Mechanistic insights of clinically proven natural products in the treatment of hepatitis B focusing on clinical evidence and pathways

• The therapeutic effects of clinically proven natural products against hepatitis B virus (HBV) in human patients are reported. • Despite the provision of an effective vaccine, HBV remains a major health concern worldwide, particularly among developing countries. • Natural compounds mediate their efficacy through modulating multiple signaling pathways and targeting receptors. • Therefore, clinically proven natural product formulas and samples of natural origin can be used as a complementary or alternative treatment option against HBV. Hepatitis B virus (HBV) is a major public health issue globally, although various licensed drugs and genetically engineered vaccines are available for HBV patients. However, due to drug resistance and dose-dependent side effects, they are only partially effective. This study was designed to explain the mechanistic aspects of only clinically proven natural products that have been shown to play a significant role against HBV. This review is based on comprehensive literature searches from PubMed, Elsevier, Science Direct, and Google Scholar databases using the keywords ‘hepatitis B virus’, ‘HBV’, ‘natural products in the treatment of HBV’, ‘clinically proven natural products in the management of HBV’ and keywords that are similar to those. Only natural products that have been clinically proven for their effects against HBV were selected for this study. The therapeutic efficiency of natural compounds and their possible mechanisms are described in this review. Natural products widely used to treat HBV include Lingmao Formula, Chinese Herbal Formula, Mushroom Agaricus blazei Murill Extract, Silymarin, Oxymatrine, and Vitamin E. These products showed significant preventive effects against HBV in a diverse study population. They appeared to show therapeutic effects through various physiological pathways, and importantly, none of them exhibited notable adverse effects in patients. This study suggests that the mentioned natural products are effective in treating HBV without causing notable adverse reactions. However, additional research is required to validate their precise molecular mechanisms and ensure their safety for human use. Graphical abstract summarizing the listed natural herbal formulas and samples of natural origin with their key molecular mechanisms against HBV.