Unveiling the Silent Regulators: Noncoding RNAs in Parasitic Disease Diagnosis and Therapy.

Parasitic diseases remain a major global health burden, particularly in tropical and low-resource regions, where limitations in early diagnosis and effective therapeutics contribute to high morbidity and mortality. Emerging evidence highlights noncoding RNAs (ncRNAs) as critical regulators of host-parasite interactions, offering novel opportunities for diagnosis, prognosis, and targeted therapy. However, most of these findings are derived from in vitro experiments and preclinical models with limited validation in clinical settings. This review comprehensively examines the roles of microRNAs (miRNAs), small interfering RNAs (siRNAs), and long noncoding RNAs (lncRNAs) in the diagnosis and treatment of major parasitic diseases, including malaria, leishmaniasis, trypanosomiasis, Chagas disease, helminthic infections, cryptosporidiosis, and scabies. Distinct miRNA expression profiles are associated with disease presence, severity, and clinical outcomes, positioning them as promising noninvasive biomarkers detectable in body fluids. Specific miRNAs such as miR-223, miR-155, miR-145, and miR-3158 modulate immune responses, inflammation, and parasite survival across multiple infections. Beyond diagnostics, miRNAs actively participate in disease pathogenesis and host defense, enabling therapeutic modulation of immune pathways. siRNA-based approaches further demonstrate therapeutic potential through RNA interference-mediated silencing of essential parasite genes, successfully impairing parasite growth, viability, and development in diseases such as cystic echinococcosis, cryptosporidiosis, and scabies. Additionally, lncRNAs have emerged as key regulators of innate and adaptive immunity, influencing cytokine signaling, macrophage differentiation, and inflammatory pathways while serving as novel biomarkers for parasitic cardiomyopathies and protozoan infections. Despite promising advances, the clinical translation of ncRNA-based diagnostics and therapeutics faces significant challenges, including delivery efficiency, stability, specificity, off-target effects, and ethical considerations. Continued research, improved delivery platforms, and well-designed clinical trials are essential to harness the full potential of ncRNAs. Therefore, while ncRNA-based strategies represent a promising direction for future research, their application in parasitic disease diagnosis and therapy remains largely at an experimental level. Continued investigation of ncRNA-based methods is required to address current limitations and enable safe and effective clinical translation.