The efficacy of artesunate in animal models of sepsis: a systematic review and meta-analysis

Abstract

Background: Sepsis is a life-threatening condition caused by a dysregulated host response to infection, characterized by biphasic immune dysregulation and high mortality rates. Artesunate (AS), a semisynthetic artemisinin derivative, has demonstrated broad pharmacological properties, yet its overall efficacy and mechanisms in sepsis remain systematically unassessed at the preclinical level.

Objectives: In this study, we aimed to conduct the first systematic review and meta-analysis to evaluate the therapeutic efficacy and underlying mechanisms of AS in animal models of sepsis.

Methods: We systematically searched five electronic databases up to 3 September 2025, for controlled in vivo studies analyzing the effects of AS in septic animals. The study quality was assessed using the SYRCLE risk-of-bias tool, and evidence certainty was rated via the GRADE approach. Statistical analyses, including meta-analysis, publication bias, and sensitivity analyses, were performed using RevMan 5.4 and Stata 17.0.

Results: Fifteen studies involving mice and rats were included. Meta-analysis indicated that AS was associated with improved survival (10 studies, OR: 6.87, 95% CI: 3.81-12.41, p < 0.00001), reduced bacterial load, and promotion of body weight recovery. Organ protection was evidenced by attenuated lung injury (reduced histological scores, MPO activity, and wet-to-dry ratio) and improved liver function (decreased AST and ALT levels). Analysis of cytokine data from different time-points suggested a potential phase-dependent immunomodulatory effect: AS suppressed pro-inflammatory cytokines (TNF-α and IL-6) during the hyperinflammatory phase while restoring immune competence in the immunosuppressive phase, accompanied by elevated IL-1β. Furthermore, AS reduced apoptosis (decreased TUNEL-positive cells) and enhanced pro-survival signaling (increased p-mTOR/mTOR ratio); however, its effect on caspase-3 was not significant. Sensitivity analyses supported the robustness of the primary findings, and no significant publication bias was detected within the limits of the available studies.

Conclusion: AS is associated with survival benefits and multi-organ protection in septic animal models through multimodal mechanisms, potential phase-aware immunomodulation, antiapoptotic effects, and enhanced bacterial clearance. Despite methodological heterogeneity across studies, these preclinical findings support further investigation of AS as a potential therapeutic candidate for sepsis treatment.

Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/view/CRD420251146068.

Keywords: animal models; artesunate; meta-analysis; sepsis; systematic review.