Carrageenan oligosaccharides alleviate radiation-induced ovarian injury through the gut microbiota-associated hydroxycitric acid and PPARγ/Nrf2 signaling axis.

Abstract

Radiation-induced ovarian injury is a severe complication of pelvic radiotherapy, yet effective interventions remain lacking. The gut-ovary axis is emerging as a promising radioprotection target, but the role of the gut microbiota in ovarian protection remains unexplored. The current study evaluated the protective effects of carrageenan oligosaccharides (COSs) against radiation-induced ovarian injury via the gut-ovary axis. We found that COSs markedly ameliorated ovarian dysfunction and offspring developmental toxicity in an irradiated zebrafish model. We further validated these effects in a mouse model of radiation-induced ovarian injury. COSs alleviated radiation-induced ovarian injury, restoring ovarian architecture and follicular reserve in mice. COSs also reshaped the gut bacterial and fungal communities, enriching beneficial bacteria including Akkermansia, Dubosiella, and Bifidobacterium animalis, as well as fungi Irpex and Morchella, and elevated gut hydroxycitric acid (HCA) levels in mice. Notably, HCA is positively correlated with ovarian PPARγ, Nrf2, and Gpx and negatively with IL-1β. Consistently, HCA supplementation restored ovarian histology and primordial follicle numbers, upregulated PPARγ and Nrf2, restored Amh and Gpx, and suppressed IL-1β and IL-6 in mice, mirroring the ovarian protective effects of COSs. Collectively, these findings indicate that COSs alleviate radiation-induced ovarian injury by elevating gut microbiota-associated HCA, which activates PPARγ/Nrf2 signaling, thereby offering a mechanistic foundation for precision nutritional strategies in pelvic radiotherapy.