Kaempferol attenuates liver fibrosis by inhibiting activin receptor–like kinase 5

Abstract

Liver fibrosis is a common public health problem. Patients with liver fibrosis are more likely to develop cirrhosis, or hepatocellular carcinoma (HCC) as a more serious consequence. Numerous therapeutic approaches have emerged, but the final clinical outcome remains unsatisfactory. Here, we discovered a flavonoid natural product kaempferol that could dramatically ameliorate liver fibrosis formation. Our data showed that intraperitoneal injection of kaempferol could significantly decrease the necroinflammatory scores and collagen deposition in the liver tissue. In addition, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), laminin (LN) and hyaluronic acid (HA) levels were significantly down‐regulated in kaempferol treatment group compared with those in the control group. Our study also demonstrated that kaempferol markedly inhibited the synthesis of collagen and activation of hepatic stellate cells (HSCs) both in vivo and in vitro. Furthermore, the results of Western blotting revealed that kaempferol could down‐regulate Smad2/3 phosphorylation dose‐dependently. These bioactivities of kaempferol may result from its targeted binding to the ATP‐binding pocket of activin receptor–like kinase 5 (ALK5), as suggested by the molecular docking study and LanthaScreen Eu kinase binding assay. Above all, our data indicate that kaempferol may prove to be a novel agent for the treatment of liver fibrosis or other fibroproliferative diseases.

Potential antioxidant effects of Narcissus tazetta phenolic compounds against cadmium chloride–induced hepatotoxicity in Swiss albino mice

“…According to Mirani et al (2012), co-administration of rutin restored GSH and Vit C contents to normal values in liver of cadmium intoxicated mice. Related studies on other xenobiotic intensi ed liver injury, con rmed that kampferol (Xu et al 2019;Zang et al 2017) and chlorogenic acid (Shi et al 2016) signi cantly restored liver glutathione consumption.…”

Network Pharmacological Analysis and Experimental Validation of the Mechanisms of Action of Si-Ni-San Against Liver Fibrosis

“…Among these, kaempferol, oleanolic acid, isorhamnetin, quercetin, mairin, sitosterol and naringenin have been identified in the different herbal components of SNS and their biological activities extensively characterized. For example, kaempferol in CH, BS, and GC has widespread pharmacological activities, such as anti-fibrosis and anti-inflammation effects ( Xu et al, 2019 ; Bian et al, 2020 ). Naringenin, widely detected in ZS and GC, exerts diverse pharmacological effects and is involved in modulation of several signaling pathways, such as pathologic angiogenesis-related VEGF/KDR and inflammatory reaction-related NLRP3/NF-κB ( Li Q. et al, 2016 ; Fan et al, 2017 ).…”

“…Apoptosis is also a selfcontrolled program that serves to maintain homeostasis. Numerous genes are involved in this process, including the Bcl-2 family, caspase family and TNF (Wei et al, 2018;Wang R. et al, 2019). The induction of fibrotic response may be attributable to persistent HPC apoptosis (Takehara et al, 2004).…”

Network pharmacology reveals the multiple mechanisms of Xiaochaihu decoction in the treatment of non-alcoholic fatty liver disease

“…Kaempferol has a variety of pharmacological effects such as anti-cancer, anti-oxidation, anti-viral, anti-inflammatory, antibacterial activities. It can also enhance the immunity and attenuate liver fibrosis via inhibiting activin receptor-like kinase 5 [ 26 , 27 ]. Both beta-sitosterol and stigmasterol are components of phytosterols, have a wide range of pharmacological effects such as anti-inflammatory, antibacterial, analgesic, and anti-cancer.…”