<em>In Vivo</em> Efficacy of LL-37 and Its Derivative Peptides Against Methicillin-Resistant <em>Staphylococcus aureus</em> in Animal Models: A Systematic Review and Meta-Analysis

<jats:p>Objectives: Methicillin-resistant Staphylococcus aureus (MRSA) is a major global pathogen with increasing resistance to conventional antibiotics. LL-37 and its derivative peptides have shown promising in vivo antibacterial activity. This study evaluated whether these peptides improve bacterial clearance, wound healing, and survival compared with controls in animal models of MRSA infection. Methods: The literature search was last updated on 21 April 2026. A systematic search of PubMed, Scopus, and Embase was conducted to identify preclinical studies assessing the antibacterial activity of LL-37 and its derivatives in MRSA animal infection models. Guided by PRISMA, 1,014 unique records were screened after removing 368 duplicates; 23 studies met the inclusion criteria, and 16 were included in the qualitative synthesis. Four studies (one comprising three independent experiments) provided sufficient data for meta-analysis. Extracted variables included sample size, bacterial counts (mean ± SD), and intervention/control details. Standardized mean differences (Hedges' g) were calculated using a random-effects model, and study quality was assessed using SYRCLE's risk-of-bias tool. Results: The meta-analysis of bacterial clearance pooled data from six independent experimental results (n = 44 animals). LL-37 and its derivatives achieved markedly greater bacterial eradication than controls, yielding a pooled standardized mean difference (SMD) of -7.86 (95% CI: -9.40 to -6.33; P &amp;lt; 0.001). All studies favoured LL-37, with no confidence intervals crossing zero. Heterogeneity was negligible (I² = 0%, τ² &amp;lt; 0.0001, P = 0.645), and the prediction interval (-9.74 to -5.99) indicated consistently large effects across similar experimental contexts. For wound healing (binary outcome), pooled analysis showed that LL-37 significantly increased complete wound closure rates compared with controls, with a pooled risk ratio (RR) of 1.25 (95% CI: 1.16-1.36). The pooled proportion of healed wounds was 89.3% in the LL-37 groups versus 70.0% in controls, indicating a clinically relevant improvement. Conclusions: LL-37 and its derivative peptides demonstrate robust antibacterial activity and significantly enhance wound healing in MRSA-infected animal models. The large and consistent effects observed across studies support their advancement toward translational research and early-phase clinical trials for potential human therapeutic use.</jats:p>