This study evaluated the association between HMGCR inhibitors and CHB, focusing on the mediating role of circulating metabolites. The results showed that genetic variation in the HMGCR inhibitor target gene is linked to a reduced risk of CHB (OR = 0.858, 95% CI 0.742–0.992, P = 0.038). Notably, the circulating metabolite citrate mediates 9.769% of the total effect of HMGCR inhibitors on CHB.

Statins, commonly used HMGCR inhibitors, have been extensively studied for their role in CHB, with mixed results. Liang et al.’s meta-analysis indicated an 18% increased risk of liver injury with HMGCR inhibitors¹⁸. Conversely, Vahedian-AzimiA et al. found that long-term statin treatment is safe for hepatitis patients and can improve their prognosis⁵. This study provides robust evidence for the protective effect of HMGCR inhibitors on CHB by utilizing genetic variation in HMGCR target genes and GWAS data. HMGCR is the rate-limiting enzyme in cholesterol synthesis. Recent studies have shown that HBV infection increases HMGCR expression, promoting cholesterol uptake and synthesis, which is crucial for viral particle formation. Targeting HMGCR to inhibit its expression can reduce cholesterol biosynthesis, thereby inhibiting HBV production^12,19,20, which is significant for CHB progression and treatment. Additionally, statins possess various pleiotropic effects, such as improving endothelial dysfunction and exhibiting antioxidant, antifibrotic, anti-inflammatory, antiproliferative, antiangiogenic, antithrombotic, and immunomodulatory properties, all beneficial for liver health^21,22,23. Statins also act as free radical scavengers, reducing oxidative stress and slowing cirrhosis progression^24,25. They also help control the inflammatory response in cirrhosis by inhibiting excessive production of free radicals and other harmful by-products, thereby preventing liver cell damage and fibrosis to some extent²⁶.

Targeted metabolomics studies have shown that changes in circulating metabolites are associated with CHB development^11,27,28. Previous research has identified metabolic changes caused by HBV infection, including upregulation of glutamate dehydrogenase 1 and isocitrate dehydrogenase²⁹, and transcriptional upregulation of lipid biosynthesis genes³⁰. HBV-induced lipid metabolism changes have also been observed in cell models and HBV transgenic mice³¹. These metabolic abnormalities not only promote virus replication but also contribute to liver cell damage, fibrosis, and even liver cancer by activating endoplasmic reticulum stress (ERS), oxidative stress, and inflammatory signaling pathways³². These findings suggest a link between HBV infection and host cell metabolic changes, making metabolic pathways potential drug targets for CHB treatment^10,12,33.

Our study confirmed that 10 metabolites, primarily lipid metabolites, associated with the pathogenesis of chronic hepatitis B. Additionally, our findings confirmed a significant causal relationship between HMGCR inhibitors and 151 circulating metabolites. Furthermore, eight circulating metabolites demonstrated a significant causal relationship with both HMGCR inhibitors and CHB, with citrate emerging as a key intermediary variable in this association based on mediation effect calculations.

Citrate, an important intermediate in the tricarboxylic acid cycle, plays a crucial role in liver metabolism. Patients with CHB often develop fatty liver due to abnormalities in liver fat metabolism^34,35, as viral infection and liver damage impair metabolic functions, including the tricarboxylic acid cycle¹¹. This disruption can alter citrate levels, which are essential for fatty acid synthesis^36,37,38. Changes in citrate levels may contribute to liver damage in CHB patients by affecting lipogenesis, ultimately compromising liver health^39,40. Furthermore, CHB patients frequently experience ongoing oxidative stress, in which citrate is involved^41,42, further exacerbating liver damage and inflammation^34,41. Additionally, citrate can regulate inflammatory responses by affecting inflammatory pathways^43,44. Chronic inflammation in CHB patients is a key factor leading to liver fibrosis and cirrhosis^45,46. Thus, citrate may mediate the effects of HMGCR inhibitors on CHB. However, Mendel’s randomized study has its limitations. Although citrate is determined to be a medium, the exact biological mechanism of citrate affecting the progress of chronic hepatitis B is still unclear. Combined with citrate being an important substance in the tricarboxylic acid cycle and previous research results, citrate is most likely to play its mediating role in controlling the development of CHB by affecting lipid metabolism, but further cell molecular biology research is needed for further confirmation.

This study used MR with existing genetic and health data from the IEU database, revealing how genetic variations mediate the beneficial effects of HMGCR inhibitors on CHB through citrate. MR studies avoid the expensive and time-consuming process of new data collection and are less affected by confounding factors, providing clearer insights into genetic variation impacts on CHB. However, the observed mediational association may not imply causality and requires further experimental verification.

This research provides a theoretical basis for using statins in CHB treatment (repurposing existing drugs) and identifies potential targets for developing new, more effective drugs based on genetic variations in HMGCR inhibitor target genes. Our findings suggest that citrate may mediate the therapeutic effect of HMGCR inhibitors on CHB, presenting a promising therapeutic target.

Despite its strengths, this study has several limitations. The genetic variants simulating HMGCR inhibitors may not reflect their short-term effects, as they only indicate causal direction, not the extent of the effect. Partial overlap between GWAS data of HMGCR inhibitors and circulating metabolites samples may introduce bias in estimating causal effects, although the high F statistics (all > 10) for the genetic variants minimize this risk. Additionally, since our MR analysis was based on public summary data from the GWAS database rather than individual-level data, a more comprehensive exploration was not possible. Finally, since all the populations used were European, the generalizability of the results to other populations may be limited.

In conclusion, this study supports genetically predicted associations between HMGCR inhibitors, circulating metabolites, and CHB, highlighting citrate’s mediating role. These findings provide genetic evidence for the mechanism by which HMGCR inhibitors may affect CHB treatment and highlight potential new targets for drug development, offering valuable insights for future mechanistic and clinical studies.