Background and Aims: The risk factors of cholelithiasis have not been clearly identified, especially for total cholesterol. Here, we try to identify these causal risk factors. Approach and Results: We obtained genetic variants associated with the exposures at the genome‐wide significance (p < 5 × 10⁻⁸) level from corresponding genome‐wide association studies. Summary‐level statistical data for cholelithiasis were obtained from FinnGen and UK Biobank (UKB) consortia. Both univariable and multivariable Mendelian randomization (MR) analyses were conducted to identify causal risk factors of cholelithiasis. Results from FinnGen and UKB were combined using the fixed‐effect model. In FinnGen, the odds of cholelithiasis increased per 1‐SD increase of body mass index (BMI) (OR = 1.631, p = 2.16 × 10⁻⁷), together with body fat percentage (OR = 2.108, p = 4.56 × 10⁻³) and fasting insulin (OR = 2.340, p = 9.09 × 10⁻³). The odds of cholelithiasis would also increase with lowering of total cholesterol (OR = 0.789, p = 8.34 × 10⁻⁵) and low‐density lipoprotein–cholesterol (LDL‐C) (OR = 0.792, p = 2.45 × 10⁻⁴). However, LDL‐C was not significant in multivariable MR. In UKB, the results of BMI, body fat percentage, total cholesterol, and LDL‐C were replicated. In meta‐analysis, the liability to type 2 diabetes mellitus and smoking could also increase the risk of cholelithiasis. Moreover, there were no associations with other predominant risk factors. Conclusions: Our MR study corroborated the risk factors of cholelithiasis from previous MR studies. Furthermore, lower total cholesterol level could be an independent risk factor.

Infection with SARS-CoV-2, the causative agent of COVID-19, causes mild to moderate disease in most patients but carries a risk of morbidity and mortality. Seriously affected individuals manifest disorders of hemostasis and a cytokine storm, but it is not understood how these manifestations of severe COVID-19 are linked. Here, we showed that the SARS-CoV-2 spike protein engaged the CD42b receptor to activate platelets via 2 distinct signaling pathways and promoted platelet-monocyte communication through the engagement of P selectin/PGSL-1 and CD40L/CD40, which led to proinflammatory cytokine production by monocytes. These results explain why hypercoagulation, monocyte activation, and a cytokine storm are correlated in patients severely affected by COVID-19 and suggest a potential target for therapeutic intervention.

Objective: Different serum lipids and lipid-modifying targets should affect the risk of cholelithiasis differently, however, whether such effects are causal is still controversial and we aimed to answer this question. Design: We prospectively estimated the associations of four serum lipids with cholelithiasis in UK Biobank using the Cox proportional hazard model, including total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG). Furthermore, we estimated the causal associations of the genetically predicted serum lipids with cholelithiasis in Europeans using the Mendelian randomisation (MR) design. Finally, both drug-target MR and colocalisation analyses were performed to estimate the lipid-modifying targets’ effects on cholelithiasis, including HMGCR , NPC1L1 , PCSK9 , APOB, LDLR, ACLY, ANGPTL3, MTTP, PPARA, PPARD and PPARG . Results: We found that serum levels of LDL-C and HDL-C were inversely associated with cholelithiasis risk and such associations were linear. However, the serum level of TC was non-linearly associated with cholelithiasis risk where lower TC was associated with higher risk of cholelithiasis, and the serum TG should be in an inverted ‘U-shaped’ relationship with it. The MR analyses supported that lower TC and higher TG levels were two independent causal risk factors. The drug-target MR analysis suggested that HMGCR inhibition should reduce the risk of cholelithiasis, which was corroborated by colocalisation analysis. Conclusion: Lower serum TC can causally increase the risk of cholelithiasis. The cholelithiasis risk would increase with the elevation of serum TG but would decrease when exceeding 2.57 mmol/L. The use of HMGCR inhibitors should prevent its risk.

Kupffer cells are liver resident macrophages and play critical role in fatty liver disease, yet the underlying mechanisms remain unclear. Here, we show that activation of G-protein coupled receptor 3 (GPR3) in Kupffer cells stimulates glycolysis and protects mice from obesity and fatty liver disease. GPR3 activation induces a rapid increase in glycolysis via formation of complexes between β-arrestin2 and key glycolytic enzymes as well as sustained increase in glycolysis through transcription of glycolytic genes. In mice, GPR3 activation in Kupffer cells results in enhanced glycolysis, reduced inflammation and inhibition of high-fat diet induced obesity and liver pathogenesis. In human fatty liver biopsies, GPR3 activation increases expression of glycolytic genes and reduces expression of inflammatory genes in a population of disease-associated macrophages. These findings identify GPR3 activation as a pivotal mechanism for metabolic reprogramming of Kupffer cells and as a potential approach for treating fatty liver disease.

Hepatocellular carcinoma (HCC), the most prevalent malignancy of the digestive tract, is characterized by a high mortality rate and poor prognosis, primarily due to its initial diagnosis at an advanced stage that precludes any surgical intervention. Recent advancements in systemic therapies have significantly improved oncological outcomes for intermediate and advanced‐stage HCC, and the combination of locoregional and systemic therapies further facilitates tumor downstaging and increases the likelihood of surgical resectability for initially unresectable cases following conversion therapies. This shift toward high conversion rates with novel, multimodal treatment approaches has become a principal pathway for prolonged survival in patients with advanced HCC. However, the field of conversion therapy for HCC is marked by controversies, including the selection of potential surgical candidates, formulation of conversion therapy regimens, determination of optimal surgical timing, and application of adjuvant therapy post‐surgery. Addressing these challenges and refining clinical protocols and research in HCC conversion therapy is essential for setting the groundwork for future advancements in treatment strategies and clinical research. This narrative review comprehensively summarizes the current strategies and clinical experiences in conversion therapy for advanced‐stage HCC, emphasizing the unresolved issues and the path forward in the context of precision medicine. This work not only provides a comprehensive overview of the evolving landscape of treatment modalities for conversion therapy but also paves the way for future studies and innovations in this field.