Previous studies have highlighted the critical roles of complement proteins in hepatic regeneration, liver injuries, and diseases such as ALD, MASLD, and autoimmune hepatitis (AIH) [5-8]. These proteins, essential in the innate immune system, function through tightly regulated enzymatic cascades and are primarily produced by the liver [6,8]. The liver is susceptible to complement-mediated injury, as alterations in complement levels from liver disease itself can contribute to the exacerbation of liver disease pathogenesis. While complement proteins can be protective, promoting hepatocyte regeneration and liver cell proliferation and survival [8], their activation can also lead to increased inflammation and liver injury, amplifying local inflammation and potentially leading to fibrosis and cirrhosis [7]. In HCC, complement proteins have been implicated in tumorigenesis, metastasis, and immune suppression, suggesting that targeting these pathways could probably offer new therapeutic avenues [9]. The presence of complement proteins in various cell types, such as platelets and neutrophils, underscores their importance in the immune response to injury and pathogens, but also highlights how their rapid mobilization can exacerbate liver disease progression [10]. Given their important role in liver diseases, research into complement-targeted therapies holds promise for developing more effective treatments targeting CLD and HCC.

Although randomized controlled trials are considered the gold standard for establishing causal relationships between outcomes and exposures, performing such studies is not always possible due to various reasons. Therefore, Mendelian randomization (MR) serves as a method for causal inference using observational data and single nucleotide polymorphisms as instrumental variables to infer causal relationships. Although MR cannot replace RCTs, it can provide complementary information [11,12]. There are several MR studies that have reported the causal association between different complement components and certain diseases such as deep vein thrombosis [13], ischemic stroke [14], periodontitis [15], multiple myeloma [16], chronic prostatitis [17], and Alzheimer’s disease [18]. As establishing a causal relationship for the effect of complement components in causing liver diseases can be challenging due to the aforementioned reasons (e.g., inverse causality), MR studies can be useful in this regard. So far, no MR studies have assessed the relationship between complement components and CLDs.

Shi et al. [19] in a recently published paper assessed the causal association between 28 circulating complement components and CLDs, including alcohol-related cirrhosis (ALC), MASLD, and three major autoimmune liver diseases, namely AIH, primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC), and HCC, through two-sample MR. In this study, the authors found a significant association between genetically predicted complement component levels of C1q C chain (C1QC) with AIH, C8 gamma chain (C8G) and complement factor H-related protein 5 (CFHR5) with PSC, CFHR1, CFHR2, and C1QC with ALC, C8G with MASLD, and finally CFHR2, C7, and C15 with HCC using the inverse-variance weighted (IVW) method. No significant association was reported between any of the 28 evaluated complement components and PBC. Additionally, when evaluating causal association with the weighted median (WM) method, only a significant association for ALC with CFHR1 and CFHR2, and for HCC with C7 and C15, was reported. Next, using identified complement proteins associated with each liver disease, the authors investigated to identify liver disease-associated proteins from the complement protein-protein interaction network in biological processes. They utilized network-based drug repositioning to assess whether specific complement proteins could serve as pharmacological targets for the treatment of liver diseases. They identified effective drugs for different liver diseases, supported by experimental or clinical evidence.

Taken together, the results via MR and evaluation of common biological processes between both proteins associated with liver disease and from the complement regulatory network demonstrate that certain complement components may play important roles in some non-viral liver diseases and HCC. It should be noted that genome-wide association study (GWAS) data for six liver diseases and the selection of complement components as instrument variables were from Icelanders and European ancestries retrospectively. Therefore, future studies should confirm the association using other available GWAS data from other ancestries to confirm the generalizability of the results in a wider population with different ethnic backgrounds. Furthermore, some of the associations identified between complement proteins and liver diseases through the IVW method were not confirmed via WM. This implies that the associations lack consistency across all studies, displaying significant heterogeneity. It underscores the necessity of conducting additional studies to validate these findings. There may be mediators, such as diseases or conditions like oxidative stress or cytokines and chemokines [20] affecting the association between complement proteins and liver diseases, and they need to be considered when adjusting the demonstrated associations.

With a drug repositioning approach, the study has attempted to propose that the identified association between complement proteins and some non-viral diseases can have clinical utility. Although the authors provided some experimental and clinical evidence for each identified drug, no hospital cohort data or clinical trials specifically validated the findings of this study or the utility of these identified drugs. On the other hand, although the authors provided some common biological processes that both liver disease-associated proteins and proteins from the complement regulatory network are involved in, information specifically related to complement deregulation from immunological mechanisms is still limited, and more studies are needed to shed light on the mechanisms involved for possible different effects of the complement system on non-viral diseases. While this study hypothetically provides an opportunity for a better understanding of the direction in identifying novel therapeutics, it could be considered an exploratory analysis, and there is certainly a need for extensive preclinical and clinical studies to assess the potential of a drug for an earlier phase clinical trial.