Fisetin Attenuates Uterine Leiomyoma in Rats: Potential Crosstalk Between HMGB1, SphK1/S1P, and TGF-β Signaling

Uterine leiomyomas (UL) represent one of the most prevalent gynecological benign tumors with a considerable global medical and economic burden. Effective therapeutic strategies that preserve the uterus and maintain fertility are still lacking. Fisetin (FIS), a naturally occurring dietary flavonoid, exhibits antitumor, anti-inflammatory, and antifibrotic properties, yet its therapeutic potential in UL remains incompletely defined. This study investigated the therapeutic effects of fisetin on UL and the possible underlying mechanisms. UL was experimentally induced in adult female rats by monosodium glutamate (MSG), and animals were assigned to Control, FIS, UL, and UL + FIS groups. Blood and tissue samples were subjected to hormonal, biochemical, histopathological, and immunohistochemical assessments. Serum estradiol, progesterone, and S1P levels were measured using ELISA, while qPCR quantified the expression of key signaling molecules, including SphK1, TGF-β1, HMGB1, TNF-α, and IL-1β. Immunohistochemistry assessed TGF-β1 and α-SMA expressions, and histopathology (H&E and Masson's Trichrome stains) evaluated tissue architecture and fibrosis. The results showed that fisetin administration significantly reduced the elevated sex hormones, inhibited S1P signaling, and suppressed proinflammatory mediators (HMGB1, TNF-α, IL-1β) and profibrotic mediators (TGF-β1, α-SMA). Histopathological evaluation confirmed decreased fibrotic remodeling and improved tissue architecture. Overall, these results suggest that fisetin's effect may involve coordinated modulation of the S1P/SphK1, TGF-β, and HMGB1 axes, highlighting its potential as a novel uterus-preserving therapeutic agent for UL.