Non-alcoholic fatty liver disease (NAFLD) is a global health burden closely linked to insulin resistance, obesity, and type 2 diabetes. The complex pathophysiology of NAFLD involves multiple cellular pathways and molecular factors. Nuclear receptors (NRs) have emerged as crucial regulators of lipid metabolism and inflammation in NAFLD, offering potential therapeutic targets for NAFLD. Targeting PPARs and FXRs has shown promise in ameliorating NAFLD symptoms and halting disease progression. However, further investigation is needed to address side effects and personalize therapy approaches. This review summarizes the current understanding of the involvement of NRs in the pathogenesis of NAFLD and explores their therapeutic potential. We discuss the role of several NRs in modulating lipid homeostasis in the liver, including peroxisome proliferator-activated receptors (PPARs), liver X receptors (LXRs), farnesoid X receptors (FXRs), REV-ERB, hepatocyte nuclear factor 4α (HNF4α), constitutive androstane receptor (CAR) and pregnane X receptor (PXR).The expanding knowledge of NRs in NAFLD offers new avenues for targeted therapies, necessitating exploration of novel treatment strategies and optimization of existing approaches to combat this increasingly prevalent disease.

Background: Disrupted protein homeostasis (proteostasis) has been demonstrated to facilitate the progression of various diseases. The cytosolic T‐complex protein‐1 ring complex (TRiC/CCT) was discovered to be a critical player in orchestrating proteostasis by folding eukaryotic proteins, guiding intracellular localisation and suppressing protein aggregation. Intensive investigations of TRiC/CCT in different fields have improved the understanding of its role and molecular mechanism in multiple physiological and pathological processes.Main body: In this review, we embark on a journey through the dynamic protein folding cycle of TRiC/CCT, unraveling the intricate mechanisms of its substrate selection, recognition, and intriguing folding and assembly processes. In addition to discussing the critical role of TRiC/CCT in maintaining proteostasis, we detail its involvement in cell cycle regulation, apoptosis, autophagy, metabolic control, adaptive immunity and signal transduction processes. Furthermore, we meticulously catalogue a compendium of TRiC‐associated diseases, such as neuropathies, cardiovascular diseases and various malignancies. Specifically, we report the roles and molecular mechanisms of TRiC/CCT in regulating cancer formation and progression. Finally, we discuss unresolved issues in TRiC/CCT research, highlighting the efforts required for translation to clinical applications, such as diagnosis and treatment.Conclusion: This review aims to provide a comprehensive view of TRiC/CCT for researchers to inspire further investigations and explorations of potential translational possibilities.

The TGF-β receptor kinase inhibitors (TRKI) have been reported to inhibit tumorigenicity in colon cancer. However, there is no direct evidence showing that these inhibitors function through inhibiting the TGF-β- mediated tumor-promoting effects in vivo. We established a TGF-β inducible reporter system by inserting a luciferase reporter gene to the vector downstream of TGF-β-inducible promoter elements, and transfected it into colon cancer cell lines. TRKIs SB431542 and LY2109761 were used to treat TGF-β inducible cells in vitro and in vivo. The luciferase activity was induced 5.24-fold by TGF-β in CT26 inducible cells, while it was marginally changed in MC38 inducible cells lacking Smad4 expression. Temporary treatment of mice with SB431542 inhibited the TGF-β pathway and TGF-β induced bioluminescence activity in vivo. Long-term treatment with LY2109761 inhibited tumorigenicity and liver metastasis in vivo in concomitant with reduced luciferase activity in the tumor. In this study, we established a model to monitor the TGF-β pathway in vivo and to compare the antitumor effects of TRKIs. Based on this novel experimental tool, we provided direct evidences that LY2109761 inhibits tumorigenicity and liver metastasis by blocking the pro-oncogenic functions of TGF-β in vivo.

