Deciphering the Multi-Target Mechanisms of Sheshang Jiedu Decoction Against Snake Envenomation-Induced Acute Hepatic...

Objective: This study aimed to experimentally validate the hepatoprotective efficacy of Sheshang Jiedu Decoction (SSJDD) against Deinagkistrodon acutus (D. acutus) venom-induced acute liver injury (ALI) and systematically elucidate its multicomponent, multitarget mechanisms using an integrated multi-omics strategy. Methods: SSJDD constituents and serum-absorbed metabolites were profiled using UPLC-Q-Exactive HFX MS, and potential targets were predicted via network pharmacology. An in vivo model was established by intraperitoneally injecting Kunming mice with D. acutus venom, followed by a 7-day oral SSJDD intervention. The therapeutic efficacy was assessed by histopathological examination, serological analysis, and detection of oxidative stress markers in liver tissues. Label-free quantitative proteomics was performed on murine livers to map dynamic protein alterations and signaling cascades. Results: Integrated metabolomic and network analyses identified 15 primary active serum metabolites converging on core regulatory targets, including TP53, AKT1, and CASP3. In vivo, SSJDD dose-dependently ameliorated venom-induced lobular necrosis, suppressed elevated transaminases, and restored redox homeostasis without intrinsic hepatotoxicity. Quantitative proteomics revealed that venom triggered profound acute oxidative stress and coagulopathies, progressing to chronic metabolic disruption. SSJDD intervention substantially attenuated these proteomic alterations-reducing differentially expressed proteins by 84%-steering the hepatic microenvironment toward baseline homeostasis. Enrichment analyses demonstrated that these effects were primarily driven by modulating the coagulation-inflammation axis and the PI3K-Akt signaling pathway. Conclusions: SSJDD provides robust protection against D. acutus venom-induced ALI. Its active metabolites synergistically orchestrate hepatic repair and restore microenvironmental stability, primarily by targeting the PI3K-Akt pathway and regulating the coagulation-inflammation axis.