Elevated de novo lipogenesis is considered to be a crucial factor in hepatocellular carcinoma (HCC) development. Herein, we identify ubiquitin-specific protease 22 (USP22) as a key regulator for de novo fatty acid synthesis, which directly interacts with deubiquitinates and stabilizes peroxisome proliferator-activated receptor gamma (PPARγ) through K48-linked deubiquitination, and in turn, this stabilization increases acetyl-CoA carboxylase (ACC) and ATP citrate lyase (ACLY) expressions. In addition, we find that USP22 promotes de novo fatty acid synthesis and contributes to HCC tumorigenesis, however, this tumorigenicity is suppressed by inhibiting the expression of PPARγ, ACLY, or ACC in in vivo tumorigenesis experiments. In HCC, high expression of USP22 positively correlates with PPARγ, ACLY or ACC expression, and associates with a poor prognosis. Taken together, we identify a USP22-regulated lipogenesis mechanism that involves the PPARγ-ACLY/ACC axis in HCC tumorigenesis and provide a rationale for therapeutic targeting of lipogenesis via USP22 inhibition.

Objective: Pancreatic cancer is a globally frequent cause of death, which can be caused by many factors. This meta-analysis was performed to assess the correlation between pancreatic cancer and metabolic syndrome (MetS).Methods: Publications were identified by searching PubMed, EMBASE, and the Cochrane Library for studies published until November 2022. Case-control and cohort studies published in English that provided information on the odds ratio (OR), relative risk (RR), or hazard ratio (HR) of metabolic syndrome and pancreatic cancer were included in the meta-analysis. Two researchers separately retrieved the core data from the included Random effects meta-analysis was conducted to summarize the findings. Results were presented as relative risk (RR) and 95% confidence interval (CI).Results: MetS showed a strong association with an increased risk of developing pancreatic cancer (RR1.34, 95% CI1.23–1.46, P<0.001), and gender differences were also observed (men: RR 1.26, 95% CI 1.03–1.54, P=0.022; women: RR 1.64, 95% CI 1.41–1.90, P< 0.001). Moreover, an increased risk of developing pancreatic cancer was strongly linked to hypertension, poor high-density lipoprotein cholesterol, and hyperglycemia (hypertension: RR 1.10 CI 1.01–1.19, P=0.027; low high-density lipoprotein cholesterol: RR 1.24 CI 1.11–1.38, P<0.001; hyperglycemia: RR 1.55, CI 1.42–1.70, P< 0.001). However, pancreatic cancer was independent of obesity and hypertriglyceridemia (obesity: RR 1.13 CI 0.96–1.32, P=0.151, hypertriglyceridemia: RR 0.96, CI 0.87–1.07, P=0.486).Conclusions: Although further prospective studies are required for confirmation, this meta-analysis indicated a strong relationship between MetS and pancreatic cancer. Regardless of gender, a greater risk of pancreatic cancer existed in people with MetS. Patients with MetS were more likely to develop pancreatic cancer, regardless of gender. Hypertension, hyperglycemia, and low HDL-c levels may largely account for this association. Further, the prevalence of pancreatic cancer was independent of obesity and hypertriglyceridemia.Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42022368980.

Objective: This study evaluated the prognostic significance of preoperative neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), lymphocyte to monocyte ratio (LMR) and tumor-infiltrating lymphocytes (TILs), and whether these preoperative blood inflammatory indicators were associated with TILs in hilar cholangiocarcinoma (HCCA).Methods: A total of 76 patients with HCCA who underwent radical resection were included. Data on their clinicopathologic characteristics, perioperative features, and survival outcomes were analyzed. The optimal cutoff levels for the NLR, PLR and LMR were defined by using the web application Cut-off Finder. The densities of specific immune cells (CD3⁺, CD4⁺, CD8⁺) within the tumor microenvironment were examined by immunohistochemical. The association of the number of CD3⁺, CD4⁺ and CD8⁺ T cells infiltration in the local tumor microenvironment with preoperative NLR, PLR and LMR level was analyzed. Survival curves were calculated using the Kaplan–Meier estimate. Univariate and multivariate logistic regression models were used to identify factors associated with overall survival.Results: The optimal cutoff value of preoperative NLR, PLR and LMR was 2.00, 117.60, and 4.02, respectively. NLR was significantly negatively correlated with CD3⁺ and CD8⁺ T cell infiltration, but not with CD4⁺ T cells. PLR had no correlation with CD3⁺, CD4⁺, or CD8⁺ T cell infiltration, while LMR had a significantly positive correlation with CD3⁺ T cells infiltration but not with CD4⁺ or CD8⁺ T cells. In the multivariate logistic regression model, T stage, lymph node metastasis, CA19-9 and LMR were independent risk factors associated with overall survival (OS). Survival curves indicated that HCCA patients with low CD3⁺ T cells infiltration and low preoperative LMR live shorter than others.Conclusions: LMR played as an independent factor for predicting the survival in patients with HCCA after R0 radical resection. A high LMR was associated with an accumulation of CD3⁺ T cells in HCCA.

