Small non-coding RNAs in human fungal diseases: Host immune modulation and clinical relevance

Abstract Fungal diseases represent a growing global health crisis, exacerbated by limited therapeutic options and the rise of antifungal resistance. A deeper understanding of the molecular mechanisms governing host-pathogen interactions is crucial for developing novel strategies. Small non-coding RNAs (sncRNAs), a diverse class of regulatory molecules under 200 nucleotides, have emerged as critical players in modulating the host immune response to infection. This article bridges traditional review with emerging perspectives to comprehensively explore sncRNAs in fungal pathogenesis. ​We highlight how microRNAs (miRNAs), such as miR-155 and miR-146a, act as first responders to balance pro and anti-inflammatory signaling and serve as promising clinical biomarkers. Futhermore, we examine the biotechnological and therapeutic potential of piwi-interacting RNAs (piRNAs) and small interfering RNAs (siRNAs) as novel antifungal agents, alongside the complex dynamics of cross-kingdom RNAi (ckRNAi) as mechanism of virulence. Finally, we propose novel functional roles for understudied classes, suggesting that small nucleolar RNA (snoRNAs) regulate immune cell differentiation and small nuclear RNA (snRNAs) drive alternative splicing during fungal adaptation. By defining these specific mechanisms and identifying critical knowledge gaps, this review outlines actionable future directions for exploiting sncRNAs in the diagnosis and the targeted treatment of fungal infections. • Host miRNAs can modulate inflammatory pathways of the antifungal immune response. • Differentially expressed miRNAs can predict the outcomes of invasive aspergillosis. • Alternative splicing from fungal infection is a key mechanism for host adaptation. • Cross-kingdom RNAi may play a role in host-pathogen communication and adaptation. • SnoRNAs and snRNAs are emerging regulators of fungal virulence and resistance.