Natural drugs modulate MAPK: targets and strategies for liver fibrosis treatment

Liver fibrosis (LF) as a critical pathological stage in the progression of various chronic liver diseases toward cirrhosis and hepatocellular carcinoma, has become a severe global public health challenge posing a serious threat to patient health. Consequently, there is an urgent need to develop novel, highly effective therapeutic drugs and intervention strategies. The application of traditional Chinese medicine (TCM) formulas and natural drugs leveraging their unique advantages of multi-target and multi-pathway mechanisms, is increasingly attracting attention in the field of LF treatment. In recent years, a growing number of studies have focused on the therapeutic value of natural drugs and TCM formulas in treating LF. This review systematically explores the clinical application potential and core therapeutic mechanisms of natural drugs and TCM formulas in LF treatment, covering natural compounds such as flavonoids, terpenoids, and glycosides, as well as TCM formulas like Tianhuang Formula and Yiqu Ronggan Formula. We demonstrate that multiple key bioactive components, such as quercetin, curcumin, and astragaloside IV, exhibit beneficial effects in LF intervention. These effects primarily occur through modulating critical pathogenic drivers including hepatic stellate cell (HSC) activation, inflammatory responses, and oxidative stress. The elucidated therapeutic mechanisms primarily include inhibiting HSC activation and proliferation, regulating inflammatory pathways, alleviating oxidative stress damage, reducing excessive extracellular matrix (ECM) deposition, and restoring liver tissue microenvironment homeostasis. This preclinical evidence supports the potential efficacy of natural drugs and TCM formulas as complementary and alternative treatment options for LF. However, most existing evidence is based on in vitro cell experiments and animal model studies, significantly limiting its clinical translational value. Further rigorous, multicenter, large-scale clinical trials are needed to validate the efficacy and long-term safety of natural drugs and TCM formulas in patients with LF, thereby providing robust evidence-based medical support for their clinical application.