Design, Synthesis, and Mechanistic Evaluation of l -Theanine Derivatives Targeting Cathepsin D for Anti-Hepatic Fibrosis

Hepatic fibrosis represents a major global public health challenge, yet effective therapeutic interventions remain limited. In this study, we synthesized 40 derivatives through systematic structural modification of l -theanine and identified compound 9a was a potent antifibrotic agent. In vitro experiments revealed that compound 9a dose-dependently inhibited TGFβ1-induced activation of hepatic stellate cells (LX-2 and mHSC). Moreover, in both rat bile duct ligation (BDL) and mouse methionine-choline-deficient high-fat diet (CDAHFD) induced liver fibrosis models, compound 9a significantly attenuated hepatic injury, fibrosis, and inflammation, demonstrating robust hepatoprotective effects. Mechanistic investigations showed that compound 9a directly interacts with Cathepsin D and promotes its degradation, thereby suppressing the expression of fibrogenic and inflammatory genes. Pharmacokinetic studies demonstrated that compound 9a undergoes metabolic conversion to yield pharmacologically active metabolites 10 and 11c . Collectively, these results highlight compound 9a as a promising l -theanine-based candidate for the treatment of hepatic fibrosis.