Disruption of cellular redox homeostasis by bigelovin triggers oxidative stress-mediated apoptosis in Fibrosarcoma.

The two main cellular antioxidant pathways, glutathione (GSH) and thioredoxin (Trx) systems, can compensate for each other when one is inhibited. This reciprocal compensation limits the effectiveness of therapies targeting either pathway alone in tumor treatment. Thus, the concurrently suppression of the GSH and Trx systems synergistically enhances anti-tumor effect. Dried floral material of Inula britannica is commercially utilized in the pharmaceutical and nutraceutical industries for producing medicinal formulations and functional teas. Derived from Inula britannica flowers, bigelovin is identified as a sesquiterpene lactone. Herein, we report that bigelovin exerts potent in vitro and in vivo anti-fibrosarcoma activity via concurrently inhibiting GSH and thioredoxin reductase (TrxR). Bigelovin was demonstrated to covalently react with GSH, with the α-alkene-γ-lactone site being prioritized over the α,β-unsaturated ketone unit as the reaction site. Furthermore, bigelovin exerts its inhibitory effect on TrxR mainly by engaging the Sec498 site of the enzyme, resulting in elevated oxidized Trx alongside diminished reduced Trx. This dual mechanism disrupts redox homeostasis, causing alterations in the GSH/GSSG ratio, total thiols, reactive oxygen species (ROS) levels, and damage to mitochondrial membrane potential (MMP) and DNA integrity. Ultimately, bigelovin leads to apoptosis driven by oxidative stress in fibrosarcoma. This work reveals an innovative molecular pathway underlying bigelovin's anti-fibrosarcoma action. The unique dual-targeting capability of bigelovin underpins a strong mechanistic foundation for its continued advancement as a fibrosarcoma therapeutic.