{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T10:43:05Z","timestamp":1789468985792,"version":"build-2803163510"},"reference-count":84,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T00:00:00Z","timestamp":1789430400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Vocal fold fibrosis is the principal pathological basis of intractable voice disorders. Previous etiological models have attributed vocal fold scarring solely to mechanical trauma and chemical irritation, whereas the local mucosal microbiota of the vocal folds and its cross-kingdom regulation of host gene expression have long received little attention. Integrating interdisciplinary advances, this review proposes a cross-kingdom pathogenic hypothesis: phonotrauma induces laryngeal dysbiosis and disassembly of the vocal fold epithelial tight junctions, and opportunistic pathogens under stress release outer membrane vesicles (OMVs) enriched in bacterial small RNAs (bsRNAs). These nanoscale carriers traverse the damaged mucosal barrier and infiltrate the vocal fold lamina propria; the bsRNAs they carry are recognized through sequence complementarity by host Argonaute proteins and loaded into the RNA-induced silencing complex (RISC), post-transcriptionally silencing Smad7, a key negative regulator of the transforming growth factor-\u03b2 (TGF-\u03b2) signaling pathway, in vocal fold fibroblasts. Post-transcriptional silencing of Smad7 releases the TGF-\u03b2\/Smad3 pro-fibrotic signaling axis from negative-feedback inhibition, driving the transition of fibroblasts into myofibroblasts and inducing excessive deposition of dense collagen. In parallel, pathogen-associated molecular patterns such as lipopolysaccharide on the OMV surface activate the Toll-like receptor 4 (TLR4)\/NF-\u03baB pathway in resident macrophages of the lamina propria; the released pro-inflammatory cytokines and the cross-kingdom RNA interference within fibroblasts reinforce each other, propelling tissue repair toward a terminal fibrotic state. The resulting \u201cmechanical trauma\u2013dysbiosis\u2013cross-kingdom RNA interference\u2013immune activation\u201d network may explain fibrotic progression maintained by persistent laryngeal dysbiosis after the initiating mechanical injury has resolved, and points to new directions for anti-fibrotic strategies based on microbiota modulation and RNA targeting.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1923591","type":"journal-article","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T09:17:07Z","timestamp":1789463827000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Cross-kingdom RNA interference in the dysbiosis-mediated network of vocal fold fibrosis: a pathogenic hypothesis and molecular intervention targets"],"prefix":"10.3389","volume":"17","author":[{"given":"Quanwei","family":"Ren","sequence":"first","affiliation":[{"name":"Department of Otolaryngology, The First Affiliated Hospital of Chongqing University of Chinese Medicine, Chongqing Traditional Chinese Medicine Hospital","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yilin","family":"Xiang","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, The First Affiliated Hospital of Chongqing University of Chinese Medicine, Chongqing Traditional Chinese Medicine Hospital","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Di","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, The First Affiliated Hospital of Chongqing University of Chinese Medicine, Chongqing Traditional Chinese Medicine Hospital","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Bao","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, The First Affiliated Hospital of Chongqing University of Chinese Medicine, Chongqing Traditional Chinese Medicine Hospital","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoli","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, The First Affiliated Hospital of Chongqing University of Chinese Medicine, Chongqing Traditional Chinese Medicine Hospital","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, The First Affiliated Hospital of Chongqing University of Chinese Medicine, Chongqing Traditional Chinese Medicine Hospital","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanli","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, The First Affiliated Hospital of Chongqing University of Chinese Medicine, Chongqing Traditional Chinese Medicine Hospital","place":["Chongqing, 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