Hepatoid adenocarcinoma of the pancreas is a rare primary malignant tumor. According to few previous reports, with poor prognosis and atypical clinical features, hepatoid adenocarcinoma of the pancreas is easily misdiagnosed. Its pathological examination often shows similar morphological and immunohistochemical features to those of hepatocellular carcinoma. There is also insufficient clinical experience in the diagnosis and treatment of hepatoid adenocarcinoma. A 45-year-old Asian woman, initially suspected to have late-stage pancreatic ductal adenocarcinoma, was admitted to our clinic with abdominal pain and jaundice. The magnetic resonance imaging scan showed a pancreatic head mass with enlarged retroperitoneal and portal lymph nodes. To confirm the diagnosis, a thorough evaluation of her medical history, clinical presentation, imaging findings, and laboratory tests was conducted. An endoscopic ultrasound-guided biopsy was performed, and the initial biopsy report suggested a neuroendocrine tumor. Based on this finding, a multidisciplinary team discussion was held, and the decision was made to proceed with radical surgery. Postoperative pathological examination unexpectedly revealed hepatoid adenocarcinoma of the pancreas, which led to a revision of the final clinical diagnosis. Following surgery, she received three cycles of postoperative adjuvant chemotherapy with a regimen of gemcitabine plus albumin-bound paclitaxel. Postoperative follow-up at 4 months indicated liver metastasis, for which she underwent microwave ablation. Subsequently, she was supplemented with adjuvant therapy combining durvalumab and S-1. At the time of writing, 16 months after her initial clinic visit, the patient remains alive without evidence of abdominal metastasis. This case of hepatoid adenocarcinoma of the pancreas achieved a better prognosis through a comprehensive treatment based on surgery after multidisciplinary team discussion, giving the patient hope for long-term survival. The multidisciplinary team, in the form of multidisciplinary experts coming together to discuss the patient’s condition, changed the patient’s treatment decision, which may be another option when it comes to complex cases.

Objectives This meta-analysis aims to evaluate the effect of n-3 polyunsaturated fatty acids (PUFAs) as a part of parenteral nutrition in patients undergoing liver surgery. Design Systematic review and meta-analysis. Data sources PubMed, the Cochrane Central Register of Controlled Trials, Springer link, Web of Science, China National Knowledge Infrastructure and VIP Database. Eligibility criteria We included randomised controlled trials (RCTs) and evaluated the outcomes of liver function, inflammatory reaction, the influence of certain markers of the immune system, and specific clinical indexes for patients undergoing liver surgery and receiving parenteral nutrition with n-3 PUFAs. Data extraction and synthesis The Cochrane Collaboration’s tool was used to assess the risk of bias for each study. Findings were summarised in Grades of Recommendation, Assessment, Development and Evaluation evidence profiles and synthesised qualitatively. Results Eight RCTs, including 748 patients (trial: 374; control: 374), were included in the meta-analysis. Compared with patients in the control group, the patients in the n-3 PUFA group who underwent liver surgery had significantly lower aspartate aminotransferase (mean difference, MD −42.72 (95% CI −71.91 to –13.52); p=0.004), alanine aminotransferase (MD −38.90 (95% CI −65.44 to –12.37); p=0.004), white cell count (MD −0.93 (95% CI −1.60 to –0.26); p=0.007) and IL-6 (MD −11.37 (95% CI −14.62 to –8.13); p<0.00001) levels and a higher albumin level (MD 0.42 (95% CI 0.26 to 0.57); p<0.00001). They also had fewer infection complications (OR 0.44 (95% CI 0.28 to 0.68); p=0.0003) and a shorter duration of hospital stay (MD −2.17 (95% CI −3.04 to –1.3); p<0.00001) than the controls. However, there were no significant differences in terms of total bilirubin, TNF-α, IL-2, IgA, IgG, IgM and CD3, biliary leakage and mortality between the two groups. Conclusions We found that n-3 PUFAs can benefit patients undergoing liver surgery by improving liver function and certain clinical indexes and decreasing related inflammation factors. However, there are limited RCTs on the application of n-3 PUFAs for patients undergoing liver surgery. Further evidence of the benefit of n-3 PUFAs in these patients warrants further exploration.

Jiayu SHI, Chao WANG, Binhao ZHANG*. Ann Hepatobiliary Pancreat Surg 2022;26:S53. https://doi.org/10.14701/ahbps.2022S1.BR-OP-2