Background: Subclinical hypothyroidism (SCH) is a common endocrine subclinical disorder, the main adverse consequences of which are the development of clinical hypothyroidism and the promotion of ischemic heart disease. Metabolic syndrome (MetS) is a collection of metabolic problems. The goal of this meta-analysis was to evaluate the relationship between MetS and SCH.Methods: Suitable publications were identified using PubMed, Embase, and the Cochrane Library. The meta-analysis included only studies in English that reported odds ratio (OR) data for MetS and SCH. Two researchers combined data using a random-effects model. OR and 95% confidence intervals (CIs) were used to present the results.Results: MetS was associated with an elevated risk of developing SCH (OR 2.56, 95% CI 1.44–4.55). However, the individual components of MetS were not associated with the risk of SCH. Subgroup analysis revealed that different definitions of MetS had varying effects on SCH. Sensitivity analysis confirmed that our results were robust.Conclusions: This meta-analysis indicates that patients with MetS have an increased risk of SCH, while there is no significant association between the five individual components of MetS and the risk of SCH.Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023454415.

Hepatocellular carcinoma (HCC) displays a high degree of metabolic and phenotypic heterogeneity and has dismal prognosis in most patients. Here, a gas chromatography–mass spectrometry (GC-MS)-based nontargeted metabolomics method was applied to analyze the metabolic profiling of 130 pairs of hepatocellular tumor tissues and matched adjacent noncancerous tissues from HCC patients. A total of 81 differential metabolites were identified by paired nonparametric test with false discovery rate correction to compare tumor tissues with adjacent noncancerous tissues. Results demonstrated that the metabolic reprogramming of HCC was mainly characterized by highly active glycolysis, enhanced fatty acid metabolism and inhibited tricarboxylic acid cycle, which satisfied the energy and biomass demands for tumor initiation and progression, meanwhile reducing apoptosis by counteracting oxidative stress. Risk stratification was performed based on the differential metabolites between tumor and adjacent noncancerous tissues by using nonnegative matrix factorization clustering. Three metabolic clusters displaying different characteristics were identified, and the cluster with higher levels of free fatty acids (FFAs) in tumors showed a worse prognosis. Finally, a metabolite classifier composed of six FFAs was further verified in a dependent sample set to have potential to define the patients with poor prognosis. Together, our results offered insights into the molecular pathological characteristics of HCC.

Background: Numerous studies have reported sarcopenia to be associated with unfavorable outcomes in patients who have undergone pancreatectomy. Therefore, in this meta-analysis, we examined the relationship between sarcopenia and survival after pancreatic surgery.Methods: PubMed, Embase, and Cochrane Library were searched for studies that examined the association between sarcopenia and survival after pancreatic surgery from the inception of the database until June 1, 2023. Hazard ratio (HR) for overall survival (OS) and/or progression-free survival (PFS) of sarcopenia and pancreatic surgery were extracted from the selected studies and random or fixed-effect models were used to summarize the data according to the heterogeneity. Publication bias was assessed using Egger’s linear regression test and a funnel plot.Results: Sixteen studies met the inclusion criteria. For 13 aggregated univariate and 16 multivariate estimates, sarcopenia was associated with decreased OS (univariate analysis: HR 1.69, 95% CI 1.48–1.93; multivariate analysis: HR 1.69; 95% CI 1.39–2.05, I² = 77.4%). Furthermore, sarcopenia was significantly associated with poor PFS of pancreatic resection (Change to univariate analysis: HR 1.74, 95% CI 1.47–2.05; multivariate analysis: HR 1.54; 95% CI 1.23–1.93, I² = 63%).Conclusion: Sarcopenia may be a significant prognostic factor for a shortened survival following pancreatectomy since it is linked to an elevated risk of mortality. Further studies are required to understand how sarcopenia affects long-term results after pancreatic resection.Systematic review registrationRegistration ID: CRD42023438208 https://www.crd.york.ac.uk/PROSPERO/#recordDetails.