Excess copper induced both oxidative stress and endoplasmic reticulum (ER) stress in liver-derived cultured cells. Excess copper also induced impairment of autophagic flux at the step of autophagosome–lysosome fusion, as well as Mallory–Denk body (MDB)-like inclusion body formation. Zinc ameliorated excess copper-induced impairment of autophagic flux and MDB-like inclusion body formation via the maintenance of ER homeostasis. Furthermore, zinc also ameliorated free fatty acid-induced impairment of autophagic flux. These results indicate that zinc may be able to protect hepatocytes from various ER stress-related conditions.

Increased circulating levels of free fatty acids, especially saturated ones, are involved in disease progression in the non-alcoholic fatty liver. Although the mechanism of saturated fatty acid-induced toxicity in the liver is not fully understood, oxidative stress may be deeply involved. We examined the effect of increased palmitic acid, the most common saturated fatty acid in the blood, on the liver of BALB/c mice via tail vein injection with palmitate. After 24 h, among several anti-oxidative stress response genes, only heme oxygenase-1 (HO-1) was significantly upregulated in palmitate-injected mice compared with that in vehicle-injected mice. Elevation of HO-1 mRNA was also observed in the fatty liver of high-fat-diet-fed mice. To further investigate the role of HO-1 on palmitic acid-induced oxidative stress, in vitro experiments were performed to expose palmitate to HepG2 cells. SiRNA-mediated knockdown of HO-1 significantly increased the oxidative stress induced by palmitate, whereas pre-treatment with SnCl₂, a well-known HO-1 inducer, significantly decreased it. Moreover, SB203580, a selective p38 inhibitor, reduced HO-1 mRNA expression and increased palmitate-induced oxidative stress in HepG2 cells. These results suggest that the HO-1-mediated anti-oxidative stress compensatory reaction plays an essential role against saturated fatty acid-induced lipotoxicity in the liver.

Background/Objectives: Durvalumab plus Tremelimumab (Dur/Tre) therapy is expected to have good therapeutic efficacy for patients with advanced hepatocellular carcinoma (HCC). However, the predictors of clinical response and prognosis have not been established. Here, we retrospectively investigated the predictors for therapeutic response and clinical prognosis of Dur/Tre therapy. Methods: This retrospective single-center study, which included 30 patients, aimed to evaluate predictors of treatment efficacy of Dur/Tre therapy for advanced HCC. Factors associated with an objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and immune-mediated adverse events (imAEs) were examined. We especially focused on the initial change in peripheral lymphocyte count at 2 weeks after Dur/Tre introduction from baseline (Δlymphocyte). Results: Seventeen patients (56.7%) diagnosed with HCC BCLC stage C were enrolled. The median observational period was 11 months. The ORR and disease control rate (DCR) were 30.0% and 53.3%, respectively. The median PFS was 3.7 months and OS was not reached. The high Δlymphocyte was an independent predictor of objective response (hazard ratio [HR], 1.004; p = 0.016). The high Δlymphocyte (above +245/µL) was an independent predictive factor for better PFS (HR, 0.308; 95% CI, 0.095–0.998; p = 0.049), and the median PFS was significantly prolonged in the high Δlymphocyte (above +245/µL) compared to low Δlymphocyte (less than +245/µL) (not reached vs. 1.96 months, log-rank p = 0.003). Conclusions: In Dur/Tre therapy, the early increase in peripheral blood lymphocyte count was useful for predicting clinical response and prognosis.