Capsaicin diet drives gut inflammation and exosomal miR-17-3p elevation in idiopathic short stature.

Idiopathic short stature (ISS) remains a major pediatric challenge with unclear causes and inconsistent responses to growth hormone therapy. Here we show that plasma exosomes from children with ISS contain elevated hsa-miR-17-3p that disrupts growth signaling and impairs cartilage cell proliferation. Elevated miR-17-3p suppresses ZNF148/SOS1 signaling, linking molecular dysfunction to dietary exposure in ISS. To investigate environmental triggers, we developed a capsaicin-rich diet rat model that recapitulates ISS, showing normal Gh/Igf-1 levels but elevated plasma miR-17-3p. The diet induced mild gut inflammation, increasing miR-17-3p in intestinal and plasma exosomes. Fecal samples from ISS children exhibited similar elevations in miR-17-3p and inflammatory markers, linking spicy diets to ISS pathogenesis. Finally, engineered exosomes designed to silence miR-17-3p, combined with localized growth hormone therapy, restored growth plate function. These findings uncover a diet-driven exosome axis underlying ISS and suggest new therapeutic strategies for children in high-capsaicin regions.