<![CDATA[Background: Sepsis-associated liver injury drives mortality in polymicrobial sepsis yet lacks targeted adjunctive therapy. Andrographis paniculata (Burm. f.) Nees, known in Indonesia as sambiloto, yields andrographolide, a diterpene lactone that suppresses nuclear factor kappa B (NF-κB) and activates nuclear factor erythroid 2-related factor 2 (Nrf2) and haem oxygenase-1 (HO-1). Objective: To evaluate standardised A. paniculata ethanolic extract (APE, 30% w/w andrographolide) in a murine caecal ligation and puncture (CLP) sepsis model. Methods: Male BALB/c mice (n = 60) were randomised to Sham, CLP + vehicle, CLP + APE 100 mg/kg, CLP + APE 200 mg/kg, or CLP + imipenem/cilastatin 30 mg/kg (n = 12 per arm), treated at 1 h and 12 h post-CLP. Outcomes at 24 h were serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin; plasma tumour necrosis factor-α (TNF-α), interleukin (IL)-6 and IL-10; hepatic NF-κB, Nrf2, HO-1 and NOD-like receptor protein 3 (NLRP3); peritoneal bacterial load; and Suzuki histology, with survival followed to 72 h. Results: APE 200 mg/kg reduced ALT by 58.4%, AST by 54.9%, TNF-α by 62.6% and IL-6 by 59.3%, and raised IL-10 2.3-fold (all p < 0.001). Hepatic p-NF-κB p65 fell 62%; nuclear Nrf2 and HO-1 rose 2.5- and 3.1-fold; peritoneal bacterial load fell 1.8 log10; the Suzuki score fell from 8.4 to 3.2; and survival at 72 h rose from 25% to 67% (log-rank p < 0.001; hazard ratio 0.42). Conclusion: Standardised APE attenuated hepatic injury and systemic hyperinflammation through dual NF-κB/Nrf2 modulation while preserving bacterial clearance, supporting its development as a complementary adjunct to antimicrobial therapy.]]>
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