Design, Synthesis, and Mechanistic Evaluation of <scp>l</scp> -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 <b>9a</b> was a potent antifibrotic agent. In vitro experiments revealed that compound <b>9a</b> 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 <b>9a</b> significantly attenuated hepatic injury, fibrosis, and inflammation, demonstrating robust hepatoprotective effects. Mechanistic investigations showed that compound <b>9a</b> directly interacts with Cathepsin D and promotes its degradation, thereby suppressing the expression of fibrogenic and inflammatory genes. Pharmacokinetic studies demonstrated that compound <b>9a</b> undergoes metabolic conversion to yield pharmacologically active metabolites <b>10</b> and <b>11c</b>. Collectively, these results highlight compound <b>9a</b> as a promising l-theanine-based candidate for the treatment of hepatic fibrosis.