INTRODUCTION:
Tobacco use remains a major global health threat, causing over seven million deaths annually and driving non-communicable diseases (NCDs) such as cancer, chronic respiratory disorders, and cardiovascular disease1. Among its lesser-known consequences is vocal fold scarring (VFS), a debilitating condition linked to cigarette smoke toxicity (CST) and e-cigarette exposure. VFS compromises communication and respiratory function, yet lacks targeted non-surgical therapies, offering only transient symptom relief. CST and e-liquid exposure degrade hyaluronan, a viscoelastic polysaccharide essential for vocal fold structure and phonation, through poorly understood inflammatory mechanisms2. To address this therapeutic gap, we investigated hyaluronan metabolism in immortalized human vocal fold fibroblasts (hVFF) exposed to cigarette smoke extract and e-liquid.

METHODS:
Immortalized human vocal fold fibroblasts (hVFF) were cultured and exposed to cigarette smoke extract (CSE) and e-liquid. Extracellular hyaluronan was isolated from untreated and treated cells and analyzed via spectroscopy and electrophoresis. To examine hyaluronan metabolism and signaling, we combined gene editing with qRT-PCR, immunoblotting, and flow cytometry to quantify inflammatory mediators and matrix remodeling enzymes. Functional assays assessed drug efficacy and cellular responses to candidate small molecule inhibitors.

RESULTS:
We identified oxidative stress–driven activation of the hyaluronidase–CD44 pathway as a key driver of hyaluronan breakdown and inflammation. Our discovery of a novel synergistic drug combination that preserves hyaluronan integrity, promotes tissue repair, and suppresses inflammatory signaling offers a promising non-surgical strategy to mitigate CST-induced VFS3.

CONCLUSIONS:
These findings contribute to building more sustainable and resilient health systems, reducing tobacco-related disease burden while protecting both individual well-being and planetary health.