Artesunate Targets MBL2 to Modulate the TLR4/NRF2/HO-1 Axis and Ameliorate Podophyllotoxin-Induced Liver Injury
In a rat model of podophyllotoxin-induced liver injury, artesunate reduced serum liver injury markers dose-dependently and bound MBL2 with KD ≈ 3.84 µM, but no human data exist.
| Population | Male Sprague-Dawley rats with podophyllotoxin (PPT)-induced liver injury |
|---|---|
| Intervention | Artesunate (ART) at multiple doses, administered orally or intraperitoneally |
| Comparator | PPT-only control group; sham group without injury |
| Outcome | Serum liver injury markers (ALT/AST); ART-MBL2 binding affinity; TLR4/NF-κB pathway protein expression; NRF2/HO-1/NQO1 expression (antioxidant defense); Hepatic oxidative stress; Hepatic histopathology; Gut microbiota (Lactobacillus) and correlation with antioxidant metabolomics |
Summary of findings
| Outcome | Effect | 95% CI | Certainty | Clinical relevance | Notes |
|---|---|---|---|---|---|
| Serum liver injury markers (ALT/AST) | dose-dependent reduction, P < 0.05; in the absolute values or 95% CI reported | — | Very low | — | 1 studies |
| ART-MBL2 binding affinity | KD ≈ 3.84 µM (SPR/MST); in the 95% CI reported | — | Very low | — | 1 studies |
| TLR4/NF-κB pathway protein expression | suppression reported, P < 0.05; in the quantitative effect size or 95% CI reported | — | Very low | — | 1 studies |
| NRF2/HO-1/NQO1 expression (antioxidant defense) | upregulation reported, P < 0.05; in the quantitative effect size or 95% CI reported | — | Very low | — | 1 studies |
| Hepatic oxidative stress | attenuation reported, P < 0.05; in the quantitative effect size or 95% CI reported | — | Very low | — | 1 studies |
| Hepatic histopathology | improved outcomes reported; in the quantitative effect size or 95% CI reported | — | Very low | — | 1 studies |
| Gut microbiota (Lactobacillus) and correlation with antioxidant metabolomics | positive correlation, P < 0.05; in the effect size, 95% CI, or causal evidence reported | — | Very low | — | 1 studies |
Context
Drug-induced liver injury (DILI) is a leading cause of drug withdrawal and has few specific therapies. Artesunate, an artemisinin derivative approved for malaria, has anti-inflammatory and antioxidant properties that may be repositioned for DILI. This study attempts to clarify its hepatoprotective mechanism using a multi-omics approach in rodents.
What the study showed
ART reduced serum ALT and AST dose-dependently (P < 0.05); absolute pre/post values and 95% CIs were not reported in the available text. ART bound MBL2 with KD ≈ 3.84 µM (SPR and MST validated). This binding suppressed TLR4/NF-κB signaling and relieved NRF2 repression, upregulating HO-1 and NQO1. Gut microbiota analysis showed Lactobacillus enrichment correlating positively with hepatic antioxidant metabolites (P < 0.05), without demonstrated causality.
How it was done
Preclinical experimental study in rats using a PPT-induced DILI model. Methods included chemical proteomics (pull-down/LC-MS/MS), biophysical validation (SPR, MST), molecular dynamics simulations, hepatic transcriptomics (RNA-seq), Western blot, targeted metabolomics, and 16S rRNA gut microbiota sequencing. Sample size per group and exact protocol duration were not reported in available text.
Effect magnitude
KD ≈ 3.84 µM for ART-MBL2 binding (SPR/MST); dose-dependent ALT/AST reduction with P < 0.05. Effect sizes (RR, OR, SMD) and 95% CIs were not reported in available text.
Risk of bias
Exclusively preclinical rodent study — no human data. Sample size per group not specified in the summary. No standardized risk of bias tool (RoB 2, ROBINS-I) was applied. Microbiota-metabolomics correlation does not imply causality. The PPT model does not replicate the heterogeneous spectrum of human clinical DILI.
What this study does NOT prove
This study does not prove artesunate is effective or safe for DILI in humans. It does not establish causality between microbiota remodeling and hepatoprotection, nor validate MBL2 as a clinically relevant therapeutic target.
In clinical practice
No basis exists to alter clinical management of DILI with artesunate based on this study alone. Clinicians should await human trials before any therapeutic consideration. The proposed MBL2/TLR4/NRF2 mechanism may inform hypotheses for future trials.
Limitations
Exclusively preclinical rodent study — no human data. Sample size per group not specified in the summary. No standardized risk of bias tool (RoB 2, ROBINS-I) was applied. Microbiota-metabolomics correlation does not imply causality. The PPT model does not replicate the heterogeneous spectrum of human clinical DILI.
What is still missing
Studies in human DILI models — including primary human hepatocytes, liver organoids, and phase I/II clinical trials — are required to evaluate safety, pharmacokinetics, and translational efficacy of artesunate in DILI.
Technical appendix
Version history
- 1.0 · 2026-11-01 — Auto-generated under Evidence Standard v1.0