Non-Coding RNAs as Emerging Biomarkers in Leishmaniasis and Chagas Disease

Leishmaniasis and Chagas disease, caused by <i>Leishmania</i> spp. and <i>Trypanosoma cruzi</i>, are neglected tropical diseases with significant global health burden, particularly in resource-limited regions. Despite their impact, diagnosis and treatment remain challenging due to limited diagnostic tools and the toxicity of available therapies. Our objective is to propose the incorporation of markers for the diagnosis of leishmaniasis and Chagas disease using ncRNA. This narrative review evaluates studies published between 2010 and 2024 (PubMed, Scopus, Google Scholar) using the SANRA scale to assess the potential of non-coding RNAs (ncRNAs) as biomarkers for these infections. Both parasites release small RNAs via extracellular vesicles that modulate host-pathogen interactions and gene expression. Although RNA interference machinery is absent in <i>T. cruzi</i> and most <i>Leishmania</i> species, it persists in early-diverging lineages. In leishmaniasis, distinct miRNA expression profiles-including miR-155-5p, miR-5011-5p, miR-6785-5p, and miR-361-3p-demonstrate high diagnostic accuracy for detecting infection (AUC up to 1.0). Serum long ncRNAs such as MALAT1 and NUTM2A-AS1 show potential diagnostic value, though clinical validation remains pending. For Chagas disease, the available evidence on ncRNAs primarily addresses the diagnosis of clinical manifestations rather than initial infection. Host miRNAs, including miR-21, miR-145, miR-146a/b, and miR-19a-3p, correlate with cardiac involvement, immune dysregulation, and inflammation during chronic <i>T. cruzi</i> infection. Circulating miRNAs exhibit modest sensitivity (57-67%) and specificity (57-80%) for diagnosing chronic Chagas cardiomyopathy, indicating their utility in assessing disease progression and organ damage rather than detecting early infection. This review distinguishes between ncRNAs that diagnose infection and those that evaluate disease severity or organ involvement. Altered ncRNA expression profiles represent promising biomarkers for species differentiation, treatment monitoring, and assessing cardiac complications in Chagas disease, with broader diagnostic applications emerging for leishmaniasis.