Healing helminths: A systematic review of the anti-inflammatory and disease-modifying potential of helminth-derived proteins.

Helminths secrete diverse immunoregulatory molecules that modulate host inflammatory responses, facilitating long-term persistence within the host. This capacity has prompted interest in helminth-derived molecules as potential therapeutics for diseases characterized by excessive or dysregulated inflammation. This systematic review with cross-study quantitative analysis synthesized evidence on helminth-derived immunomodulatory peptides, polypeptides, and proteins (HDIPs), focusing on their disease-modifying and anti-inflammatory effects in in vivo animal models of inflammatory disease. Following PRISMA 2020 guidelines, PubMed, Web of Science, and Medline were systematically searched for studies published up to February 2026. Sixty-five studies were included, encompassing >65 HDIPs derived from 20 helminth species. Most studies investigated mouse models of colitis, asthma, arthritis, and sepsis, with Fasciola hepatica and Acanthocheilonema viteae the most extensively studied helminth species. Across models, HDIPs consistently reduced disease severity, accompanied by decreased pro-inflammatory cytokine levels and increased anti-inflammatory cytokine levels. These findings demonstrate broad disease-modifying and anti-inflammatory activity across diverse HDIPs and experimental disease models. Collectively, the evidence supports HDIPs as promising candidates for the development of novel immunoregulatory therapies for inflammatory diseases.