Progress of research on the role of active ingredients of Citri Reticulatae Pericarpium in liver injury

Liver is a vital organ responsible for metabolizing and detoxifying both endogenous and exogenous substances in the body. However, it is susceptible to damage from chemical and natural toxins. The high incidence and mortality rates of liver disease and its associated complications impose a significant economic burden and survival pressure on patients and their families. Various liver diseases exist, including cholestasis, viral and non-viral hepatitis, fatty liver disease, drug-induced liver injury, alcoholic liver injury, and severe end-stage liver diseases such as cirrhosis, hepatocellular carcinoma (HCC), and cholangiocellular carcinoma (CCA). Recent research has shown that flavonoids found in Citri Reticulatae Pericarpium (CRP) have the potential to normalize blood glucose, cholesterol levels, and liver lipid levels. Additionally, these flavonoids exhibit anti-inflammatory properties, prevent oxidation and lipid peroxidation, and reduce liver toxicity, thereby preventing liver injury. Given these promising findings, it is essential to explore the potential of active components in CRP for developing new drugs to treat liver diseases. Recent studies have revealed that flavonoids, including hesperidin (HD), hesperetin (HT), naringenin (NIN), nobiletin (NOB), naringin (NRG), tangerine (TN), and erodcyol (ED), are the primary bioactive components in CRP. These flavonoids exhibit various therapeutic effects on liver injury, including anti-oxidative stress, anti-cytotoxicity, anti-inflammatory, anti-fibrosis, and anti-tumor mechanisms. In this review, we have summarized the research progress on the hepatoprotective effects of HD, HT, NIN, NOB, NRG, TN, ED and limonene (LIM), highlighting their underlying molecular mechanisms. Despite their promising effects, the current clinical application of these active ingredients in CRP has some limitations. Therefore, further studies are needed to explore the full potential of these flavonoids and develop new therapeutic strategies for liver diseases. For this review, we conducted a systematic search of three databases (ScienceNet, PubMed, and Science Direct) up to July 2022, using the search terms "CRP active ingredient," "liver injury," and "flavonoids." The search data followed the PRISMA standard. Our findings indicate that flavonoids found in CRP can effectively reduce drug-induced liver injury, alcoholic liver injury, and non-alcoholic liver injury. These therapeutic effects are mainly attributed to the ability of flavonoids to improve liver resistance to oxidative stress and inflammation while normalizing cholesterol and liver lipid levels by exhibiting anti-free radical and anti-lipid peroxidation properties. Our review provides new insights into the potential of active components in CRP for preventing and treating liver injury by regulating various molecular targets within different cell signaling pathways. This information can aid in the development of novel therapeutic strategies for liver disease.